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WO2024157205A1 - Dérivés de 1-amino-4-phénylphtalazine utiles pour le traitement de maladies neurodégénératives - Google Patents

Dérivés de 1-amino-4-phénylphtalazine utiles pour le traitement de maladies neurodégénératives Download PDF

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Publication number
WO2024157205A1
WO2024157205A1 PCT/IB2024/050721 IB2024050721W WO2024157205A1 WO 2024157205 A1 WO2024157205 A1 WO 2024157205A1 IB 2024050721 W IB2024050721 W IB 2024050721W WO 2024157205 A1 WO2024157205 A1 WO 2024157205A1
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pyridazin
amino
phenol
cyclopropane
tetrahydro
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PCT/IB2024/050721
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English (en)
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Mark E. Adams
Jason W. Brown
Edcon Chang
Kristin SCHLEICHER
Mingnam Tang
Feng Zhou
Huikai SUN
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Takeda Pharmaceutical Company Limited
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Publication of WO2024157205A1 publication Critical patent/WO2024157205A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • 1-AMINO-4-PHENYLPHTHALAZINE DERIVATIVES FIELD OF THE INVENTION This invention relates to 1-amino-4-phenylphthalazine derivatives which are inhibitors of the NLRP3 inflammasome, to pharmaceutical compositions which contain them, and to their use to treat diseases, disorders, and conditions associated with NLRP3, including neurodegenerative diseases, such as Parkinson's disease.
  • neurodegenerative diseases such as Parkinson's disease.
  • More than 1% of the world's population suffers from neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and prion disease, all of which lack effective therapies.
  • Microglia which are myeloid cells of the CNS, play a major role during innate immune responses in the CNS. They express pattern recognition receptors (PRRs) which enable the host to recognize pathogen-associated molecular patterns (PAMPS) and host- or environment-derived danger-associated molecular patterns (DAMPS).
  • PRRs pattern recognition receptors
  • PAMPS pathogen-associated molecular patterns
  • DAMPS host- or environment-derived danger-associated molecular patterns
  • PRRs include Toll-like receptors, C-type lectin receptors, RIG-1 like receptors, and nucleotide-binding oligomerization domain-like receptors (NLRs). See P. Broz and V. M. Dixit, “Inflammasomes: mechanism of assembly, regulation and signaling,” Nat Rev Immunol 16(7):407-20 (2016). Engagement of PRRs activates a variety of inflammatory signaling pathways to eliminate infection and repair damaged tissue. The ongoing inflammation found in a variety of neurodegenerative diseases can be maintained by the key innate immune sensor for danger signals, the inflammasomes. There are several different inflammasomes, all defined by the PRRs they contain.
  • the NLRs – NLRP1, NLRP3, NLRC4 –and two other PRRs – Pyrin and AIM2 – are known to form inflammasomes. See D. Zheng, T. Liwinski and E. Elinav, “Inflammasome activation and regulation: toward a better understanding of complex mechanisms,” Cell Discov 6:36 (2020). [0005]
  • the NLRP3 (nucleotide-binding domain (NOD)-, leucine-rich repeats-containing domain (LRR), and pyrin domain-containing 3) inflammasome has been the subject of intense interest in the past decade. See N. Kelley, D. Jeltema, Y.
  • the NLRP3 inflammasome consists of three main components: a pattern recognition receptor (PRR) protein, NLRP3; an apoptosis-associated speck-like protein (ASC) containing a caspase activation and recruitment domain (CARD), which functions as a central adaptor protein; and an inflammatory caspase, caspase-1.
  • PRR pattern recognition receptor
  • ASC apoptosis-associated speck-like protein
  • CARD caspase activation and recruitment domain
  • NLRP3 is comprised of three domains: an amino-terminal pyrin domain (PYD); a central NACHT domain, having ATPase activity that is vital for NLRP3 self-association and oligomerization; and a carboxy-terminal LLR domain.
  • PYD amino-terminal pyrin domain
  • NACHT domain having ATPase activity that is vital for NLRP3 self-association and oligomerization
  • carboxy-terminal LLR domain See Broz and Dixit (2016).
  • the activation of NLRP3 inflammasome involves a two-step process.
  • a first “priming” signal is generated by the detection of PAMPs or DAMPs via TLRs. This priming signal results in NF- ⁇ B-dependent transcriptional upregulation of NLRP3 and pro-IL-1, but also controls post-translational modifications of NLRP3. See J. Yang, Z. Liu and T. S.
  • CAPS cryopyrin-associated periodic syndromes
  • NLRP3 inhibitors include Bay 11-7082, CY-09, oridonin, tranilast, INF-39, glyburide and JC-124. See W. Jiang, M. Li, F. He, et al., “Inhibition of NLRP3 inflammasome attenuates spinal cord injury- induced lung injury in mice,” J Cell Physiol 234(5):6012-6022 (2019).
  • MCC-950 has been used in many studies as a pharmacological tool to demonstrate NLRP3 inflammasome as a viable drug target to development therapeutics for human diseases. See S. E. Corcoran, R. Halai and M. A. Cooper, “Pharmacological Inhibition of the Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome with MCC950,” Pharmacol Rev 73(3):968-1000 (2021). [0010] Inhibitors of the NLRP3 inflammasome pathways are expected to be useful for treating neurodegenerative diseases, including Parkinson's disease, and for treating CAPS disorders associated with heterozygous gain of function mutations in the NLRP3 gene.
  • This invention provides 1-amino-4-phenylphthalazine derivatives and pharmaceutically acceptable salts thereof.
  • This invention also provides pharmaceutical compositions that contain the 1-amino-4-phenylphthalazine derivatives and provides for their use to treat diseases, disorders and conditions associated with NLRP3, including Parkinson's disease and other neurodegenerative disorders.
  • One aspect of the invention provides a compound of Formula 1: or a pharmaceutically acceptable salt thereof in which: ⁇ is a single bond and ⁇ is a single bond; and (i) X 1 is CH2, CH(CH3), or X C ; X 2 is O and X 3 is CH2 or X C , or X 2 is CH 2 or X C and X 3 is O; and X 4 is a bond, CH2, CH2CH2, or X C ; wherein X C is selected from C3-6 cycloalkylidene and C3-5 oxacycloalkylidene, each substituted with 0 to 4 substituents independently selected from halo, and wherein one, and no more than one, of X 1 , X 2 , X 3 and X 4 is X C ; or (ii) X 1 is C(HR 1 ); X 2 is O; X 3 is C(HR 3 ); and X 4 is CH 2 ; wherein R 1 and R 3
  • Another aspect of the invention provides a compound which is selected from the group of compounds described in the examples and their pharmaceutically acceptable salts.
  • a further aspect of the invention provides a compound or pharmaceutically acceptable salt as defined in the preceding paragraphs for use as a medicament.
  • An additional aspect of the invention provides a pharmaceutical composition which includes a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs; and a pharmaceutically acceptable excipient.
  • Another aspect of the invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs, for treatment of a disease, disorder or condition associated with NLRP3, including a disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene such as cryopyrin-associated periodic syndrome (CAPS).
  • a disease, disorder or condition associated with NLRP3 including a disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene such as cryopyrin-associated periodic syndrome (CAPS).
  • CAPS cryopyrin-associated periodic syndrome
  • a further aspect of the invention provides a use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs, for the manufacture of a medicament for the treatment of a disease, disorder or condition associated with NLRP3, including a disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene such as cryopyrin-associated periodic syndrome (CAPS).
  • a disease, disorder or condition associated with NLRP3 including a disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene such as cryopyrin-associated periodic syndrome (CAPS).
  • CAPS cryopyrin-associated periodic syndrome
  • An additional aspect of the invention provides a method for treating a disease, disorder or condition associated with NLRP3, including a disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene such as cryopyrin-associated periodic syndrome (CAPS), the method comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs.
  • a disease, disorder or condition associated with NLRP3 including a disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene such as cryopyrin-associated periodic syndrome (CAPS)
  • CAPS cryopyrin-associated periodic syndrome
  • Another aspect of the invention provides a method for treating a cryopyrin- associated periodic syndrome (CAPS), including neonatal-onset multisystem inflammatory disease (NOMID/CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS), the method comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs.
  • CAPS cryopyrin- associated periodic syndrome
  • NOMID/CINCA neonatal-onset multisystem inflammatory disease
  • MWS Muckle-Wells syndrome
  • FCAS familial cold autoinflammatory syndrome
  • a further aspect of the invention provides a method for treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs, wherein the disease, disorder or condition is a neurodegenerative disease, disorder or condition.
  • An additional aspect of the invention provides a method for treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs, wherein the disease, disorder or condition is selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and prion disease.
  • Another aspect of the invention provides an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs; and at least one additional pharmacologically active agent.
  • Alkyl refers to straight chain and branched saturated hydrocarbon groups, generally having a specified number of carbon atoms (e.g., C1-4 alkyl refers to an alkyl group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms, C 1-6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, and so on).
  • alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-1-yl, 3- methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl, and the like.
  • Alkanediyl refers to divalent alkyl groups, where alkyl is defined above, and generally having a specified number of carbon atoms (e.g., C1-4 alkanediyl refers to an alkanediyl group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms, C1-6 alkanediyl refers to an alkanediyl group having 1 to 6 carbon atoms, and so on).
  • alkanediyl groups include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, butane- 1,1-diyl, isobutane-1,3-diyl, isobutane-1,1-diyl, isobutane-1,2-diyl, and the like.
  • alkenyl refers to straight chain and branched hydrocarbon groups having one or more carbon-carbon double bonds, and generally having a specified number of carbon atoms.
  • alkenyl groups include ethenyl, 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1- buten-1-yl, 1-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1- propen-1-yl, 2-methyl-2-propen-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, and the like.
  • Alkynyl refers to straight chain or branched hydrocarbon groups having one or more triple carbon-carbon bonds, and generally having a specified number of carbon atoms. Examples of alkynyl groups include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3- butyn-1-yl, 3-butyn-2-yl, 2-butyn-1-yl, and the like.
  • Alkoxy refers to straight chain and branched saturated hydrocarbon groups attached through an oxygen atom, generally having a specified number of carbon atoms (e.g., C 1-4 alkoxy refers to an alkoxy group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms, C 1-6 alkoxy refers to an alkoxy group having 1 to 6 carbon atoms, and so on).
  • alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t- butoxy, pent-1-yloxy, pent-2-yloxy, pent-3-yloxy, 3-methylbut-1-yloxy, 3-methylbut-2- yloxy, 2-methylbut-2-yloxy, 2,2,2-trimethyleth-1-yloxy, n-hexoxy, and the like.
  • Alkanediyloxy refers to divalent alkoxy groups, where alkoxy is defined above, and generally having a specified number of carbon atoms (e.g., C 1-3 alkanediyloxy refers to an alkanediyl group having 1 to 3 (i.e., 1, 2 or 3) carbon atoms, C 1-2 alkanediyl refers to an alkanediyl group having 1 or 2 carbon atoms, and so on).
  • alkanediyl groups include methane-1,1-diyloxy, ethane-1,2-diyloxy, ethane-1,1-diyloxy, propane-1,3-diyloxy, propane-1,2-diyloxy, propane-1,1-diyloxy, propane-2,2-diyloxy, and the like.
  • Alkylcarbonyl and “alkylsulfonyl” refer to an alkyl group, as defined above, which is attached, respectively, through a carbonyl (C(O)) group or a sulfonyl (SO2) group, and generally having a specified number of carbon atoms, including the carbon atom of the carbonyl group.
  • C 1-4 alkylcarbonyl refers to an alkylcarbonyl group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms, including the carbonyl moiety
  • C1-6 alkylsulfonyl refers to an alkylsulfonyl group having 1 to 6 carbon atoms, and so on.
  • alkylcarbonyl groups include carbonyl (formyl), methylcarbonyl (acetyl), ethylcarbonyl, i-propylcarbonyl, n-propylcarbonyl, and the like.
  • alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, i-propylsulfonyl, n-propylsulfonyl, and the like.
  • Halo “halogen” and halogeno” may be used interchangeably and refer to fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers, respectively, to alkyl, alkenyl, and alkynyl groups substituted with one or more halogen atoms, where alkyl, alkenyl, and alkynyl are defined above, and generally having a specified number of carbon atoms.
  • haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1- chloroethyl, 1,1-dichloroethyl, 1-fluoro-1-methylethyl, 1-chloro-1-methylethyl, and the like.
  • Cycloalkyl refers to saturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms that comprise the ring or rings (e.g., C 3-8 cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms as ring members).
  • Bicyclic hydrocarbon groups may include isolated rings (two rings sharing no carbon atoms), spiro rings (two rings sharing one carbon atom), fused rings (two rings sharing two carbon atoms and the bond between the two common carbon atoms), and bridged rings (two rings sharing two carbon atoms, but not a common bond).
  • the cycloalkyl group may be attached through any ring atom unless such attachment would violate valence requirements, and where indicated, may optionally include one or more non-hydrogen substituents unless such substitution would violate valence requirements.
  • Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • fused bicyclic cycloalkyl groups include bicyclo[2.1.0]pentanyl (i.e., bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, and bicyclo[2.1.0]pentan-5-yl), bicyclo[3.1.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.3.0]octanyl, bicyclo[4.2.0]octanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, and the like.
  • bicyclo[2.1.0]pentanyl i.e., bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, and bicyclo[2.1.0]pentan-5-yl
  • bicyclo[3.1.0]hexanyl bicyclo[3.2.0]hept
  • bridged cycloalkyl groups include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[4.1.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[4.2.1]nonanyl, bicyclo[3.3.2]decanyl, bicyclo[4.2.2]decanyl, bicyclo[4.3.1]decanyl, bicyclo[3.3.3]undecanyl, bicyclo[4.3.2]undecanyl, bicyclo[4.3.3]dodecanyl, and the like.
  • spiro cycloalkyl groups include spiro[3.3]heptanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, and the like.
  • isolated bicyclic cycloalkyl groups include those derived from bi(cyclobutane), cyclobutanecyclopentane, bi(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, bi(cyclohexane), etc.
  • Cycloalkanediyl refers to divalent cycloalkyl groups, where cycloalkyl is defined above, and generally having a specified number of carbon atoms (e.g., C3-5 cycloalkanediyl refers to a cycloalkanediyl group having 3 to 5 (i.e., 3, 4 or 5) carbon atoms, C3-6 cycloalkanediyl refers to a cycloalkanediyl group having 3 to 6 carbon atoms, and so on).
  • C3-5 cycloalkanediyl refers to a cycloalkanediyl group having 3 to 5 (i.e., 3, 4 or 5) carbon atoms
  • C3-6 cycloalkanediyl refers to a cycloalkanediyl group having 3 to 6 carbon atoms, and so on).
  • cycloalkanediyl groups include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and the like.
  • Cycloalkylidene refers to a divalent monocyclic cycloalkyl group, where cycloalkyl is defined above, which is attached through a single carbon atom of the group, and generally having a specified number of carbon atoms that comprise the ring (e.g., C3-6 cycloalkylidene refers to a cycloalkylidene group having 3 to 6 carbon atoms as ring members). Examples include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.
  • Oxacycloalkylidene refers to a divalent cycloalkyl group, as defined above, in which one of carbon atom is replaced with an oxygen atom, and which is attached through a single carbon atom of the group, and generally having a specified number of carbon atoms that comprise the ring (e.g., C3-5 oxacycloalkylidene refers to a cycloalkylidene group having 3 to 5 carbon atoms and one oxygen atom as ring members).
  • Cycloalkenyl refers to partially unsaturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms that comprise the ring or rings. As with cycloalkyl groups, the bicyclic cycloalkenyl groups may include isolated, spiro, fused, or bridged rings.
  • cycloalkenyl group may be attached through any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements.
  • cycloalkenyl groups include the partially unsaturated analogs of the cycloalkyl groups described above, such as cyclobutenyl (i.e., cyclobuten-1-yl and cyclobuten-3-yl), cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, and the like.
  • Aryl refers to fully unsaturated monocyclic aromatic hydrocarbons and to polycyclic hydrocarbons having at least one aromatic ring, both monocyclic and polycyclic aryl groups generally having a specified number of carbon atoms that comprise their ring members (e.g., C6-14 aryl refers to an aryl group having 6 to 14 carbon atoms as ring members).
  • the group may be attached through any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements.
  • aryl groups include phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthalenyl, benzocycloheptanyl, biphenylenyl, fluorenyl, groups derived from cycloheptatriene cation, and the like.
  • “Arylene” refers to divalent aryl groups, where aryl is defined above. Examples of arylene groups include o-phenylene (i.e., benzene-1,2-diyl).
  • Heterocycle and “heterocyclyl” may be used interchangeably and refer to saturated or partially unsaturated monocyclic or bicyclic groups having ring atoms composed of carbon atoms and one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both the monocyclic and bicyclic groups generally have a specified number of carbon atoms in their ring or rings (e.g., C2-6 heterocyclyl refers to a heterocyclyl group having 2 to 6 carbon atoms and, e.g., 1 to 4 heteroatoms, as ring members). As with bicyclic cycloalkyl groups, bicyclic heterocyclyl groups may include isolated rings, spiro rings, fused rings, and bridged rings.
  • heterocyclyl group may be attached through any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound.
  • heterocyclyl groups include oxiranyl, thiiranyl, aziridinyl (e.g., aziridin-1-yl and aziridin-2-yl), oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4- dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl,
  • Heterocycle-diyl refers to heterocyclyl groups which are attached through two ring atoms of the group, where heterocyclyl is defined above. They generally have a specified number of carbon atoms in their ring or rings (e.g., C2-6 heterocycle-diyl refers to a heterocycle-diyl group having 2 to 6 carbon atoms and, e.g., 1 to 4 heteroatoms, as ring members).
  • heterocycle-diyl groups include the multivalent analogs of the heterocycle groups described above, such as morpholine-3,4-diyl, pyrrolidine-1,2-diyl, 1- pyrrolidinyl-2-ylidene, 1-pyridinyl-2-ylidene, 1-(4H)-pyrazolyl-5-ylidene, 1-(3H)-imidazolyl- 2-ylidene, 3-oxazolyl-2-ylidene, 1-piperidinyl-2-ylidene, 1-piperazinyl-6-ylidene, and the like.
  • Heteroaromatic and “heteroaryl” may be used interchangeably and refer to unsaturated monocyclic aromatic groups and to polycyclic groups having at least one aromatic ring, each of the groups having ring atoms composed of carbon atoms and one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both the monocyclic and polycyclic groups generally have a specified number of carbon atoms as ring members (e.g., C 1-9 heteroaryl refers to a heteroaryl group having 1 to 9 carbon atoms and, e.g., 1 to 4 heteroatoms, as ring members) and may include any bicyclic group in which any of the above-listed monocyclic heterocycles are fused to a benzene ring.
  • the heteroaryl group may be attached through any ring atom (or ring atoms for fused rings), and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound.
  • heteroaryl groups include monocyclic groups such as pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl), furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5- diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and
  • heteroaryl groups also include bicyclic groups such as benzofuranyl, isobenzofuranyl, benzothienyl, benzo[c]thienyl, 1H-indolyl, 3H-indolyl, isoindolyl, 1H- isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, 1H-indazolyl, 2H-indazolyl, benzotriazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2- c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5- c]pyridinyl, 1H-pyrazolo[4,3-b]pyridin
  • Heteroarylene refers to heteroaryl groups which are attached through two ring atoms of the group, where heteroaryl is defined above. They generally have a specified number of carbon atoms in their ring or rings (e.g., C3-5 heteroarylene refers to a heteroarylene group having 3 to 5 carbon atoms and, e.g., 1 to 4 heteroatoms, as ring members). Examples of heteroarylene groups include the multivalent analogs of the heteroaryl groups described above, such as pyridine-2,3-diyl, pyridine-3,4-diyl, pyrazole-4,5- diyl, pyrazole-3,4-diyl, and the like.
  • Leaving group refers to any group that leaves a molecule during a fragmentation process, including substitution reactions, elimination reactions, and addition-elimination reactions. Leaving groups may be nucleofugal, in which the group leaves with a pair of electrons that formerly served as the bond between the leaving group and the molecule, or may be electrofugal, in which the group leaves without the pair of electrons. The ability of a nucleofugal leaving group to leave depends on its base strength, with the strongest bases being the poorest leaving groups.
  • nucleofugal leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including alkylsulfonates (e.g., mesylate), fluoroalkylsulfonates (e.g., triflate, hexaflate, nonaflate, and tresylate), and arylsulfonates (e.g., tosylate, brosylate, closylate, and nosylate).
  • Others include carbonates, halide ions, carboxylate anions, phenolate ions, and alkoxides.
  • Opte enantiomer refers to a molecule that is a non-superimposable mirror image of a reference molecule, which may be obtained by inverting all the stereogenic centers of the reference molecule. For example, if the reference molecule has S absolute stereochemical configuration, then the opposite enantiomer has R absolute stereochemical configuration. Likewise, if the reference molecule has S,S absolute stereochemical configuration, then the opposite enantiomer has R,R stereochemical configuration, and so on.
  • Stepoisomer and “stereoisomers” of a compound with given stereochemical configuration refer to the opposite enantiomer of the compound and to any diastereoisomers, including geometrical isomers (Z/E) of the compound.
  • Z/E geometrical isomers
  • a compound has S,R,Z stereochemical configuration
  • its stereoisomers would include its opposite enantiomer having R,S,Z configuration
  • its diastereomers having S,S,Z configuration, R,R,Z configuration, S,R,E configuration, R,S,E configuration, S,S,E configuration, and R,R,E configuration.
  • stereoisomer refers to any one of the possible stereochemical configurations of the compound.
  • “Substantially pure stereoisomer” and variants thereof refer to a sample containing a compound having a specific stereochemical configuration and which comprises at least about 95% of the sample.
  • “Pure stereoisomer” and variants thereof refer to a sample containing a compound having a specific stereochemical configuration and which comprises at least about 99.5% of the sample.
  • Subject refers to a mammal, including a human.
  • “Pharmaceutically acceptable” substances refer to those substances which are suitable for administration to subjects.
  • Treating refers to reversing, alleviating, inhibiting the progress of, or preventing a disease, disorder or condition to which such term applies, or to reversing, alleviating, inhibiting the progress of, or preventing one or more symptoms of such disease, disorder or condition.
  • Treatment refers to the act of “treating,” as defined immediately above.
  • “Drug,” “drug substance,” “active pharmaceutical ingredient,” and the like refer to a compound (e.g., compounds of Formula 1, including subgeneric compounds and compounds specifically named in the specification) that may be used for treating a subject in need of treatment.
  • Effective amount of a drug refers to the quantity of the drug that may be used for treating a subject and may depend on the weight and age of the subject and the route of administration, among other things.
  • Excipient refers to any diluent or vehicle for a drug.
  • “Pharmaceutical composition” refers to the combination of one or more drug substances and one or more excipients.
  • “Drug product,” “pharmaceutical dosage form,” “dosage form,” “final dosage form” and the like refer to a pharmaceutical composition suitable for treating a subject in need of treatment and generally may be in the form of tablets, capsules, sachets containing powder or granules, liquid solutions or suspensions, patches, films, and the like.
  • “Condition associated with NLRP3” and similar phrases relate to a disease, disorder or condition in a subject for which inhibition of the NLRP3 inflammasome pathway may provide a therapeutic or prophylactic benefit.
  • this disclosure concerns compounds of Formula 1 and their pharmaceutically acceptable salts.
  • This disclosure also concerns materials and methods for preparing compounds of Formula 1, pharmaceutical compositions which contain them, and the use of compounds of Formula 1 and their pharmaceutically acceptable salts (optionally in combination with other pharmacologically active agents) for treating diseases, disorders or conditions of the CNS, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and other diseases, disorders or conditions associated with NLRP3.
  • neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and other diseases, disorders or conditions associated with NLRP3.
  • the compounds of Formula 1, and pharmaceutically acceptable salts thereof include those in which: (1) ⁇ is a single bond and ⁇ is a single bond; and (i) X 1 is CH 2 , CH(CH 3 ), or X C ; X 2 is O and X 3 is CH2 or X C , or X 2 is CH2 or X C and X 3 is O; and X 4 is a bond, CH 2 , CH 2 CH 2 , or X C ; wherein X C is selected from C3-6 cycloalkylidene and C3-5 oxacycloalkylidene, each substituted with 0 to 4 substituents independently selected from halo, and wherein one, and no more than one, of X 1 , X 2 , X 3 and X 4 is X C ; or (ii) X 1 is C(HR 1 ); X 2 is O; X 3 is C(HR 3 ); and X 4 is CH2; wherein R 1 and R
  • the compounds of Formula 1 include those in which: (61) ⁇ is a single bond and ⁇ is a single bond; and (i) X 1 is CH2, CH(CH3), or X C ; X 2 is O and X 3 is CH2 or X C , or X 2 is CH 2 or X C and X 3 is O; and X 4 is a bond, CH2, CH2CH2, or X C ; wherein X C is selected from C3-6 cycloalkylidene and C3-5 oxacycloalkylidene, each substituted with 0 to 4 substituents independently selected from halo, and wherein one, and no more than one, of X 1 , X 2 , X 3 and X 4 is X C ; or (ii) X 1 is C(HR 1 ); X 2 is O; X 3 is C(HR 3 ); and X 4 is CH 2 ; wherein R 1 and R 3 taken together represent a
  • the compounds of Formula 1 include those in which: (62) X 1 is CH2, CH(CH3), or X C ; X 2 is O and X 3 is CH2 or X C , or X 2 is CH 2 or X C and X 3 is O; and X 4 is a bond, CH2, CH2CH2, or X C ; wherein X C is selected from C 3-6 cycloalkylidene and C 3-5 oxacycloalkylidene, each substituted with 0 to 4 substituents independently selected from halo, and wherein one, and no more than one, of X 1 , X 2 , X 3 and X 4 is X C .
  • the compounds of Formula 1 include those in which: (63) X C is selected from C 3-4 cycloalkylidene and C 3-5 oxacycloalkylidene, each substituted with 0 to 4 substituents independently selected from halo; (64) X C is C 3-4 cycloalkylidene, which is substituted with 0 to 4 substituents independently selected from halo; (65) X C is cyclopropylidene, which is substituted with 0 to 4 substituents independently selected from halo; (66) X C is cyclobutylidene, which is substituted with 0 to 4 substituents independently selected from halo; (67) X C is C3-5 oxacycloalkylidene, which is substituted with 0 to 4 substituents independently selected from halo; (68) X C is oxacyclobutylidene, which is substituted with 0 to 4 substituent
  • the compounds of Formula 1 include those in which: (74) X 1 is CH2 or X C ; X 2 is O and X 3 is CH2 or X C , or X 2 is CH 2 or X C and X 3 is O; and X 4 is CH2 or X C ; (75) X 1 is CH 2 or X C ; X 2 is O and X 3 is CH 2 or X C , or X 2 is CH2 or X C and X 3 is O; and X 4 is a bond; (76) X 1 is CH 2 or X C ; X 2 is O and X 3 is CH 2 or X C ; and X 4 is a bond; (77) X 1 is X C ; X 2 is O and X 3 is CH 2 , or X 2 is CH2 and X 3 is O; and X 4 is a bond; (78) X 1 is X C ; X 2 is O and X 3 is CH 2 , or X 2
  • the compounds of Formula 1 include those in which: (81) X C is substituted with 0 to 3 substituents independently selected from halo; (82) X C is substituted with 0 to 2 substituents independently selected from halo; (83) X C is substituted with 0 to 1 substituents independently selected from halo; or (84) X C is unsubstituted.
  • the compounds of Formula 1 include those in which: (85) X C is substituted with 0 to 4 fluoro; (86) X C is substituted with 0 to 3 fluoro; (87) X C is substituted with 0 to 2 fluoro; or (88) X C is substituted with 0 to 1 fluoro.
  • the compounds of Formula 1 include those in which X 1 is C(HR 1 ), X 2 is O, X 3 is C(HR 3 ) and X 4 is CH2, wherein R 1 and R 3 taken together represent: (89) a C 1-3 alkanediyl bridging the carbon atoms to which R 1 and R 3 are attached; (90) a C 1-2 alkanediyl bridging the carbon atoms to which R 1 and R 3 are attached; (91) methane-1,1-diyl bridging the carbon atoms to which R 1 and R 3 are attached; or (92) ethane-1,2-diyl bridging the carbon atoms to which R 1 and R 3 are attached.
  • the compounds of Formula 1 include those in which X 1 is CH2, X 2 is C(HR 2 ), X 3 is O and X 4 is C(HR 4 ), wherein R 2 and R 4 taken together represent: (93) a C 1-3 alkanediyl bridging the carbon atoms to which R 2 and R 4 are attached; (94) a C1-2 alkanediyl bridging the carbon atoms to which R 2 and R 4 are attached; (95) methane-1,1-diyl bridging the carbon atoms to which R 2 and R 4 are attached; or (96) ethane-1,2-diyl bridging the carbon atoms to which R 2 and R 4 are attached.
  • the compounds of Formula 1 include those in which: (97) X 1 is C(HR 1 ); X 2 is O and X 3 is CH 2, or X 2 is CH2 and X 3 is O; and X 4 is C(HR 4 ); wherein R 1 and R 4 taken together represent a C 1-3 alkanediyl; (98) X 1 is C(HR 1 ); X 2 is O; X 3 is CH 2, and X 4 is C(HR 4 ); wherein R 1 and R 4 taken together represent a C1-3 alkanediyl; or (99) X 1 is C(HR 1 ); X 2 is CH2; X 3 is O; and X 4 is C(HR 4 ); wherein R 1 and R 4 taken together represent a C 1-3 alkanediyl.
  • the compounds of Formula 1 include those in which R 1 and R 4 taken together represent: (100) a C 1-2 alkanediyl bridging the carbon atoms to which R 1 and R 4 are attached; (101) methane-1,1-diyl bridging the carbon atoms to which R 1 and R 4 are attached; or (102) ethane-1,2-diyl bridging the carbon atoms to which R 1 and R 4 are attached.
  • the compounds of Formula 1 include those in which: (103) X 1 is C(HR 1 ); X 2 is CH 2 ; X 3 is C(HR 3 ); and X 4 is CH2; wherein R 1 and R 3 taken together represent a C1-2 alkanediyloxy or O bridging the carbon atoms to which R 1 and R 3 are attached.
  • the compounds of Formula 1 include those in which R 1 and R 3 taken together represent: (104) a C 1-2 alkanediyloxy bridging the carbon atoms to which R 1 and R 3 are attached; (105) methane-1,1-diyloxy bridging the carbon atoms to which R 1 and R 3 are attached; (106) ethane-1,2-diyloxy bridging the carbon atoms to which R 1 and R 3 are attached; or (107) O.
  • the compounds of Formula 1 include those in which: (108) X 1 is C(HR 1 ); X 2 is CH2; X 3 is CH2; and X 4 is C(HR 4 ); wherein R 1 and R 4 taken together represent a C1-2 alkanediyloxy or O bridging the carbon atoms to which R 1 and R 4 are attached.
  • the compounds of Formula 1 include those in which R 1 and R 4 taken together represent: (109) a C1-2 alkanediyloxy bridging the carbon atoms to which R 1 and R 4 are attached; (110) methane-1,1-diyloxy bridging the carbon atoms to which R 1 and R 4 are attached; (111) ethane-1,2-diyloxy bridging the carbon atoms to which R 1 and R 4 are attached; or (112) O.
  • the compounds of Formula 1 include those in which m is: (116) 0; or (117) 1 or 2.
  • the compounds of Formula 1 include those in which: (118) each R a and R b is independently selected from hydrogen and C1-4 alkyl; (119) each R a and R b is independently selected from hydrogen and C 1-3 alkyl; (120) each R a and R b is independently selected from hydrogen and methyl; (121) each R a is methyl and each R b is hydrogen; (122) each R a is methyl and each R b is methyl; (123) each R a is hydrogen and each R b is hydrogen; (124) each R a and R b is independently selected from hydrogen and C1-4 alkyl, or R a and R b , together with a carbon atom to which both R a and R b are attached, form a cyclopropylidene or cyclobutylidene, provided if m is 2, then no more than one R a and R b , together with the carbon atom to which R a and R b are
  • each R a and R b is independently selected from hydrogen and methyl, or R a and R b , together with a carbon atom to which both R a and R b are attached, form a cyclopropylidene, provided if m is 2, then no more than one R a and R b , together with the carbon atom to which R a and R b are attached, form a cyclopropylidene; or (128) each R a and R b is hydrogen, or R a and R b , together with a carbon atom to which both R a and R b are attached, form a cyclopropylidene, provided if m is 2, then no more than one R a and R b , together with the carbon atom to which R a and R b are attached, form a cyclopropylidene.
  • the compounds of Formula 1 include those in which R 5 is: (129) C3-8 cycloalkyl, which is substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) amino, which is substituted with 0 to 2 substituents independently selected from C1-4 alkyl; and (iii) C 1-4 alkyl, C 1-4 alkylcarbonyl and C 1-4 alkoxy, each substituted with 0 to 3 substituents independently selected from halo; (130) C4-7 cycloalkyl, which is substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) amino, which is substituted with 0 to 2 substituents independently selected from C1-4 alkyl; and (iii) C 1-4 alkyl, C 1-4 alkylcarbonyl and C 1-4 al
  • the compounds of Formula 1 include those in which the R 5 cycloalkyl is substituted with 0 to 5 substituents independently selected from: (137) (i) halo, hydroxy and oxo; (ii) amino, which is substituted with 0 to 2 substituents independently selected from C 1-4 alkyl; and (iii) C1-4 alkyl, C1-4 alkylcarbonyl and C1-4 alkoxy, each substituted with 0 to 3 substituents independently selected from halo; (138) (i) halo and hydroxy; (ii) amino, which is substituted with 0 to 2 substituents independently selected from C1-4 alkyl; and (iii) C 1-4 alkyl, C 1-4 alkylcarbonyl and C 1-4 alkoxy, each substituted with 0 to 3 substituents independently selected from halo; (139) (i) hydroxy and fluoro; (ii) amino,
  • the compounds of Formula 1 include those in which the R 5 cycloalkyl is: (150) substituted with 0 to 4 substituents; (151) substituted with 0 to 3 substituents; (152) substituted with 0 to 2 substituents; (153) substituted with 0 to 1 substituents; or (154) is unsubstituted.
  • the compounds of Formula 1 include those in which R 5 is: (155) C 3-8 heterocyclyl in which up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) amino, which is substituted with 0 to 2 substituents independently selected from C 1-4 alkyl; and (iii) C 1-4 alkyl, C 1-4 alkylcarbonyl and C 1-4 alkoxy, each substituted with 0 to 3 substituents independently selected from halo; and in which a nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from: (i) C1-4 alkyl, C1-4 alkylcarbonyl and C1-4 alkylsulfonyl, each substituted with 0 to 3 substituents independently selected from halo; (ii) C 3-8 cycloal
  • the compounds of Formula 1 include those in which up to 3 carbon ring atoms of the R 5 heterocyclyl are each independently substituted with 0 to 2 substituents independently selected from: (160) (i) halo, hydroxy and oxo; (ii) amino, which is substituted with 0 to 2 substituents independently selected from C1-4 alkyl; and (iii) C1-4 alkyl, C1-4 alkylcarbonyl and C1-4 alkoxy, each substituted with 0 to 3 substituents independently selected from halo; (161) (i) halo and oxo; (ii) amino, which is substituted with 0 to 2 substituents independently selected from C 1-4 alkyl; and (iii) C 1-4 alkyl, C 1-4 alkylcarbonyl and C 1-4 alkoxy, each substituted with 0 to 3 substituents independently selected from halo; (162) (i) halo;
  • the compounds of Formula 1 include those in which: (174) up to 2 carbon ring atoms of the R 5 heterocyclyl are each substituted; (175) up to 1 carbon ring atoms of the R 5 heterocyclyl is substituted; or (176) none of the carbon ring atoms of the R 5 heterocyclyl is substituted.
  • the compounds of Formula 1 include those in which R 5 is C 3-8 heterocyclyl in which a nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from: (177) (i) C1-3 alkyl, C1-3 alkylcarbonyl and C1-3 alkylsulfonyl, each substituted with 0 to 3 substituents independently selected from halo; (ii) C 3-8 cycloalkyl-(CH 2 ) n , which C 3-8 cycloalkyl moiety is substituted with 0 to 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 alkylcarbonyl, C1-4 alkoxy and oxo; and (iii) phenyl-(CH 2 ) n and pyridinyl-(CH 2 ) n , which phenyl and pyridinyl moie
  • the compounds of Formula 1 include those in which: (199) R 5 is C3-8 heterocyclyl and n is 0; or (200) R 5 is C 3-8 heterocyclyl and n is 1.
  • the compounds of Formula 1 include those in which R 5 is phenyl, which is: (201) substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C1-4 alkyl and C1-4 alkoxy, provided at least one of the substituents is hydroxy; (202) substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl and C1-3 alkoxy, provided at least one of the substituents is hydroxy; (203) substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, methyl and methoxy, provided at least one of the substituents is hydroxy; (204) substituted with 0 to 2 substituents independently selected from halo, hydroxy, cyano, methyl and methoxy, provided at least one of the substituents is hydroxy; (205) unsubstituted or substituted with hydroxy; or (206) unsubstitute
  • the compounds of Formula 1 include those in which R 6 is selected from: (207) hydrogen and C 1-3 alkyl; (208) hydrogen and methyl; (209) methyl; or (210) hydrogen. [0093] In addition to any one of embodiments (1) to (210) in the preceding paragraphs, the compounds of Formula 1 include those in which: (211) X 8 is CR 8 .
  • the compounds of Formula 1 include those in which R 7 , R 8 and R 11 are each independently selected from: (212) (i) hydrogen, halo and hydroxy; (ii) C 1-4 alkyl and C 1-4 alkoxy, each substituted with 0 to 3 substituents independently selected from halo; and (iii) C 3-8 cycloalkyl which is substituted with 0 to 3 substituents independently selected from halo, C 1-4 alkyl and C 1-4 alkoxy; (213) (i) hydrogen, halo and hydroxy; and (ii) C1-4 alkyl and C1-4 alkoxy, each substituted with 0 to 3 substituents independently selected from halo; (214) (i) hydrogen, halo and hydroxy; and (ii) C1-3 alkyl and C1-3 alkoxy, each substituted with 0 to 3 substituents independently selected from halo; (215) (i) hydrogen,
  • the compounds of Formula 1 include those in which R 7 and R 8 are both hydrogen, and R 11 is selected from: (217) (i) hydrogen, halo and hydroxy; and (ii) C1-3 alkyl and C1-3 alkoxy, each substituted with 0 to 3 substituents independently selected from halo; (218) (i) hydrogen, halo and hydroxy; and (ii) methyl and methoxy, each substituted with 0 to 3 substituents independently selected from halo; or (219) (i) hydrogen, halo and hydroxy; and (ii) methyl and methoxy, each substituted with 0 to 3 fluoro.
  • the compounds of Formula 1 include those in which R 9 and R 10 are each independently selected from: (220) (i) hydrogen, halo, hydroxy and cyano; (ii) C 1-4 alkyl and C 1-4 alkoxy, each substituted with 0 to 3 substituents independently selected from halo; and (iii) C3-8 cycloalkyl which is substituted with 0 to 3 substituents independently selected from halo, C 1-4 alkyl and C 1-4 alkoxy; (221) (i) hydrogen, halo, hydroxy and cyano; (ii) C1-4 alkyl and C1-3 alkoxy, each substituted with 0 to 3 substituents independently selected from halo; and (iii) C 3-8 cycloalkyl which is substituted with 0 to 3 substituents independently selected from halo, C1-4 alkyl and C1-4 alkoxy; (222) (i) hydrogen, halo, hydroxy and cyano; (ii) C 1-4 alkyl and C
  • Compounds of Formula 1 include embodiments (1) through (231) described in the preceding paragraphs and compounds specifically named in the examples, may exist as salts, complexes, solvates, hydrates, and liquid crystals. Likewise, compounds of Formula 1 that are salts may exist as complexes, solvates, hydrates, and liquid crystals. [0098] Compounds of Formula 1 may form pharmaceutically acceptable complexes, salts, solvates and hydrates. These salts include acid addition salts (including di-acids) and base salts.
  • Pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acids, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acids
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and
  • Such salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate,
  • Pharmaceutically acceptable base salts include salts derived from bases, including metal cations, such as an alkali or alkaline earth metal cation, as well as amines.
  • suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum.
  • suitable amines include arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, N-methylglucamine, olamine, 2-amino-2-hydroxymethyl-propane-1,3-diol, and procaine.
  • salts may be prepared using various methods. For example, a compound of Formula 1 may be reacted with an appropriate acid or base to give the desired salt. Alternatively, a precursor of the compound of Formula 1 may be reacted with an acid or base to remove an acid- or base-labile protecting group or to open a lactone or lactam group of the precursor.
  • a salt of the compound of Formula 1 may be converted to another salt (or free form) through treatment with an appropriate acid or base or through contact with an ion exchange resin. Following reaction, the salt may be isolated by filtration if it precipitates from solution, or by evaporation to recover the salt. The degree of ionization of the salt may vary from completely ionized to almost non-ionized.
  • Compounds of Formula 1 may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • the term “amorphous” refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid.
  • Such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (“glass transition”).
  • glass transition typically second order
  • crystalline refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks.
  • Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (“melting point”).
  • Compounds of Formula 1 may also exist in unsolvated and solvated forms.
  • solvate describes a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol).
  • solvent molecules e.g., ethanol
  • hydrate is a solvate in which the solvent is water.
  • Pharmaceutically acceptable solvates include those in which the solvent may be isotopically substituted (e.g., D2O, acetone-d6, DMSO-d6).
  • a currently accepted classification system for solvates and hydrates of organic compounds is one that distinguishes between isolated site, channel, and metal-ion coordinated solvates and hydrates. See, e.g., K. R. Morris (H. G. Brittain ed.) Polymorphism in Pharmaceutical Solids (1995).
  • Isolated site solvates and hydrates are ones in which the solvent (e.g., water) molecules are isolated from direct contact with each other by intervening molecules of the organic compound.
  • the solvent molecules lie in lattice channels where they are next to other solvent molecules.
  • metal-ion coordinated solvates the solvent molecules are bonded to the metal ion.
  • Compounds of Formula 1 may also exist as multi-component complexes (other than salts and solvates) in which the compound (drug) and at least one other component are present in stoichiometric or non-stoichiometric amounts.
  • Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions but could also be a complex of a neutral molecule with a salt.
  • Co- crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together. See, e.g., O. Almarsson and M. J.
  • compounds of Formula 1 may exist in a mesomorphic state (mesophase or liquid crystal).
  • the mesomorphic state lies between the true crystalline state and the true liquid state (either melt or solution).
  • lyotropic Mesomorphism arising as the result of a change in temperature is described as “thermotropic” and mesomorphism resulting from the addition of a second component, such as water or another solvent, is described as “lyotropic.”
  • Compounds that have the potential to form lyotropic mesophases are described as “amphiphilic” and include molecules which possess a polar ionic moiety (e.g., -COO ⁇ Na + , -COO ⁇ K + , -SO 3 ⁇ Na + ) or polar non-ionic moiety (such as -N ⁇ N + (CH 3 ) 3 ). See, e.g., N. H. Hartshorne and A.
  • Each compound of Formula 1 may exist as polymorphs, stereoisomers, tautomers, or some combination thereof, may be isotopically-labeled, may result from the administration of a prodrug, or form a metabolite following administration.
  • “Prodrugs” refer to compounds having little or no pharmacological activity that can, when metabolized in vivo, undergo conversion to compounds having desired pharmacological activity. Prodrugs may be prepared by replacing appropriate functionalities present in pharmacologically active compounds with “pro-moieties” as described, for example, in H. Bundgaar, Design of Prodrugs (1985).
  • prodrugs examples include ester, ether or amide derivatives of compounds of Formula 1 having carboxylic acid, hydroxy, or amino functional groups, respectively.
  • prodrugs see e.g., T. Higuchi and V. Stella “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series 14 (1975) and E. B. Roche ed., Bioreversible Carriers in Drug Design (1987).
  • “Metabolites” refer to compounds formed in vivo upon administration of pharmacologically active compounds. Examples include hydroxymethyl, hydroxy, secondary amino, primary amino, phenol, and carboxylic acid derivatives of compounds of Formula 1 having methyl, alkoxy, tertiary amino, secondary amino, phenyl, and amide groups, respectively.
  • Compounds of Formula 1 may exist as stereoisomers that result from the presence of one or more stereogenic centers, one or more double bonds, or both.
  • the stereoisomers may be pure, substantially pure, or mixtures. Such stereoisomers may also result from acid addition or base salts in which the counter-ion is optically active, for example, when the counter-ion is D-lactate or L-lysine.
  • Compounds of Formula 1 may exist as tautomers, which are isomers resulting from tautomerization. Tautomeric isomerism includes, for example, imine-enamine, keto-enol, oxime-nitroso, and amide-imidic acid tautomerism.
  • Compounds of Formula 1 may exhibit more than one type of isomerism.
  • Geometrical (cis/trans) isomers may be separated by conventional techniques such as chromatography and fractional crystallization.
  • Conventional techniques for preparing or isolating a compound having a specific stereochemical configuration include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC).
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula 1 contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of Formula 1 contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography, fractional crystallization, etc., and the appropriate diastereoisomer converted to the compound having the requisite stereochemical configuration.
  • Compounds of Formula 1 may possess isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.
  • Isotopes suitable for inclusion in compounds of Formula 1 include, for example, isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, such as 11 C, 13 C and 14 C; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O, 17 O and 18 O; isotopes of sulfur, such as 35 S; isotopes of fluorine, such as 18 F; isotopes of chlorine, such as 36 Cl, and isotopes of iodine, such as 123 I and 125 I.
  • isotopic variations may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
  • certain isotopic variations of the disclosed compounds may incorporate a radioactive isotope (e.g., tritium, 3 H, or 14 C), which may be useful in drug and/or substrate tissue distribution studies.
  • positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N, may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds may be prepared by processes analogous to those described elsewhere in the disclosure using an appropriate isotopically-labeled reagent in place of a non-labeled reagent.
  • the compounds of Formula 1 may be prepared using the techniques described below. Some of the methods and examples may omit details of common reactions, including oxidations, reductions, and so on, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like), and analytical procedures, which are known to persons of ordinary skill in the art of organic chemistry. The details of such reactions and techniques can be found in several treatises, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi- volume series edited by Michael B.
  • reaction schemes may omit minor products resulting from chemical transformations (e.g., an alcohol from the hydrolysis of an ester, CO2 from the decarboxylation of a di-acid, etc.).
  • reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).
  • certain compounds may be prepared using protecting groups, which prevent undesirable chemical reaction at otherwise reactive sites. Protecting groups may also be used to enhance solubility or otherwise modify physical properties of a compound.
  • the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, non-polar solvents, or some combination.
  • Representative solvents include saturated aliphatic hydrocarbons (e.g., n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane); aromatic hydrocarbons (e.g., benzene, toluene, xylenes); halogenated hydrocarbons (e.g., methylene chloride, chloroform, carbon tetrachloride); aliphatic alcohols (e.g., methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, 2-methyl- propan-1-ol, butan-2-ol, 2-methyl-propan-2-ol, pentan-1-ol, 3-methyl-butan-1
  • substituent identifiers e.g., ⁇ , ⁇ , m, R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R a , R b , X 1 , X 2 , X 3 , X 4 and X 8
  • substituent identifiers are as defined above for Formula 1.
  • some of the starting materials and intermediates may include protecting groups, which are removed prior to the final product.
  • the substituent identifier refers to moieties defined in Formula 1 and to those moieties with appropriate protecting groups.
  • a starting material or intermediate in the synthetic methods may include a potentially reactive (secondary) amine.
  • Schemes A and B show general methods for preparing compounds of Formula 1.
  • a 1,4-dihalophthalazine derivative or analog (A1 in which, e.g., X is Cl) is reacted with an amine (A2) in the presence of a base (e.g., DIPEA, K2CO3, etc.) and solvent (e.g., ACN, DMSO, NMP, etc.) at elevated temperature (e.g., 80°C to 150°C) to give a halophthalazine amine (A3).
  • a base e.g., DIPEA, K2CO3, etc.
  • solvent e.g., ACN, DMSO, NMP, etc.
  • elevated temperature e.g. 80°C to 150°C
  • the amine (A3) is subsequently reacted with a diboronic acid or ester (A4 in which, e.g., each R 12 is H or C1-4 alkyl) in the presence of a palladium catalyst (e.g., Pd(PPH 3 ) 4 , Pd(dppf)Cl 2 , Pd(dppf)Cl 2 .CH 2 Cl 2 , AmPhos PdCl 2 , XPhos PdCl 2 , etc.), base (e.g., Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , KF, etc.) and one or more solvents (e.g., 1,4- dioxane, DMF, ACN, EtOH, H2O, etc.) at elevated temperature (e.g., 50-110°C) to give the compound of Formula 1, directly or indirectly, e.g., after removal of protecting groups, further elaboration of functional groups, separation of stereoisomers or regiois
  • the 1,4-dihalophthalazine derivative or analog (A1) may be first reacted with the diboronic acid or ester (A4) in the presence of a palladium catalyst, base and solvent as noted for Scheme A.
  • the resulting aromatic-substituted halophthalazine (B1) is then reacted with the amine (A2) in the presence of a base and solvent at elevated temperature, as described for Scheme A, to give the compound of Formula 1, either directly or after removal of protecting groups, further elaboration of functional groups, separation of stereoisomers or regioisomers, etc.
  • the methods depicted in the schemes may be varied as desired.
  • protecting groups may be added or removed and products may be further elaborated via, for example, alkylation, acylation, hydrolysis, oxidation, reduction, amidation, sulfonation, alkynation, and the like to give the desired final product.
  • any intermediate or final product which comprises mixture of stereoisomers may be optionally purified by chiral column chromatography (e.g., supercritical fluid chromatography) or by derivatization with optically-pure reagents as described above to give a desired stereoisomer.
  • Compounds of Formula 1 which include compounds named above, and their pharmaceutically acceptable complexes, salts, solvates and hydrates, should be assessed for their biopharmaceutical properties, such as solubility and solution stability across pH, permeability, and the like, to select an appropriate dosage form and route of administration.
  • Compounds that are intended for pharmaceutical use may be administered as crystalline or amorphous products, and may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, evaporative drying, microwave drying, or radio frequency drying.
  • Compounds of Formula 1 may be administered alone or in combination with one another or with one or more pharmacologically active compounds which are different than the compounds of Formula 1. Generally, one or more of these compounds are administered as a pharmaceutical composition (a formulation) in association with one or more pharmaceutically acceptable excipients. The choice of excipients depends on the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form, among other things. Useful pharmaceutical compositions and methods for their preparation may be found, for example, in A. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000). [0126] Compounds of Formula 1 may be administered orally.
  • Oral administration may involve swallowing in which case the compound enters the bloodstream via the gastrointestinal tract.
  • oral administration may involve mucosal administration (e.g., buccal, sublingual, supralingual administration) such that the compound enters the bloodstream through the oral mucosa.
  • Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges which may be liquid-filled; chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal or mucoadhesive patches.
  • Liquid formulations include suspensions, solutions, syrups and elixirs.
  • Such formulations may be employed as fillers in soft or hard capsules (made, e.g., from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) and one or more emulsifying agents, suspending agents or both.
  • a carrier e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil
  • emulsifying agents emulsifying agents, suspending agents or both.
  • Liquid formulations may also be prepared by the reconstitution of a solid (e.g., from a sachet).
  • Compounds of Formula 1 may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents (2001) 11(6):981-986.
  • the active pharmaceutical ingredient may comprise from about 1 wt% to about 80 wt% of the dosage form or more typically from about 5 wt% to about 60 wt% of the dosage form.
  • tablets may include one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, anti- oxidants, colorants, flavoring agents, preservatives, and taste-masking agents.
  • disintegrants examples include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, C 1-6 alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate.
  • the disintegrant will comprise from about 1 wt% to about 25 wt% or from about 5 wt% to about 20 wt% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation.
  • Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. [0131] Tablets may also include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents may comprise from about 0.2 wt% to about 5 wt% of the tablet, and glidants may comprise from about 0.2 wt% to about 1 wt% of the tablet.
  • Tablets may also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants may comprise from about 0.25 wt% to about 10 wt% or from about 0.5 wt% to about 3 wt% of the tablet.
  • Tablet blends may be compressed directly or by roller compaction to form tablets.
  • Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. If desired, prior to blending one or more of the components may be sized by screening or milling or both.
  • the final dosage form may comprise one or more layers and may be coated, uncoated, or encapsulated. Exemplary tablets may contain up to about 80 wt% of API, from about 10 wt% to about 90 wt% of binder, from about 0 wt% to about 85 wt% of diluent, from about 2 wt% to about 10 wt% of disintegrant, and from about 0.25 wt% to about 10 wt% of lubricant.
  • a typical film includes one or more film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity-modifying agents, and solvents.
  • film ingredients may include anti-oxidants, colorants, flavorants and flavor enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants, and taste-masking agents.
  • Some components of the formulation may perform more than one function.
  • the amount of API in the film may depend on its solubility.
  • the API would typically comprise from about 1 wt% to about 80 wt% of the non-solvent components (solutes) in the film or from about 20 wt% to about 50 wt% of the solutes in the film.
  • a less soluble API may comprise a greater proportion of the composition, typically up to about 88 wt% of the non-solvent components in the film.
  • the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and typically comprises from about 0.01 wt% to about 99 wt% or from about 30 wt% to about 80 wt% of the film.
  • Film dosage forms are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper, which may be carried out in a drying oven or tunnel (e.g., in a combined coating-drying apparatus), in lyophilization equipment, or in a vacuum oven.
  • Useful solid formulations for oral administration may include immediate release formulations and modified release formulations. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release. For a general description of suitable modified release formulations, see US Patent No.6,106,864.
  • Compounds of Formula 1 may also be administered directly into the blood stream, muscle, or an internal organ of the subject.
  • Suitable techniques for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.
  • Suitable devices for parenteral administration include needle injectors, including microneedle injectors, needle-free injectors, and infusion devices.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (e.g., pH of from about 3 to about 9).
  • compounds of Formula 1 may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • a suitable vehicle such as sterile, pyrogen-free water.
  • the preparation of parenteral formulations under sterile conditions may be readily accomplished using standard pharmaceutical techniques.
  • the solubility of compounds which are used in the preparation of parenteral solutions may be increased through appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate or modified release.
  • Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.
  • compounds of Formula 1 may be formulated as a suspension, a solid, a semi-solid, or a thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(DL-lactic-coglycolic)acid (PGLA) microspheres.
  • PGLA poly(DL-lactic-coglycolic)acid
  • Compounds of Formula 1 may also be administered topically, intradermally, or transdermally to the skin or mucosa.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions.
  • Liposomes may also be used.
  • Typical carriers may include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Topical formulations may also include penetration enhancers. See, e.g., Finnin and Morgan, J. Pharm. Sci. 88(10):955-958 (1999).
  • Topical administration examples include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject TM and Bioject TM ) injection.
  • Formulations for topical administration may be formulated to be immediate or modified release as described above.
  • Compounds of Formula 1 may also be administered intranasally or by inhalation, typically in the form of a dry powder, an aerosol spray, or nasal drops.
  • An inhaler may be used to administer the dry powder, which comprises the API alone, a powder blend of the API and a diluent, such as lactose, or a mixed component particle that includes the API and a phospholipid, such as phosphatidylcholine.
  • the powder may include a bioadhesive agent, e.g., chitosan or cyclodextrin.
  • a pressurized container, pump, sprayer, atomizer, or nebulizer may be used to generate the aerosol spray from a solution or suspension comprising the API, one or more agents for dispersing, solubilizing, or extending the release of the API (e.g., EtOH with or without water), one or more solvents (e.g., 1,1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) which serve as a propellant, and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • An atomizer using electrohydrodynamics may be used to produce a fine mist.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is usually comminuted to a particle size suitable for delivery by inhalation (typically 90% of the particles, based on volume, having a largest dimension less than 5 microns). This may be achieved by any appropriate size reduction method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing, high pressure homogenization, or spray drying.
  • Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mixture of the active compound, a suitable powder base such as lactose or starch, and a performance modifier such as L-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or monohydrated.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
  • a suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from about 1 ⁇ g to about 20 mg of the API per actuation and the actuation volume may vary from about 1 ⁇ L to about 100 ⁇ L.
  • a typical formulation may comprise one or more compounds of Formula 1, propylene glycol, sterile water, EtOH, and NaCl.
  • Alternative solvents, which may be used instead of propylene glycol, include glycerol and polyethylene glycol.
  • Formulations for inhaled administration, intranasal administration, or both, may be formulated to be immediate or modified release using, for example, PGLA.
  • Suitable flavors such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, may be added to formulations intended for inhaled/intranasal administration.
  • the dosage unit is determined by means of a valve that delivers a metered amount. Units are typically arranged to administer a metered dose or “puff” containing from about 10 ⁇ g to about 1000 ⁇ g of the API. The overall daily dose will typically range from about 100 ⁇ g to about 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the active compounds may be administered rectally or vaginally, e.g., in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal or vaginal administration may be formulated to be immediate or modified release as described above.
  • Compounds of Formula 1 may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable implants (e.g.
  • the formulation may include one or more polymers and a preservative, such as benzalkonium chloride.
  • Typical polymers include crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, cellulosic polymers (e.g., hydroxypropylmethylcellulose, hydroxyethylcellulose, methyl cellulose), and heteropolysaccharide polymers (e.g., gelan gum).
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular or aural administration may be formulated to be immediate or modified release as described above.
  • compounds of Formula 1 may be combined with soluble macromolecular entities, including cyclodextrin and its derivatives and polyethylene glycol-containing polymers.
  • soluble macromolecular entities including cyclodextrin and its derivatives and polyethylene glycol-containing polymers.
  • API-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer.
  • Alpha-, beta- and gamma-cyclodextrins are commonly used for these purposes. See, e.g., WO 91/11172, WO 94/02518, and WO 98/55148.
  • one or more compounds of Formula 1, including compounds specifically named above, and their pharmaceutically active complexes, salts, solvates and hydrates may be combined with each other or with one or more other active pharmaceutically active compounds to treat various diseases, conditions and disorders.
  • the active compounds may be combined in a single dosage form as described above or may be provided in the form of a kit which is suitable for coadministration of the compositions.
  • the kit comprises (1) two or more different pharmaceutical compositions, at least one of which contains a compound of Formula 1; and (2) a device for separately retaining the two pharmaceutical compositions, such as a divided bottle or a divided foil packet.
  • a device for separately retaining the two pharmaceutical compositions such as a divided bottle or a divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets or capsules.
  • the kit is suitable for administering different types of dosage forms (e.g., oral and parenteral) or for administering different pharmaceutical compositions at separate dosing intervals, or for titrating the different pharmaceutical compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a memory aid.
  • the total daily dose of the claimed and disclosed compounds is typically in the range of about 0.1 mg to about 3000 mg depending on the route of administration.
  • oral administration may require a total daily dose of from about 1 mg to about 3000 mg
  • an intravenous dose may only require a total daily dose of from about 0.1 mg to about 300 mg.
  • the total daily dose may be administered in single or divided doses and, at the physician's discretion, may fall outside of the typical ranges given above. Although these dosages are based on an average human subject having a mass of about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for a patient (e.g., an infant) whose mass falls outside of this weight range.
  • the compounds of Formula 1 may be used to treat diseases, disorders, and conditions for which inhibition of the NLRP3 inflammasome pathway is indicated, including diseases, disorders or conditions associated with a heterozygous gain of function mutation in the NLRP3 gene, such as a cryopyrin-associated periodic syndrome (CAPS). These may include neonatal-onset multisystem inflammatory disease (NOMID/CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS). [0156] The compounds of Formula 1 may be used to treat neurodegenerative diseases, disorders, and conditions associated with NLRP3.
  • CAPS cryopyrin-associated periodic syndrome
  • NOMID/CINCA neonatal-onset multisystem inflammatory disease
  • MWS Muckle-Wells syndrome
  • FCAS familial cold autoinflammatory syndrome
  • the compounds of Formula 1 may be used to treat neurodegenerative diseases, disorders, and conditions associated with NLRP3.
  • Parkinson's disease Huntington's disease
  • amyotrophic lateral sclerosis prion disease
  • Alzheimer's disease and other forms of dementia (i.e., major or mild neurocognitive disorders) associated with one or more medical conditions, including frontotemporal lobar degeneration, Lewy body disease, vascular disease, traumatic brain injury, substance or medication use, HIV infection, prion disease, Parkinson's disease, and Huntington's disease.
  • the compounds of Formula 1 may also be used to treat major or mild neurocognitive disorders associated with depression, schizophrenia, bipolar disorder, and autism.
  • the claimed and disclosed compounds may be combined with one or more other pharmacologically active compounds or therapies to treat one or more disorders, diseases or conditions for which inhibition of the NLRP3 inflammasome pathway is indicated. Such combinations may offer significant therapeutic advantages, including fewer side effects, improved ability to treat underserved patient populations, or synergistic activity.
  • compounds of Formula 1 which include compounds specifically named above, and their pharmaceutically acceptable complexes, salts, solvates and hydrates, may be administered simultaneously, sequentially or separately in combination with one or more compounds or therapies for treating Alzheimer's disease, including beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs, such as apazone, aspirin, celecoxib, diclofenac (with and without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylates, salsalate, and sulindac), vitamin
  • the compounds of Formula 1 may be combined with sedatives, hypnotics, anxiolytics, antipsychotics, tranquilizers, and other medications that are used in the treatment of Alzheimer's disease.
  • the compounds of Formula 1 may be combined with one or more agents for treating depression (antidepressants) and/or schizophrenia (atypical or typical antipsychotics) including amitriptyline, amoxapine, aripiprazole, asenapine, bupropion, chlordiazepoxide, citalopram, chlorpromazine, clozapine, desipramine, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, fluoxetine, fluphenazine, haloperidol, iloperidone, imipramine, isocarboxazid, lamotrigine, levomilnacipran, lurasidone, mirtazapine, nefazodone, nortriptyline, olanzapine, paliperidone, paroxetine, perphenazine, phenelzine, protriptyline, quetiapine, risperidone, se
  • the compounds of Formula 1 may be combined with one or more agents for treating anxiety (anxiolytics) including benzodiazepines (alprazolam, chlordiazepoxide, clobazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, prazepam, quazepam, temazepam, and triazolam), antihistamines (hydroxyzine), non-benzodiazepines (eszopiclone, zaleplon, zolpidem, and zopiclone) and buspirone.
  • benzodiazepines alprazolam, chlordiazepoxide, clobazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam,
  • the compounds of Formula 1 may also be combined with one or more agents for treating epilepsy (antiepileptics or anticonvulsants) including acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.
  • epilepsy antiepileptics or anticonvulsants
  • agents for treating epilepsy including acetazolamide, carbamazepine, clobazam, clonazepam, eslic
  • BIOLOGICAL ACTIVITY The biological activity of the compound of Formula 1 with respect to NLRP3 may be determined using the following in vitro methods.
  • IL-1 ⁇ Assay (reported as IC50)
  • Monocytic THP-1 cells (ATCC: TIB-202) are maintained in accordance with the provider's instructions in RPMI media (Life Technologies, Cat # A10491-01); RPMI is supplemented with 10% heat inactivated fetal bovine serum (Hyclone Cat # SH30396.03). The cells are differentiated into macrophages by the addition of 25 ng/mL IFN- ⁇ (PeproTech, Cat # 300-02-100UG) for 24 hours at 37°C/5% CO2.
  • Media is exchanged with fresh media with no FBS, and the cells are treated with 50 ng/mL LPS (priming step) for 24 hours at 37°C/5% CO 2 (LPS-EK: Invivogen, Cat # tlrl-peklps). Media is exchanged with fresh media with no FBS.
  • the cells are plated at 40,000 cells per well in 384-well flat-bottom cell culture plates (Costar 3764) containing compounds (added in 1:1000) in a 1:3.16 serial dilution series in DMSO and are incubated for 30 minutes at 37°C/5% CO 2 .
  • the NLRP3 inflammasome is activated with the addition of 2.5 mM ATP (Sigma Cat # A3377) and the cells are incubated for 2 hours at 37°C/5% CO2. At the end of the incubation period, 40 ⁇ L supernatant is removed, and IL-1 ⁇ levels are monitored using an ELISA (Human IL-1 ⁇ ELISA, R&D systems, Cat # DY201) in accordance with the manufacturer's instructions.
  • ELISA Human IL-1 ⁇ ELISA, R&D systems, Cat # DY201
  • TNF- ⁇ Assay Description of the TNF- ⁇ Assay (reported as IC50) [0166] Monocytic THP-1 cells (ATCC: TIB-202) are maintained in accordance with the provider's instructions in RPMI media (Life Technologies, Cat # A10491-01); RPMI is supplemented with 10% heat inactivated fetal bovine serum (Hyclone Cat # SH30396.03). The cells are differentiated into macrophages by the addition of 25 ng/mL IFN- ⁇ for 24 hours at 37°C/5% CO2. Media is exchanged with fresh media with no FBS.
  • the cells are plated at 40,000 cells per well in 384-well flat-bottom cell culture plates (Costar 3764) containing compounds (added in 1:1000) in a 1:3.16 serial dilution series in DMSO and are incubated for 30 minutes at 37°C/5% CO 2 .
  • the NF- ⁇ B pathway is activated with the addition of 50 ng/mL LPS and the cells are incubated for 3 hours at 37°C/5% CO 2 .
  • supernatant 40 ⁇ L
  • IL-1 ⁇ levels are monitored using an ELISA (Human TNF- ⁇ ELISA, R&D systems, Cat # DY210) according to the manufacturer's instructions.
  • the curve fitting was conducted with internally developed software.
  • MDCK-MDR1 Assay (reported as Apparent Permeability and Efflux Ratio)
  • MDCK Madine-Darby Canine Kidney cells transfected with Multidrug resistance protein 1 (MDR1) are maintained in accordance with the provider’s instructions in Dulbecco’s Modified Eagle media (DMEM, Fisher Scientific Cat# 10569044).
  • DMEM fetal bovine serum
  • Penicillin-Streptomycin 100 units/mL
  • an inducer of P-gp, colchicine 200 nM
  • the cells are seeded onto the apical side of HTS- Transwell-96 Plates (0.4 ⁇ m pore size, Corning Cat# 3381) at a density of 6.25 x 10 3 cells per well with 75 ⁇ L and 250 ⁇ L of DMEM media in apical and basolateral wells, respectively, and are incubated at 37°C/5% CO 2 .
  • Fresh DMEM media is exchanged in the apical and basolateral compartments after 72 hours and cells are allowed to grow into a monolayer for 144 hours before beginning the experimental incubation. Incubations are performed in Hanks’ Balanced Salt Solution (HBSS, Fisher Scientific Cat# 14025134) at pH 7.4 with 1% Bovine Serum Albumin (Sigma, Cat# A9418) and 10 mM HEPES (Fisher Scientific, Cat# 15630080). DMEM media is removed and cells are rinsed with warm (37°C) HBSS.
  • HBSS Hanks’ Balanced Salt Solution
  • HBSS with test compound at 1 ⁇ M substrate concentration (0.1% v/v DMSO) is added to either the apical or basolateral compartment (75 ⁇ L or 250 ⁇ L, respectively) and blank HBSS buffer is added to the compartment which lacks test compound in singlicate.
  • the cells are incubated for 60 minutes at 37°C/5% CO 2 .
  • 50 ⁇ L of sample is removed from each receiver compartment and diluted into 150 ⁇ L of acetonitrile (Fisher Scientific, Cat# A996SK4) + 0.1% formic acid (Sigma, Cat# F0507).
  • sample samples are centrifuged at 2000 rcf for 10 minutes at 4°C, after which 100 ⁇ L of supernatant is transferred to a new microplate and diluted with 100 ⁇ L of HPLC grade water (Fisher Scientific, Cat# W64).
  • Samples are analyzed using a triple quadrupole mass spectrometer API-5500QTrap (ABSciex, Serial No. AU23291006) along with associated autosampler and high performance liquid chromatography pump instrumentation optimized for the detection of test articles through a Kinetix 2.1 x 50 mm C18100 ⁇ column (Phenomenex, Cat# 00B- 4605-AN).
  • Apparent permeability (Papp) values and efflux ratio are calculated using the following equations: P ⁇ ⁇ (nm ⁇ Conc ⁇ ⁇ 0.25 ⁇ 10000 ⁇ 0.075 ⁇ 10000 A ⁇ t ⁇ 10 ; P ; ⁇ ⁇ ⁇ where P app A-B is the apparent permeability from the apical well to basolateral well; P app B-A is the apparent permeability from the basolateral well to the apical well; ConcBL is the basolateral well concentration; ConcAP is the apical well concentration; A is the well surface area (cm 2 ), which for the above assay is 0.143 cm 2 ; t is the incubation time (seconds), which for the above assay is 3600 seconds; and ER is the P-gp mediated efflux ratio.
  • HPLC Method A Column Phenomenex Gemini® C18 Mobile Phase ACN (0.035% TFA) and water (0.005% TFA) Gradient 10% to 100% ACN (unless indicated otherwise)
  • HPLC Method B Column Xtimate C18; Boston Green ODS; Welch Xtimate C18; Waters Xbridge BEH C18; YMC-Triart Prep C18; Phenomenex Gemini-NX Mobile Phase Water (0.225% FA) and ACN Gradient 15% to 45% ACN gradient over 10 minutes (unless indicated otherwise)
  • Table 4 lists equipment, materials, and conditions for some of the SFC separations. [0180] TABLE 4: SFC Method Column OD-H (21 mm x 250 mm) 5 micron or AS-H column with 30% isopropyl alcohol Mobile Phase CO 2 and EtOH + 0.05% DEA (diethyl amine) or CO 2 and MeOH + 0.05% DEA [0181] Besides HPLC, some of the preparations and examples may employ flash chromatography or preparative thin layer chromatography (TLC). Preparative TLC is typically carried out on silica gel 60 F 254 plates.
  • the solvent may be removed and the product cried in a centrifugal evaporator (e.g., GeneVac TM ), rotary evaporator, evacuated flask, etc.
  • a centrifugal evaporator e.g., GeneVac TM
  • rotary evaporator e.g., rotary evaporator
  • evacuated flask e.g., a centrifugal evaporator
  • Reactions in an inert (e.g., nitrogen) or reactive (e.g., H 2 ) atmosphere are typically carried out at a pressure of about 1 atmosphere (14.7 psi).
  • PREPARATION 1 5,5-difluoro-1-methylpiperidin-3-amine
  • STEP 1 tert-butyl (5,5-difluoro-1-methylpiperidin-3-yl)carbamate
  • PREPARATION 4 (R)-1-(1-methylcyclopropyl)piperidin-3-amine
  • STEP 1 tert-butyl (R)-(1-acetylpiperidin-3-yl)carbamate
  • STEP 2 tert-butyl (R)-(1-(1-methylcyclopropyl)piperidin-3-yl)carbamate
  • tert-butyl (R)-(1-acetylpiperidin-3-yl)carbamate 900 mg, 3.71 mmol
  • Ti(i-PrO)4 2.11 g, 7.43 mmol, 2.19 mL
  • EtMgBr 3 M, 6.19 mL
  • PREPARATION 5 (3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-amine
  • STEP 1 tert-butyl ((3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-yl)carbamate
  • a solution of tert-butyl ((3R,5R)-5-fluoropiperidin-3-yl)carbamate (0.327 g, 1.50 mmol) in THF (5 mL), MeOH(5 mL) and acetic acid (1.0 mL) was treated with (1- ethoxycyclopropoxy)trimethylsilane (0.523 g, 3.00 mmol), followed by sodium cyanoborohydride (0.283 g, 4.50 mmol).
  • PREPARATION 22 (R)-1-(2-fluoroethyl)piperidin-3-amine
  • STEP 1 tert-butyl (R)-(1-(2-fluoroethyl)piperidin-3-yl)carbamate
  • tert-butyl (R)-piperidin-3-ylcarbamate 15 g, 74.90 mmol
  • 1- bromo-2-fluoroethane (19.02 g, 149.79 mmol) in ACN (80 mL) were added NaI (5.61 g, 37.45 mmol) and K 2 CO 3 (51.76 g, 374.48 mmol).
  • PREPARATION 56 1',4'-dichloro-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4- d]pyridazine]
  • STEP 1 methyl 1-(2-(1,3-dioxolan-2-yl)ethoxy)cyclopropane-1-carboxylate
  • STEP 5 1-(2-(3,6-dichloropyridazin-4-yl)ethoxy)cyclopropane-1-carboxylic acid
  • PREPARATION 57 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazine]
  • STEP 1 ((4-oxaspiro[2.5]oct-6-en-7-yl)oxy)(tert-butyl)dimethylsilane
  • PREPARATION 58 4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-7',8'- dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine] [0233]
  • PREPARATION 59 1'-chloro-4'-(2-(methoxymethoxy)-4-methylphenyl)-7',8'- dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine] [0234] To a mixture of 1',4'-dichloro-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4- d]pyridazine] (200 mg, 865.51 ⁇ mol) and 2-(2-(methoxymethoxy)-4-methylphenyl)-4,4,5,5- tetramethyl-1
  • PREPARATION 60 and 61 4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] and 1'-chloro-4'-(2- (methoxymethoxy)-4-methylphenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazine] [0236] To a solution of 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazine] (500 mg, 2.16 mmol) and 2-(2-(methoxymethoxy)-4-methylphenyl)-4,4,5,5- tetramethyl-1,3,2-dio
  • PREPARATION 62 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazine
  • 8-oxabicyclo[3.2.1]octan-3- one (2500 mg, 19.8 mmol)
  • 4-methylbenzenesulfonic acid monohydrate 38 mg, 0.198 mmol
  • pyrrolidine 1.6 mL, 19.8 mmol
  • PREPARATION 63 5-chloro-2-(4-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-1-yl)phenol
  • PREPARATION 64 5-chloro-2-(1-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-4-yl)phenol
  • a mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (1500 mg, 6.5 mmol), Cs2CO3 (4.2 g, 13.0 mmol), Pd(dppf)Cl2.CH2Cl2 (530 mg, 0.65 mmol) and (4-chloro-2-hydroxyphenyl)boronic acid (1.12 g, 6.5 mmol) in 1,4-di
  • PREPARATION 65 rac-4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)- 4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine]
  • PREPARATION 66 rac-1'-chloro-4'-(2-(methoxymethoxy)-4-methylphenyl)- 4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine]
  • STEP 1 tert-butyl-(2,6-dioxas
  • STEP 2 1',4'-dichloro-4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4- d]pyridazine]
  • a mixture of 3,6-dichloro-1,2,4,5-tetrazine (0.83 g, 5.47 mmol) in toluene (8 mL) was cooled to 0°C.
  • a solution of tert-butyl-(2,6-dioxaspiro[4.5]dec-8-en-9- yloxy)dimethylsilane (1.48 g, 5.47 mmol) in toluene (3 mL) was added dropwise.
  • PREPARATION 68 4'-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-amine and 1'-chloro-N-((3R,5R)- 5-fluoro-1-methylpiperidin-3-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazin]-4'-amine [0251] To a solution of 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazine] (550 mg, 2.38 mmol), (3R,5R)-5-fluoro-1-methyl-piperidin-3-amine
  • PREPARATION 69 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazine
  • 8-oxabicyclo[3.2.1]octan-3-one 2500 mg, 19.8 mmol
  • p-toluenesulfonic acid monohydrate 38 mg, 0.198 mmol
  • pyrrolidine 1.6 mL, 19.8 mmol
  • PREPARATION 70 4-chloro-1-(2-(methoxymethoxy)-4-methylphenyl)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine
  • PREPARATION 71 1-chloro-4-(2-(methoxymethoxy)-4-methylphenyl)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine
  • a mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine 600 mg, 2.6 mmol
  • Cs 2 CO 3 (1.69 g, 5.19 mmol
  • Pd(dppf)Cl 2 .CH 2 Cl 2 212 mg, 0.26 mmol
  • PREPARATION: 73 2-((5R,8S)-4-chloro-5,7,8,9-tetrahydro-5,8- epoxyoxepino[3,4-d]pyridazin-1-yl)-5-methylphenol
  • PREPARATION: 74 2-((5R,8S)-1-chloro-5,7,8,9-tetrahydro-5,8- epoxyoxepino[3,4-d]pyridazin-4-yl)-5-methylphenol
  • a mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (900 mg, 3.9 mmol), Cs 2 CO 3 (3.1 g, 9.65 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2 (315 mg, 0.39 mmol), and (2-hydroxy-4-methyl-phenyl)boronic acid (0.587
  • PREPARATION 75 4-chloro-1-(2-fluoro-6-(methoxymethoxy)-4-methylphenyl)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine
  • PREPARATION 76 1-chloro-4-(2-fluoro-6-(methoxymethoxy)-4-methylphenyl)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine
  • reaction mixture was purified by flash chromatography (ISCO® 40 g SepaFlash® silica gel column) eluting with 50% EtOAc in heptane (24 mL/min) to give the two title compounds.
  • a solution of rac-(1S,4R)-7-oxabicyclo[2.2.1]heptan-2-one (200 mg, 1.78 mmol) in toluene (8.9182 mL) was treated with pyrrolidine (0.15 mL, 1.78 mmol) and p- toluenesulfonic acid monohydrate (3.4 mg, 0.0178 mmol) and stirred for 30 minutes at room temperature.
  • reaction mixture was purified by flash chromatography (ISCO® 40 g SepaFlash® silica gel column) eluting with 50% EtOAc in heptane (24 mL/min) to give the title compound.
  • PREPARATION 79 1,4-dichlorospiro[5,7-dihydropyrano[3,4-d]pyridazine-8,1'- cyclopropane]
  • STEP 1 methyl 1-((prop-2-yn-1-yloxy)methyl)cyclopropane-1-carboxylate
  • PREPARATION 80 (1R,2R)-2-((4'-chloro-5'H,7'H-spiro[cyclopropane-1,8'- pyrano[3,4-d]pyridazin]-1'-yl)amino)cyclohexan-1-ol
  • PREPARATION 81 (1R,2R)-2-((1'-chloro-5'H,7'H-spiro[cyclopropane-1,8'- pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclohexan-1-ol
  • Starting materials 1',4'-dichloro-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,4- d]pyridazine] 200 mg, 865.51 ⁇ mol
  • (1R,2R)-2-aminocyclohexan-1-ol 2
  • the sealed tube was heated at 180°C for 3 hours in a microwave reactor. LC-MS showed the desired mass was detected.
  • the mixture was purified by preparative HPLC (Boston Green ODS-5 ⁇ m, 30 mm x 150 mm column) using a gradient of 21 to 61% ACN in water (with formic acid).
  • the crude product was purified by flash chromatography (ISCO® 10 g SepaFlash® silica gel column) using a gradient of 0 to 10% EtOAc in PE (30 mL/min).
  • the title compound of Preparation 80 was obtained as a yellow solid (70 mg).
  • PREPARATION 82 4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-5'H,7'H- spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazine] and 1'-chloro-4'-(2-(methoxymethoxy)-4- methylphenyl)-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazine] [0282] To a mixture of 1',4'-dichloro-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,4- d]pyridazine] (310 mg, 1.34 mmol) in dioxane (4 mL) and water (1 mL) were added 2-(2- (methoxymethoxy)-4-methylphenyl)-4,4,5,5-t
  • PREPARATION 83 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazine
  • STEP 1 1-(8-oxabicyclo[3.2.1]oct-2-en-3-yl)pyrrolidine
  • TsOH 2,6-oxabicyclo[3.2.1]octan-3-one
  • pyrrolidine 23.69 g, 332.93 mmol, 27.80 mL.
  • PREPARATION 84 (1R,2R)-2-(((5S,8R)-1-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-4-yl)amino)cyclohexan-1-ol
  • PREPARATION 85 (1R,2R)-2-(((5R,8S)-1-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-4-yl)amino)cyclohexan-1-ol
  • Starting materials 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazine (1 g, 4.33 mmol)
  • (1R,2R)-2-aminocyclohexanol (1.25 g, 10.82 mmol)
  • DIPEA 1,4-dichlor
  • the sealed tube was heated at 180°C for 3 hours in a microwave reactor. LC-MS showed starting material was consumed completely and one main peak with desired mass was detected.
  • the reaction mixture was concentrated under reduced pressure to remove solvent.
  • the residue was purified by flash chromatography (ISCO® 40 g SepaFlash® silica gel column) using a gradient of 0 to 10% MeOH/DCM (35 mL/min) to give a mixture of stereoisomers as a colorless oil (1.2 g, crude with NMP).
  • the stereoisomers were separated by chiral SFC (DAICEL CHIRALPAK® AD-10 ⁇ m, 30 mm x 250 mm column) using a mobile phase of CO2 and 40% iPrOH (with 0.1% NH3OH).
  • PREPARATION 86 4-chloro-1-(4-cyclopropyl-2-(methoxymethoxy)phenyl)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine
  • the crude product was further purified by SFC (REGIS (S,S) WHELK-O® 1-5 ⁇ m, 30 mm x 250 mm column) using a mobile phase of CO2 and 45% EtOH (with 0.1% NH3OH) to give the title compound as a white solid (600 mg, 24.8%).
  • SFC REGIS (S,S) WHELK-O® 1-5 ⁇ m, 30 mm x 250 mm column
  • PREPARATION 87 4-chloro-1-(4-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine
  • PREPARATION 88 1-chloro-4-(4-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine [0295] The title compounds were synthesized like Preparation 86.
  • PREPARATION 89 2-(4-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol
  • PREPARATION 90 2-(1-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-4-yl)-5-(trifluoromethoxy)phenol
  • the title compounds were synthesized like Preparation 86.
  • PREPARATION 91 4'-chloro-1'-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [0300] To a 20 mL vial were added 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazine] (300 mg, 1.30 mmol), 2-(2-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (431 mg, 1.30 mmol), Pd(dppf)Cl2.CH2Cl2 (106 mg, 0.130 mmol), and tripotassium tris(hydrogen phosphate)
  • PREPARATION 92 2-(4'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0302] To a 20 mL vial were added 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazine] (220 mg, 0.952 mmol), (2-hydroxy-4- (trifluoromethyl)phenyl)boronic acid (196 mg, 0.952 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2 (78 mg, 0.0952 mmol), and tripotassium tris(hydrogen phosphate) (406 mg, 1.90 mmol) in 1,4- dioxane (6.8041 mL) and water (1.7
  • the reaction was heated to 80°C and allowed to stir overnight.
  • the reaction mixture was allowed to cool to room temperature and was extracted with EtOAc (2 x 20 mL) and water (20 mL).
  • the organics were dried with MgSO4 and filtered.
  • the solution was concentrated with silica gel and purified by flash chromatography, using a gradient of 0 to 50% EtOAc in heptane, to give the title compound as the first eluting compound (71 mg, 20.9%).
  • PREPARATION 93 4'-chloro-1'-(4-(methoxymethoxy)-2,3-dihydro-1H-inden-5- yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]
  • PREPARATION 94 1'-chloro-4'-(4-(methoxymethoxy)-2,3-dihydro-1H-inden-5- yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]
  • a microwave vial was charged with 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane- 1,7'-pyrano[3,4-d]pyridazine] (178 mg 0.769 mmol), 2-(4-(4-chloro-1'-
  • the vial was capped and a stream of nitrogen was bubbled through the solution for 15 minutes.
  • the reaction mixture was heated to 100°C in a microwave reactor and stirred for 3 hours.
  • the reaction was quenched with saturated aq NH4Cl and the mixture extracted with DCM.
  • the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • the residue was purified by flash chromatography (ISCO® 120g SepaFlash® silica gel column) using a gradient of 0 to 50% EtOAc in heptane (40 mL/min).
  • the title compound of Preparation 93 was obtained as pale- yellow oil (97.6 mg, 34%).
  • PREPARATION 95 (1R,2R)-2-((1'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclopentan-1-ol
  • (1R,2R)-2-aminocyclopentan-1-ol (2.19 g, 21.6 mmol
  • NaI (6.49 g, 43.3 mmol
  • DIPEA 15 mL, 86.6 mmol
  • the reaction mixture was diluted with H 2 O (200 mL) to furnish a brown solution.
  • the crude product was extracted with EtOAc (2 x 200 mL). The organic extracts were combined, dried over Na 2 SO 4 , filtered, rinsed with EtOAc, and concentrated via rotary evaporation to provide the crude product as a brown oil (7.25 g).
  • the crude material was dissolved in toluene (10 mL), concentrated via rotary evaporation, reconstituted in toluene (8 mL) and purified via medium pressure chromatography (RediSep ® Rf Gold 330 g silica gel column) using a gradient of 0 to 100% EtOAc in heptane.
  • the early fractions were combined, concentrated via rotary evaporation, and dried in vacuo to provide the title compound as an orange oil (crude).
  • the oil was dissolved in iPrOAc (5 mL) at reflux and cooled to room temperature.
  • the resulting solid was filtered, rinsed with iPrOAc (3 x 1 mL), and dried in vacuo to provide the title compound as an ivory solid (115.6 mg, 4.5%).
  • the filtrate and the mixed fractions were combined and purified via medium pressure chromatography using a gradient of 1 to 100% EtOAc in heptane.
  • the early fractions were combined, concentrated via rotary evaporation, and dried in vacuo to provide a second crop of the title compound (340.0 mg, 13.3%) as a white solid.
  • PREPARATION 96 4'-chloro-1'-(2-(methoxymethoxy)-6-methyl-4- (trifluoromethyl)phenyl)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazine] [0309] The title compound was synthesized like Preparation 86.
  • PREPARATION 97 4'-chloro-1'-(4-chloro-2-(methoxymethoxy)-6-methylphenyl)- 4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazine] [0311] The title compound was synthesized like Preparation 86.
  • PREPARATION 98 2-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane
  • STEP 1 4-bromo-3-(methoxymethoxy)benzaldehyde
  • PREPARATION 99 4'-chloro-1'-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [0320] A mixture of 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazine] (173 mg, 748.66 ⁇ mol), 2-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (235.18 mg, 748.66 ⁇ mol), Pd(dppf)Cl 2 (109.56 mg, 149.73 ⁇ mol), Cs2CO3 (975.72 mg, 2.99 m
  • PREPARATION 100 2-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane [0322] To a mixture of 1-cyclopropyl-3-(methoxymethoxy)benzene (2 g, 11.22 mmol) and TMEDA (2.74 g, 23.57 mmol, 3.56 mL) in THF (20 mL) was added n-BuLi (2.5M in n- hexane) (2.5 M, 9.43 mL) in one portion at 0°C under N 2 .
  • n-BuLi 2.5M in n- hexane
  • the residue was purified by flash chromatography (ISCO® 12 g SepaFlash® silica gel column) using a gradient of 0 to 5% EtOAc in PE (40 mL/min).
  • the product was further purified by preparative HPLC (Welch Ultimate XB-CN-10 ⁇ m, 50 mm x 250 mm) using a gradient of 1 to 17% of EtOH in hexane.
  • the title compound was obtained as a colorless oil (1.48 g, 39% yield, 90% purity).
  • PREPARATION 101 4'-chloro-1'-(4-cyclopropyl-2-(methoxymethoxy)phenyl)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]
  • the product was purified by SFC (DAICEL CHIRALPAK® AD-H-5 ⁇ m, 30 mm x 250 mm column) using a mobile phase of CO2 and 30% EtOH (with 0.1% NH3OH). The title compound was obtained as a yellow solid (109 mg, 13.1% yield, 96.7% purity).
  • PREPARATION 102 4'-chloro-1'-(2-fluoro-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazine]
  • STEP 1 2-(4'-chloro-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'- yl)-3-fluoro-5-(trifluoromethyl)phenol
  • a mixture of 1',4'-dichloro-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4- d]pyridazine] 200 mg, 0.809 mmol), 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-d
  • PREPARATION 103 4'-chloro-1'-(2-fluoro-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazine]
  • STEP 1 1',4'-dichloro-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazine]
  • PREPARATION 104 1',4'-dichloro-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazine]
  • STEP 1 tert-butyldimethyl(1-(prop-2-yn-1-yl)cyclopropoxy)silane
  • 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)acetaldehyde (11.5 g, 53.64 mmol) in MeOH (90 mL) were added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (20.61 g, 107.29 mmol) and K 2 CO 3 (7.41 g, 53.64 mmol).
  • STEP 2 5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-one
  • a 50-mL flame-dried flask was charged with tert-butyldimethyl(1-(prop-2-yn-1- yl)cyclopropoxy)silane (15.7 g, 74.62 mmol) and THF (40 mL). The solution was cooled to - 78°C and n-BuLi (2.5 M in hexane, 32.83 mL) was added dropwise.
  • STEP 4 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6- dichloropyridazin-4-yl)ethan-1-ol
  • STEP 5 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6- dichloropyridazin-4-yl)ethyl 4-methylbenzenesulfonate [0347] To a solution of 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6- dichloropyridazin-4-yl)ethan-1-ol (5.4 g, 14.31 mmol) in acetone (80 mL) were added K 2 CO 3 (5.93 g, 42.93 mmol) and toluenesulfonyl chloride (5.46 g, 28.62 mmol).
  • PREPARATION 105 4'-chloro-1'-(2-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazine]
  • a mixture of 1',4'-dichloro-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazine] 150 mg, 611.98 ⁇ mol
  • 2-(2-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 203.25 mg, 611.98 ⁇ mol
  • Pd(dppf)Cl2 89.56 mg, 122.40 ⁇ mol
  • Cs2CO3 797.58 mg
  • the mixture was purified by SFC (DAICEL CHIRALPAK® IK-10 ⁇ m, 50 mm x 250 mm column) using a mobile phase of CO 2 and 15% MeOH (with 0.1% NH3OH).
  • the title compound (retention time: 4.189 min) was obtained as a white solid (131 mg, 50.9% yield, 99% purity).
  • PREPARATION 109 4'-chloro-1'-(4-cyclopropyl-2-(methoxymethoxy)phenyl)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [0359] To a solution of 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazine] (500 mg, 2.16 mmol) and 2-(4-cyclopropyl-2-(methoxymethoxy)phenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (658.19 mg, 2.16 mmol) in dioxane (4 mL) and H 2 O (1 mL) was added Cs2CO3 (2.82 g, 8.66 mmol) followed by Pd(d
  • a mixture of the title compound and its regioisomer was obtained as a white solid (total 350 mg) which was purified by SFC (DAICEL CHIRALPAK® AD-H-5 ⁇ m, 30 mm x 250 mm column) using a mobile phase of CO2 and 30% EtOH (with 0.1% NH3OH).
  • the title compound (retention time: 6.793 min) was obtained as a yellow solid (109 mg, 13.1% yield, 96.7% purity).
  • PREPARATION 110 4'-chloro-1'-(4-cyclopropyl-2,6-difluorophenyl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] and 1'-chloro-4'-(4-cyclopropyl- 2,6-difluorophenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [0361] To a 20 mL vial were added 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazine] (500 mg, 2.16 mmol), 2-(4-cyclopropyl-2,6-difluoro-phenyl)- 4,4,5,5-
  • PREPARATION 111 4'-chloro-1'-(4-cyclopropyl-2-fluorophenyl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] and 1'-chloro-4'-(4-cyclopropyl-2- fluorophenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [0363] To a 20 mL vial fitted with a stir bar were added 1',4'-dichloro-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (500 mg, 2.16 mmol), 2-(4- cyclopropyl-2-fluoro-phenyl)-4,4,5,5-tetramethyl-1,
  • PREPARATION 112 4-chloro-1-(2-(methoxymethoxy)-4-methylphenyl)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine
  • a mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (460 mg, 2.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd(dppf)Cl2.CH2Cl2 (146 mg, 0.2 mmol), and 2-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.61 g, 2.0 mmol) in THF (10.4 mL) and 0.5 M K 3 PO 4 (2.6 mL) was stirred in a sealed
  • the mixture was diluted with saturated NH4Cl (50 mL) and extracted with DCM (50 mL x 3). The organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated to give a mixture of regioisomers, which were separated by flash chromatography (ISCO® 80 g x 2 stacked silica columns) using heptane/dioxane (4:1). The first eluting isomer was assigned as the title compound (75 mg, 20.45%).
  • PREPARATION 114 1',4'-dichloro-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazine]
  • STEP 1 1-(2,2-dimethoxyethyl)cyclopropan-1-ol
  • the reaction mixture was diluted with THF (500 mL) and quenched with aq NH 4 Cl (2000 mL). The resulting white precipitate was filtered off and the filtrate was extracted with EtOAc (1000 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • STEP 2 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)acetaldehyde
  • STEP 3 tert-butyl-dimethyl-(1-prop-2-ynylcyclopropoxy)silane
  • 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)acetaldehyde (11.5 g, 53.64 mmol) in MeOH (90 mL) were added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (20.61 g, 107.29 mmol) and K 2 CO 3 (7.41 g, 53.64 mmol). The mixture was stirred at 0°C for 10 hours.
  • STEP 4 5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-one
  • a 50-mL flame-dried flask was charged with tert-butyl-dimethyl-(1-prop-2- ynylcyclopropoxy)silane (15.7 g, 74.62 mmol) and THF (40 mL). The solution was cooled to -78°C and n-BuLi (2.5 M in hexane, 32.83 mL) was added dropwise.
  • STEP 6 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6- dichloropyridazin-4-yl)ethan-1-ol
  • STEP 7 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6- dichloropyridazin-4-yl)ethyl 4-methylbenzenesulfonate [0382] To a solution of 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6- dichloropyridazin-4-yl)ethan-1-ol (5.4 g, 14.31 mmol) in acetone (80 mL) was added K 2 CO 3 (5.93 g, 42.93 mmol) and TsCl (5.46 g, 28.62 mmol).
  • STEP 8 1',4'-dichloro-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazine]
  • TBAF 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6- dichloropyridazin-4-yl)ethyl 4-methylbenzenesulfonate (4.45 g, 8.37 mmol) in THF (250 mL) was added TBAF (1 M, 20.93 mL). The mixture was stirred at -20°C for 3 hours.
  • PREPARATION 115 and PREPARATION 116 (1R,2R)-2-(((5R,8S)-1-chloro- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclopentan-1-ol and (1R,2R)-2-(((5S,8R)-1-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4- yl)amino)cyclopentan-1-ol [0386] The title compounds were synthesized like Preparations 84 and 85.
  • PREPARATION 117 1'-chloro-N-((1R,2R)-2-methoxycyclopentyl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-amine
  • a mixture of 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazine] (0.20 g, 0.844 mmol)
  • (1R,2R)-2-methoxycyclopentan-1-amine hydrochloride (0.32 g, 2.11 mmol
  • sodium iodide (0.63 g, 4.22 mmol)
  • DIPEA 1.5 mL, 8.44 mmol
  • the reaction mixture was transferred to a 100 mL separatory funnel and the layers were separated. The bottom layer was diluted with H 2 O (20 mL) to furnish a brown solution.
  • the crude product was extracted with EtOAc (2 x 20 mL). The organic extracts were combined, dried over Na 2 SO 4 , filtered, rinsed with EtOAc, and concentrated via rotary evaporation to provide the crude product as a brown oil (0.864 g).
  • PREPARATION 118 1'-chloro-N-((1R,2R)-2-methoxycyclobutyl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-amine
  • 1',4'-dichloro-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] 330 mg, 1.43 mmol
  • DIPEA 2.5 mL, 14.3 mmol
  • (1R,2R)-2-methoxycyclobutanamine 361 mg, 3.57 mmol
  • NMP 7.5 mL
  • PREPARATION 119 1'-chloro-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-amine
  • 3S,4R 3-methoxytetrahydro-2H-pyran-4-amine
  • 1',4'-dichloro-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] 500 mg, 2.16 mmol
  • DIPEA 3.8 mL, 21.6 mmol
  • sodium iodide 1622 mg, 10.8 mmol
  • the reaction mixture was stirred in a Biotage microwave reactor at 180°C for 1 hour and then extracted with EtOAc (2 x 50 mL) and brine (50 mL). The organics were separated and dried with MgSO4. The solution was filtered, concentrated under reduced pressure, and purified by flash chromatography, using a gradient of 20 to 80% EtOAc in heptane, to give the title compound as the first eluting peak (21 mg, 2.98%).
  • PREPARATION 120 (1R,2R)-2-((1'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclobutan-1-ol
  • 1R,4'-dichloro-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] 600 mg, 2.60 mmol
  • DIPEA 4.5 mL, 26.0 mmol
  • (1R,2R)-2-aminocyclobutan-1-ol (566 mg, 6.49 mmol)
  • sodium iodide (1946 mg, 13.0 mmol) in NMP (10 mL).
  • the reaction mixture was heated in a Biotage microwave reactor at 180°C for 1 hour and then extracted with EtOAc (2 x 50 mL) and brine (50 mL). The organics were separated, dried with MgSO4, filtered and concentrated under reduced pressure. The resulting oil was purified by flash chromatography, eluting with a gradient of 0 to 100% EtOAc in heptane, to give the title compound as the first eluting peak (91 mg, 11%).
  • EXAMPLE 233 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7',8'- dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol
  • STEP 1 N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-1'-(2-(methoxymethoxy)-4- methylphenyl)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazin]-4'-amine
  • EXAMPLE 234 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7',8'- dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol [0401] STEP 1: N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-4'-(2-(methoxymethoxy)-4- methylphenyl)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazin]-1'-amine [0402] To a mixture of 1'-chloro-4'-(2-(methoxymethoxy)-4-methylphenyl)-7',8'- dihydrospiro[cyclopropane-1,5'-pyrano[3,4
  • STEP 2 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7',8'- dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol [0404] A mixture of N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-4'-(2-(methoxymethoxy)- 4-methylphenyl)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazin]-1'-amine (59 mg, 133.33 ⁇ mol) in DCM (3 mL) and TFA (0.6 mL) was stirred at 28°C for 2 hours.
  • EXAMPLE 235 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol
  • EXAMPLE 236 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol
  • STEP 1 N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-1'-(2-(methoxymethoxy)-4- methylphenyl)-5',8'-dihydrospiro[
  • STEP 2 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol and 2-(4'- (((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0410] To a mixture of N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-1'-(2- (methoxymethoxy)-4-methylphenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyr
  • Example 236 The title compound of Example 236 was obtained as a white solid (15.8 mg, 100% purity).
  • 1 H NMR (400 MHz, CDCl 3 ) ⁇ ppm 0.48 - 0.59 (m, 2 H), 0.88 (s, 1 H), 0.91 - 0.98 (m, 2 H), 1.70 - 1.90 (m, 1 H), 2.31 - 2.38 (m, 4 H), 2.38 - 2.48 (m, 2 H), 2.48 - 2.62 (m, 2 H), 2.70 (br s, 1 H), 2.96 (s, 2 H), 3.08 (br s, 1 H), 4.54 (br s, 3 H), 4.80 (br s, 2 H), 6.75 (d, J 8.1 Hz, 1 H), 6.95 (s, 1 H), 7.30 (br s, 1 H); ESI-MS m/z [M+H] + 399.1.
  • EXAMPLE 237 5-chloro-2-((5R,8S)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3- yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol [0412] EXAMPLE 238: 5-chloro-2-((5S,8R)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3- yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol [0413] A mixture of 5-chloro-2-(4-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-1-yl)phenol (160 mg,
  • reaction mixture was concentrated under vacuum to give a crude product mixture, which was purified by preparative HPLC (Method A) using a gradient of 10 to 30% ACN (0.035% TFA) in water (0.005% TFA).
  • a TFA salt of the title compound of Example 237 was obtained as a colorless oil (5.5 mg, 2.1%).
  • EXAMPLE 239 5-chloro-2-((5S,8R)-1-(((3R,5R)-5-fluoro-1-methylpiperidin-3- yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol [0415] EXAMPLE 240: 5-chloro-2-((5R,8S)-1-(((3R,5R)-5-fluoro-1-methylpiperidin-3- yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol [0416] A mixture of 5-chloro-2-(1-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-4-yl)phenol (160 mg,
  • a TFA salt of the title compound of Example 240 was obtained as a pink oil (16 mg, 6.0%).
  • EXAMPLE 241 (R)-5-methyl-2-(1-((1-methylpiperidin-3-yl)amino)-7,8-dihydro- 5H-pyrano[3,4-d]pyridazin-4-yl)phenol [0418] A mixture of 1-chloro-4-(2-(methoxymethoxy)-4-methylphenyl)-7,8-dihydro-5H- pyrano[3,4-d]pyridazine (60 mg, 0.187 mmol), (R)-1-methylpiperidin-3-amine (26 mg, 0.224 mmol), Pd 2 (dba) 3 (17 mg, 0.0187 mmol), R-BINAP (23 mg, 0.0374 mmol), and Cs 2 CO 3 (183 mg, 0.561 mmol) in toluene (4.8 mL) was purged with nitrogen for 5 minutes, then heated at 100°C under nitrogen overnight.
  • EXAMPLE 242 (R)-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-7,8-dihydro- 5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol
  • EXAMPLE 243 (R)-2-(1-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-7,8-dihydro- 5H-pyrano[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol [0421] To a mixture of (R)-2-(3-((1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4- yl)amino)piperidin-1-yl)ethan-1-ol and (R)-2-(3-(((4-chloro-7,8-
  • Example 243 The title compound of Example 243 was obtained as a white solid (30 mg, 26%).
  • EXAMPLE 244 (R)-2-(4-((1-(2-methoxyethyl)piperidin-3-yl)amino)-7,8-dihydro- 5H-pyrano[3,4-d]pyridazin-1-yl)-5-methylphenol [0423] A mixture of 4-chloro-1-[2-(methoxymethoxy)-4-methyl-phenyl]-7,8-dihydro-5H- pyrano[3,4-d]pyridazine (61 mg, 0.190 mmol), (R)-1-(2-methoxyethyl)piperidin-3-amine dihydrochloride (44 mg, 0.190 mmol), Pd 2 (dba) 3 (17 mg, 0.0190 mmol), R-BINAP (24 mg, 0.0380 mmol), and Cs2CO3 (248 mg, 0.761 mmol) in toluene (6 mL) was purged with nitrogen for 5
  • EXAMPLE 245 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8- dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [0425] A mixture of 1-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-7,8-dihydro- 5H-pyrano[3,4-d]pyridazin-4-amine (50 mg, 166.25 ⁇ mol), (2-hydroxy-4- (trifluoromethyl)phenyl)boronic acid (51.35 mg, 249.37 ⁇ mol), Pd(dppf)Cl 2 .CH 2 Cl 2 (13.58 mg, 16.62 ⁇ mol), and Cs 2 CO 3 (216.66 mg, 664.98 ⁇ mol) in a mixture of dioxane (2 m
  • EXAMPLE 246 2-((5R,8S)-1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)- 5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4-d]pyridazin-4-yl)-5-methylphenol [0427] A mixture of 2-((5R,8S)-1-chloro-5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4- d]pyridazin-4-yl)-5-methylphenol (40 mg, 0.131 mmol), Cs 2 CO 3 (128 mg, 0.4 mmol), Pd 2 (dba) 3 (12 mg, 0.0131 mmol), R-BINAP (16 mg, 0.0263 mmol), and (3R,5R)-5-fluoro-1- methylpiperidin-3-amine dihydrochloride (54 mg, 0.263
  • the title compound was obtained as a yellow oil (14 mg, 27%).
  • EXAMPLE 247 2-((5R,8S)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)- 5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4-d]pyridazin-1-yl)-5-methylphenol [0429] A mixture of 2-((5R,8S)-4-chloro-5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4- d]pyridazin-1-yl)-5-methylphenol (40 mg, 0.131 mmol), Cs 2 CO 3 (128 mg, 0.4 mmol), Pd 2 (dba) 3 (12 mg, 0.0131 mmol), R-BINAP (16 mg, 0.0263 mmol), and (3R,5R)-5-fluoro-1- methylpiperidin-3-amine dihydrochloride (54 mg, 0.263
  • the title compound was obtained as an orange oil (3.0 mg, 6%).
  • EXAMPLE 248 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol [0431] EXAMPLE 249: 2-((5R,8S)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol [0432] EXAMPLE 250: 2-((5S,8R)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[
  • the reaction mixture was added to solution of TFA (2 mL) in DCM (10 mL), stirred for 1 hour at 60°C, and then concentrated under vacuum to give a crude product mixture.
  • the product mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a 10 to 30% gradient of ACN (0.035% TFA) in water (0.005% TFA) to give the title compound of Example 248 as a mixture of diastereomers.
  • the diastereomers were separated by preparative SFC (Waters, ChiralTech IC, 5 ⁇ m, 21 mm ID x 150 mm column) using a gradient of 40 to 50% MeOH (with 0.1% NH4OH) in CO2.
  • the first product was the title compound of Example 249, which was obtained as a yellow semi-solid (31 mg, 9.0%).
  • 1 H NMR 400 MHz, CD3OD
  • the second product was the title compound of Example 250, which was obtained as a yellow-semi solid (37 mg, 11%).
  • 1 H NMR 400 MHz, CD 3 OD
  • ppm 1.62 - 1.89 (m, 2 H), 1.95 - 2.04 (m, 1 H), 2.27 (br s, 5 H), 2.30 (s, 3 H), 2.31 (s, 3 H), 2.32 - 2.39 (m, 1 H), 2.86 - 3.06 (m, 2 H), 3.08 - 3.18 (m, 1 H), 4.63 - 4.78 (m, 2 H), 4.91 - 5.01 (m, 1 H), 5.11 - 5.17 (m, 1 H), 6.69 - 6.76 (m, 2 H), 7.04 (d, J 7.53 Hz, 1 H); ESI-MS [M+H] + calc'd for C 22 H 27 FN 4 O 2 398.21; found 399.2.
  • EXAMPLE 251 2-(1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-methylphenol
  • EXAMPLE 252 2-((5S,8R)-1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-methylphenol
  • reaction mixture was added to solution of TFA (2 mL) in DCM (10 mL), stirred for 1 hour at 60°C, and then concentrated under vacuum to give a crude product mixture.
  • the product mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10 to 30% ACN (0.035% TFA) in water (0.005% TFA).
  • a TFA salt of the title compound of Example 251 was obtained as a light-yellow semi-solid (55 mg, 12.4%).
  • EXAMPLE 253 5-chloro-2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol
  • a mixture of 5-chloro-2-(1-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-4-yl)phenol 100 mg, 0.309 mmol
  • Cs2CO3 (302 mg, 0.93 mmol
  • Pd2(dba)3 28 mg, 0.0309 mmol
  • R-BINAP 108 mg
  • EXAMPLE 254 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-4,5,5',8'- tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0440] A mixture of rac-4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-4,5,5',8'- tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine] (17 mg, 0.0451 mmol), (3R,5R)-5- fluoro-1-methylpiperidin-3-amine dihydrochloride (11 mg, 0.0541 mmol), Pd 2 (dba) 3 (4.1 mg, 0.00451 mmol), R-BINAP (5.6 mg
  • EXAMPLE 255 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-4,5,5',8'- tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol [0442] A mixture of rac-1'-chloro-4'-(2-(methoxymethoxy)-4-methylphenyl)-4,5,5',8'- tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine] (80 mg, 0.212 mmol), (3R,5R)-5- fluoro-1-methylpiperidin-3-amine dihydrochloride (52 mg, 0.255 mmol), Pd 2 (dba) 3 (19 mg, 0.0212 mmol), R-BINAP (26 mg, 0.0425
  • EXAMPLE 256 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)- 2,3,5,5',6,8'-hexahydrospiro[pyran-4,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0444] The title compound was synthesized from starting material 1,9- dioxaspiro[5.5]undecan-4-one, using a procedure analogous to Example 254.
  • EXAMPLE 257 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0446]
  • EXAMPLE 258 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)-5-(trifluoromethyl)phenol [0447] To a stirred solution of a mixture of 4'-chloro-N-((3R,5R)-5-fluoro-1- methylpiperidin-3-yl)-5',8'-di
  • Example 257 The title compound of Example 257 was obtained as a white solid (8 mg, 38%).
  • the reaction mixture was then concentrated under vacuum to give the crude product mixture.
  • the product mixture was purified by Preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10 to 30% ACN (0.035% TFA) in water (0.005% TFA).
  • the title compound was obtained as a yellow semi-solid (25 mg, 19.6%).
  • EXAMPLE 260 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5,6,7,8- tetrahydro-5,8-epoxyphthalazin-1-yl)-5-methylphenol [0451] A mixture of 2-(4-chloro-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl)-5- methylphenol (10 mg, 0.0346 mmol), Cs2CO3 (34 mg, 0.104 mmol), Pd2(dba)3 (3.2 mg, 0.00346 mmol), R-BINAP (4.3 mg, 0.0069 mmol), and (3R,5R)-5-fluoro-1-methylpiperidin- 3-amine dihydrochloride (10.6 mg, 0.052 mmol) in toluene (1 mL) was stirred in a sealed tube on metal heating block at 100°C for 16 hours.
  • the reaction mixture was then concentrated under vacuum to give a crude product mixture.
  • EXAMPLE 262 4-fluoro-2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0453] EXAMPLE 263: 4-fluoro-2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol [0454] A mixture of 4'-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-5',8'- dihydrospiro[cyclo[cyclo[
  • Example 263 The title compound of Example 263 was obtained as a white solid (10 mg, 91%).
  • EXAMPLE 264 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol
  • EXAMPLE 265 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)phenol
  • Example 264 The title compound of Example 264 was obtained as a white solid (22 mg).
  • 1 H NMR (400 MHz, CD3OD) ⁇ ppm 0.45 - 0.51 (m, 2 H), 0.82 - 0.88 (m, 2 H), 1.70 - 1.89 (m, 1 H), 2.10 - 2.21 (m, 1 H), 2.26 - 2.45 (m, 5 H), 2.58 - 2.63 (m, 2 H), 2.98 (br t, J 10.26 Hz, 1 H), 3.11 - 3.24 (m, 1 H), 4.49 - 4.59 (m, 2 H), 4.68 - 4.80 (m, 1 H), 4.94 - 5.01 (m, 1 H), 6.85 - 6.96 (m, 2 H), 7.15 - 7.31 (m, 2 H); ESI-MS [M+H] + calc'd for C21H25FN4O2, 384.20; found, 385.4.
  • EXAMPLE 266 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-4,5- dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0459] The title compound was prepared from starting material 1,7-dioxaspiro[4.4]nonan- 3-one, using a procedure analogous to Example 254.
  • EXAMPLE 267 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H- spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0461]
  • the title compound was prepared from starting materials 1,7-dioxaspiro[4.4]nonan- 3-one and (1R,2R)-2-aminocyclohexan-1-ol, using a procedure analogous to Example 254.
  • EXAMPLE 268 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro- 5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol [0463] A mixture of 4-chloro-1-(2-(methoxymethoxy)-4-methylphenyl)-6,7,8,9-tetrahydro- 5H-5,8-epoxycyclohepta[d]pyridazine (107 mg, 0.31 mmol), Cs2CO3 (302 mg, 0.93 mmol), Pd2(dba)3 (28 mg, 0.031 mmol), R-BINAP (39 mg, 0.062 mmol), and (1R,2R)-2- aminocyclohexan-1-ol (71 mg, 0.62 mmol) in toluene (1 mL) was stirred in a
  • reaction mixture was added to solution of TFA (2 mL) and DCM (10 mL), stirred for 1 hour at 60°C, and concentrated under vacuum to give a crude product mixture.
  • the product mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10 to 30% ACN (0.035% TFA) in water (0.005% TFA). The title compound was obtained as a yellow solid (30 mg, 25%).
  • EXAMPLE 269 2-(4-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol
  • reaction mixture was added to solution of TFA (2 mL) and DCM (10 mL), stirred for 1 hour under 60°C, and concentrated under vacuum to give a crude product mixture.
  • the product mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10 to 30% ACN (0.035% TFA) in water (0.005% TFA).
  • the title compound was obtained as a yellow oil (50 mg, 44%).
  • EXAMPLE 270 2-(4-(((1R,3R)-3-hydroxy-3-methylcyclobutyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol [0467] A mixture of 4-chloro-1-(2-(methoxymethoxy)-4-methylphenyl)-6,7,8,9-tetrahydro- 5H-5,8-epoxycyclohepta[d]pyridazine (107 mg, 0.31 mmol), Cs 2 CO 3 (302 mg, 0.93 mmol), Pd2(dba)3 (28 mg, 0.031 mmol), R-BINAP (39 mg, 0.062 mmol), and (1R,3R)-3-amino-1- methylcyclobutan-1-ol (31 mg, 0.31 mmol) in toluene (1 mL
  • the reaction mixture was added to solution of TFA (2 mL) and DCM (10 mL), stirred for 1 hour at 60°C, and concentrated under vacuum to give a crude product mixture.
  • the product mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10 to 30% ACN (0.035% TFA) in water (0.005% TFA). The title compound was obtained as a yellow oil (53 mg, 47%).
  • EXAMPLE 271 3-fluoro-2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol
  • reaction mixture was added to solution of TFA (2 mL) and DCM (10 mL), stirred for 1 hour at 60°C, and concentrated under vacuum to give a crude product mixture.
  • EXAMPLE 272 3-fluoro-2-(1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-methylphenol
  • the reaction mixture was added to solution of TFA (2 mL) and DCM (10 mL), stirred for 1 hour at 60°C, and concentrated under vacuum to give a crude product mixture.
  • EXAMPLE 274 (R)-2-(1'-((1-(2-fluoroethyl)piperidin-3-yl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol
  • EXAMPLE 275 2-(1'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol
  • EXAMPLE 276 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol
  • EXAMPLE 277 2-(4-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8- dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-methylphenol
  • 1 H NMR 400 MHz, CD3OD
  • EXAMPLE 278 2-(1-(((1R,2R)-2-hydroxycyclohexyl)oxy)-7,8-dihydro-5H- pyrano[3,4-d]pyridazin-4-yl)-5-methylphenol
  • EXAMPLE 279 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-7',8'- dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol
  • EXAMPLE 280 2-(4'-(((1R,2R)-2-hydroxy-2-methylcyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol
  • 1 H NMR 400 MHz, CDCl3
  • ⁇ ppm 0.43 - 0.60 m, 2 H
  • EXAMPLE 281 2-((R*)-1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-4,5- dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-4'-yl)-5-methylphenol [0490]
  • 1 H NMR 400 MHz, CD 3 OD) ⁇ ppm 1.21 - 1.31 (m, 1 H), 1.69 - 1.88 (m, 1 H), 2.04 - 2.12 (m, 1 H), 2.17 - 2.28 (m, 2 H), 2.33 (s, 4 H), 2.39 (s, 3 H), 2.41 - 2.52 (m, 1 H), 2.99 - 3.28 (m, 2 H), 3.78 (s, 3 H), 4.70 - 4.78 (m, 1 H), 4.91 (br s, 1 H), 6.73 - 6.79 (m, 2 H), 6.99 -
  • EXAMPLE 282 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-7H-spiro[furo[3,4- d]pyridazine-5,3'-oxetan]-1-yl)-5-methylphenol
  • 1 H NMR 400 MHz, CD 3 OD
  • EXAMPLE 283 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7H- spiro[furo[3,4-d]pyridazine-5,3'-oxetan]-1-yl)-5-methylphenol
  • 1 H NMR 400 MHz, CD3OD
  • ppm 1.88 - 2.05 (m, 1 H), 2.17 - 2.30 (m, 1 H), 2.36 (d, J 14.43 Hz, 7 H), 2.52 - 2.66 (m, 1 H), 2.71 - 2.81 (m, 1 H), 3.01 - 3.08 (m, 1 H), 4.75 - 5.01 (m, 4 H), 5.09 - 5.16 (m, 2 H), 5.39 (s, 2 H), 6.73 - 6.78 (m, 1 H), 6.82 - 6.86 (m, 1 H), 6.98 - 7.03 (m, 1 H); ESI
  • EXAMPLE 284 5-methyl-2-((5RS,8SR)-4-(((R)-tetrahydrofuran-3-yl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol
  • 1 H NMR 400 MHz, CD3OD
  • EXAMPLE 286 5-chloro-2-((5S*,8R*)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol [0500] 1 H NMR (400 MHz, CD3OD) ⁇ ppm 1.41 - 1.70 (m, 4 H), 1.81 - 2.11 (m, 4 H), 2.26 (br s, 4 H), 3.06 - 3.13 (m, 1 H), 3.66 (s, 1 H), 3.76 - 3.86 (m, 1 H), 4.74 - 4.78 (m, 1 H), 5.29 - 5.40 (m, 2 H), 6.92 - 7.05 (m, 2 H), 7.19 - 7.27 (m, 1 H); ESI-MS m/z [M+H] + calc'd for C 20 H 23 N 3
  • EXAMPLE 287 5-chloro-2-((5R*,8S*)-4-((((S)-tetrahydrofuran-2- yl)methyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol
  • 1 H NMR 400 MHz, CD 3 OD
  • EXAMPLE 288 5-chloro-2-((5S*,8R*)-4-((((S)-tetrahydrofuran-2- yl)methyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol
  • 1 H NMR 400 MHz, CD3OD
  • ppm 1.65 - 1.79 (m, 2 H), 1.92 - 2.05 (m, 2 H), 2.05 - 2.19 (m, 2 H), 2.21 - 2.37 (m, 3 H), 3.06 - 3.17 (m, 1 H), 3.52 - 3.61 (m, 1 H), 3.63 - 3.70 (m, 1 H), 3.77 - 3.84 (m, 1 H), 3.88 - 3.96 (m, 1 H), 4.19 - 4.28 (m, 1 H), 4.74 - 4.79 (m, 1 H), 5.22 - 5.29
  • EXAMPLE 290 5-cyclopropyl-4-fluoro-2-(1-(((1R,2R)-2- hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4- yl)phenol
  • 1 H NMR 400 MHz, CD3OD
  • ppm 0.72 - 0.84 ppm, 2 H
  • EXAMPLE 291 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'- dihydrospiro[oxetane-3,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol
  • 1 H NMR 400 MHz, CD 3 OD
  • ppm 1.31 - 1.48 (m, 4 H), 1.71 - 1.82 (m, 2 H), 2.05 - 2.23 (m, 2 H), 2.32 (s, 3 H), 2.83 - 3.01 (m, 2 H), 3.54 - 3.64 (m, 1 H), 4.02 - 4.10 (m, 1 H), 4.51 - 4.55 (m, 2 H), 4.57 - 4.61 (m, 2 H), 4.70 - 4.74 (m, 2 H), 6.71 - 6.74 (m, 1 H), 6.74 - 6.79 (m, 1 H), 7.03 -
  • EXAMPLE 292 2-(4'-(((1R,2S)-2-hydroxy-2-methylcyclohexyl)amino)-7',8'- dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol
  • 1 H NMR 400 MHz, CD3OD
  • EXAMPLE 293 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'- dihydrospiro[oxetane-3,7'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol
  • 1 H NMR 400 MHz, CD3OD
  • EXAMPLE 294 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'- dihydrospiro[oxetane-3,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol
  • 1 H NMR 400 MHz, CD3OD
  • EXAMPLE 296 3-fluoro-2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol
  • 1 H NMR 400 MHz, CD 3 OD
  • EXAMPLE 297 5-cyclopropyl-3-fluoro-2-(4-(((1R,2R)-2- hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1- yl)phenol
  • 1 H NMR 400 MHz, CD 3 OD
  • EXAMPLE 300 2-(4-(((1S,3S)-3-fluoro-5-methylcyclohexyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol
  • 1 H NMR 400 MHz, CD3OD
  • ppm 2.33 (br d, J 4.40 Hz, 7 H)
  • 2.49 - 2.71 (m, 2 H), 3.00 - 3.07 (m, 3 H), 3.08 - 3.23 (m, 2 H), 3.77 - 3.95 (m, 2 H), 4.79 - 4.83 (m, 1 H), 5.24 - 5.42 (m, 2 H), 7.30 (s, 2 H), 7.56 (br d, J 7.70 Hz, 1 H);
  • ESI-MS m/z [M+H] + calc'd for C22H24
  • EXAMPLE 301 5-cyclopropyl-2-((5R,8S)-4-(((3R,5R)-5-fluoro-1-methylpiperidin- 3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol [0530] EXAMPLE 302: 5-cyclopropyl-2-((5S,8R)-4-(((3R,5R)-5-fluoro-1-methylpiperidin- 3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol [0531] STEP 1: 1-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-N-((3R,5R)-5-fluoro-1- methylpiperidin-3-yl)
  • STEP 2 5-cyclopropyl-2-((5R,8S)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3- yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol and 5- cyclopropyl-2-((5S,8R)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol [0534] To a solution of 1-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-N-((3R,5R)-5- fluoro-1-methylpiperidin-3-yl)-6,7,8,9-tetra
  • Example 301 The title compound of Example 301 was obtained as a white solid (11.5 mg, 23.7% yield, 99.4% purity).
  • Example 302 The title compound of Example 302 was obtained as a white solid (17.1 mg, 35.3% yield, 99.4% purity).
  • 1 H NMR 400 MHz, CD 3 OD
  • EXAMPLE 303 5-cyclopropyl-2-((5R,8S)-4-(((1R,2R)-2- hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1- yl)phenol
  • STEP 1 (1R,2R)-2-(((5R,8S)-1-(4-cyclopropyl-2-(methoxymethoxy)phenyl)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclohexan-1-ol
  • STEP 2 5-cyclopropyl-2-((5R,8S)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol [0539] To a solution of (1R,2R)-2-(((5R,8S)-1-(4-cyclopropyl-2- (methoxymethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4- yl)amino)cyclohexan-1-ol (300 mg, 664.37 ⁇ mol) in DCM (12 mL) was added TFA (4.61 g, 40.39 mmol, 3 mL).
  • EXAMPLE 304 5-cyclopropyl-2-((5S,8R)-4-(((1R,2R)-2- hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1- yl)phenol [0541] STEP 1: (1R,2R)-2-(((5S,8R)-1-(4-cyclopropyl-2-(methoxymethoxy)phenyl)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclohexan-1-ol [0542] A mixture of (1R,2R)-2-(((5S,8R)-1-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyrida
  • EXAMPLE 305 2-(1'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5'H,7'H- spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol [0546] To a mixture of (1R,2R)-2-((4'-chloro-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,4- d]pyridazin]-1'-yl)amino)cyclohexan-1-ol (70 mg, 225.96 ⁇ mol) in dioxane (2 mL) and H2O (0.5 mL) were added 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (58.19 mg, 248.56 ⁇ mol), Pd(dppf)
  • EXAMPLE 306 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H- spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0548] The title compound was synthesized from starting material (1R,2R)-2- aminocyclohexan-1-ol, using a procedure analogous to Example 254.
  • EXAMPLE 307 2-((S*)-4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro- 2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0550]
  • EXAMPLE 308 2-((R*)-4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro- 2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0551] The title compounds were obtained from chiral separation of Example 306 by supercritical fluid chromatography.
  • EXAMPLE 309 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5'H,7'H- spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol
  • EXAMPLE 310 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5'H,7'H- spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol
  • STEP 1 N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-4'-(2-(methoxymethoxy)-4- methylphenyl)-5'H,7'H-spiro[cyclo[cyclo[cyclo[cyclo[
  • STEP 2 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5'H,7'H- spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol and 2-(4'-(((3R,5R)- 5-fluoro-1-methylpiperidin-3-yl)amino)-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,4- d]pyridazin]-1'-yl)-5-methylphenol [0557] To a mixture of N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-4'-(2- (methoxymethoxy)-4-methylphenyl)-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,
  • Example 310 was obtained as a white solid (80.8 mg).
  • Example 309 The title compound of Example 309 was obtained as a white solid (71 mg).
  • EXAMPLE 311 2-(4-(((R)-tetrahydrofuran-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [0559] Using a procedure analogous to Example 237, the title compound was obtained as a light-yellow oil (3.0 mg, 0.007 mmol, 7%).
  • EXAMPLE 312 2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro- 5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-(trifluoromethyl)phenol [0561] Using a procedure analogous to Example 237, the title compound was obtained as a white semi-solid (8.0 mg, 18%).
  • EXAMPLE 313 2-(4'-(((1R,2S)-2-hydroxy-2-methylcyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0563] STEP 1: (1S,2R)-2-((1'-(2-(methoxymethoxy)-4-methylphenyl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)-1-methylcyclohexan-1- ol [0564] A mixture of 4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyr
  • STEP 2 2-(4'-(((1R,2S)-2-hydroxy-2-methylcyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0566] To a solution of (1S,2R)-2-((1'-(2-(methoxymethoxy)-4-methylphenyl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)-1-methylcyclohexan-1- ol in DCE (1 mL) was added TFA (0.5 mL).
  • the solution was stirred at RT for 3 hours.
  • the solution was concentrated under reduced pressure and purified by HPLC (Gemini 30 mm ID x 150 mm column) using a 10-100% gradient of ACN (0.05% TFA) in water (0.035% TFA) to give the title compound (7.7 mg, 26% over two steps).
  • EXAMPLE 314 2-(4'-(((1R,2S)-3,3-difluoro-2-hydroxycyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0568] The title compound was prepared using a procedure analogous to Example 313.
  • EXAMPLE 315 2-(4'-(((1R,2S)-2-hydroxycyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0570]
  • the title compound was prepared using a procedure analogous to Example 313.
  • EXAMPLE 316 2-(4'-(((1R,3R)-3-hydroxycyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0572]
  • the title compound was prepared using a procedure analogous to Example 313.
  • EXAMPLE 317 2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0574]
  • the title compound was prepared using a procedure analogous to Example 313.
  • EXAMPLE 318 (3R,4S)-4-(((5S,8R)-1-(4-chloro-2-hydroxyphenyl)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)tetrahydrofuran-3-ol
  • R-BINAP (12 mg, 0.0186 mmol)
  • 5- chloro-2-((5R,8S)-4-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1- yl)phenol (15 mg, 0.0464 mmol)
  • Cs 2 CO 3 60 mg, 0.186 mmol
  • (3R,4S)-4- aminotetrahydrofuran-3-ol hydrochloride 26 mg, 186 mmol
  • EXAMPLE 319 5-chloro-2-((5S,8R)-4-((2-methoxy-2-methylpropyl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol
  • the title compound was prepared like Example 318, using R-BINAP (12 mg, 0.0186 mmol), 5-chloro-2-((5R,8S)-4-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-1-yl)phenol (15 mg, 0.0464 mmol), Cs 2 CO 3 (60 mg, 0.186 mmol), 2-methoxy-2-methylpropan-1-amine (19.2 mg, 0.186 mmol), and palladium(II) acetate (2.1 mg, 0.00928 mmol) in toluene (0.8 mL) to
  • EXAMPLE 320 5-chloro-2-((5S,8R)-4-((2-hydroxy-2-methylpropyl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol [0580] The title compound was prepared like Example 318, using R-BINAP (12 mg, 0.0186 mmol), 5-chloro-2-((5R,8S)-4-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-1-yl)phenol (15 mg, 0.0464 mmol), Cs 2 CO 3 (60 mg, 0.186 mmol), 1-amino-2-methyl-propan-2-ol (16.55 mg, 0.186 mmol),
  • EXAMPLE 322 4-(((5S,8R)-1-(4-chloro-2-hydroxyphenyl)-6,7,8,9-tetrahydro-5H- 5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)tetrahydrofuran-3-ol
  • the title compound was prepared like Example 318, using R-BINAP (12 mg, 0.0186 mmol), 5-chloro-2-((5R,8S)-4-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-1-yl)phenol (15 mg, 0.0464 mmol), Cs 2 CO 3 (60 mg, 0.186 mmol), (3R,4S)-4-aminotetrahydrofuran-3-ol hydrochloride (25.9 mg, 0.186 mmol), and palladium(II) acetate (2.1 mg, 0.009
  • EXAMPLE 323 5-chloro-2-((5S,8R)-4-(((R)-tetrahydrofuran-3-yl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol
  • the title compound was prepared like Example 318, using R-BINAP (12 mg, 0.0186 mmol), 5-chloro-2-((5R,8S)-4-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-1-yl)phenol (15 mg, 0.0464 mmol), Cs 2 CO 3 (60 mg, 0.186 mmol), (3R)-tetrahydrofuran-3-amine (16.2 mg, 0.186 mmol), and palladium(II) acetate (2.1 mg, 0.00928 mmol) in toluene
  • EXAMPLE 324 (3S,4R)-4-(((5S,8R)-1-(4-chloro-2-hydroxyphenyl)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol
  • the title compound was prepared like Example 318, using R-BINAP (12 mg, 0.0186 mmol), 5-chloro-2-((5R,8S)-4-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-1-yl)phenol (15 mg, 0.0464 mmol), Cs2CO3 (60 mg, 0.186 mmol), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (28.5 mg, 0.186 mmol), and palladium(II)
  • EXAMPLE 325 2-(4'-(((1R,2R)-2-hydroxycyclobutyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0590] To a 5 mL vial fitted with a stir bar was added R-BINAP (19 mg, 0.0299 mmol), (1R,2R)-2-aminocyclobutanol hydrochloride (37 mg, 0.299 mmol), 4'-chloro-1'-(2- (methoxymethoxy)-4-(trifluoromethyl)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazine] (30 mg, 0.0749 mmol), Cs 2 CO 3 (122 mg, 0.374
  • the reaction mixture was heated at 100°C overnight.
  • the solution was concentrated and stirred in DCM (1.298 mL) and trifluoroacetic acid (0.58 mL, 7.49 mmol) for 3 hours.
  • the reaction mixture was concentrated and extracted with EtOAc (2 x 10 mL) and saturated NaHCO 3 (10 mL). The organics were separated, dried with MgSO 4 , and concentrated under reduced pressure.
  • the resulting solid was dissolved in DMF (1 mL) and MeOH (1 mL).
  • the solution was filtered and purified via Shimadzu preparative HPLC using a TFA-containing mobile phase to give a TFA salt of the title compound (2.3 mg, 7.5%).
  • EXAMPLE 326 rac-5-(4-(((1R,2R)-2-methoxycyclohexyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol
  • the title compound was obtained as a colorless oil (10.0 mg, 24%).
  • EXAMPLE 327 rac-5-(1-(((1R,2R)-2-methoxycyclohexyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-2,3-dihydro-1H-inden-4-ol
  • the title compound was obtained as a colorless oil (14.0 mg, 33%).
  • EXAMPLE 328 2-(1'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)-5-(trifluoromethyl)phenol [0596] The title compound was prepared using a procedure analogous to Example 313.
  • EXAMPLE 329 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-7'H- spiro[cyclobutane-1,5'-furo[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0598]
  • the title compound was prepared from starting material 5-oxaspiro[3.4]octan-7-one, using a procedure analogous to Example 254.
  • EXAMPLE 330 5-chloro-2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0600] A mixture of (1R,2R)-2-((1'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazin]-4'-yl)amino)cyclopentan-1-ol (30 mg, 0.101 mmol), 5-chloro-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (34 mg, 0.132 mmol), XPhos palladacycle G4 (8.7 mg, 0.0101 mmol), and tripotassium phosphate (
  • the reaction mixture was concentrated via rotary evaporation, diluted with in MeOH (1 mL) and DMF (1 mL), filtered through a 0.45 ⁇ m PTFE Membrane filter (VWR), rinsed with MeOH (0.5 mL), and purified via preparative HPLC (Shimadzu) using a gradient of 10 to 100% ACN in H 2 O (0.05% TFA). The appropriate fractions were combined and concentrated via rotary evaporation at 45°C. The resulting mixture was dried in vacuo to provide a crude TFA salt of the title compound (15.0 mg) as a white solid.
  • the TFA salt was dissolved in MeOH (1 mL), passed through a 100 mg Agilent StratoSpheres SPE cartridge (PL-HCO 3 MP SPE) to remove TFA, and the cartridge was rinsed with MeOH (3 x 1 mL). The filtrate was concentrated via rotary evaporation and dried in vacuo to provide the impure title compound as a yellow film.
  • the impure material was dissolved in MeOH (0.5 mL), filtered through a 0.45 ⁇ m PTFE Membrane filter (VWR), rinsed with MeOH (0.5 mL), and purified via preparative HPLC (Shimadzu) using a gradient of 40 to 100% ACN (4:1 ACN/H2O with 10mM NH 4 HCO 3 ) in H 2 O (10mM NH 4 HCO 3 ). The pure fractions were combined and concentrated via rotary evaporation at 45°C. The resulting mixture was dried in vacuo to provide the title compound as a light-yellow solid (7.2 mg, 18%).
  • EXAMPLE 331 5-chloro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0602]
  • the title compound was prepared using a procedure analogous to Example 318, starting from R-BINAP (22 mg, 0.0359 mmol), 5-chloro-2-(4'-chloro-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol (29 mg, 0.0897 mmol), Cs 2 CO 3 (117 mg, 0.359 mmol), (1R,2R)-2-aminocyclohexanol (41.3 mg, 0.359 mmol), and palladium(II) acetate (4.0 mg
  • EXAMPLE 332 5-chloro-2-(4'-(((1R,2R)-2-hydroxycyclobutyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0604] The title compound was prepared using a procedure analogous to Example 318, starting from R-BINAP (22 mg, 0.0359 mmol), 5-chloro-2-(4'-chloro-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol (29 mg, 0.0897 mmol), Cs 2 CO 3 (117 mg, 0.359 mmol), (1R,2R)-2
  • EXAMPLE 334 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-7'H- spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0608]
  • the title compound was prepared from starting material 4-oxaspiro[2.4]heptan-6- one using a procedure analogous to Example 254.
  • EXAMPLE 335 2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0610] To a 5 mL vial fitted with a stir bar were added R-BINAP (28 mg, 0.0449 mmol), (1R,2R)-2-aminocyclopentan-1-ol hydrochloride (62 mg, 0.449 mmol), 4'-chloro-1'-(2- (methoxymethoxy)-4-(trifluoromethyl)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazine] (45 mg, 0.112 mmol), Cs 2 CO 3 (183 mg, 0.112
  • the reaction mixture was heated at 100°C overnight.
  • the solution was concentrated and stirred in DCM (1.947 mL) and trifluoroacetic acid (0.87 mL, 11.2 mmol) for 3 hours.
  • the solution was concentrated and extracted with EtOAc (2 x 10 mL) and saturated NaHCO3 (10 mL). The organics were separated, dried with MgSO4, and concentrated under reduced pressure.
  • the resulting solid was dissolved in DMF (1 mL) and MeOH (1 mL).
  • the solution was filtered and purified via Shimadzu preparative HPLC using a TFA-containing mobile phase. The title compound was obtained as a TFA salt (5.3 mg, 11%).
  • EXAMPLE 336 5-(4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro- 5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol
  • the title compound was obtained as a light-yellow semi-solid (7.0 mg, 18%).
  • EXAMPLE 337 5-(4-(((1R,2R)-2-hydroxycyclobutyl)amino)-6,7,8,9-tetrahydro- 5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol
  • the title compound was obtained as a light-yellow semi-solid (1.2 mg, 3%).
  • EXAMPLE 338 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro- 5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol
  • the title compound was obtained as a light-yellow semi-solid (3.0 mg, 7%).
  • EXAMPLE 339 2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro- 5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-(trifluoromethoxy)phenol [0618] Using a procedure analogous to Example 237, starting from 2-(1-chloro-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-(trifluoromethoxy)phenol, the title compound was obtained as a light-yellow semi-solid (4.8 mg, 11%).
  • EXAMPLE 340 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0620] To a 5 mL vial fitted with a stir bar were added (1R,2R)-2-aminocyclohexan-1-ol (32 mg, 0.280 mmol), 2-(4'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol (25 mg, 0.0701 mmol), Cs2CO3 (114 mg, 0.350 mmol), palladium(II) acetate (1.6 mg, 0.00701 mmol
  • EXAMPLE 341 (S)-2-(4'-((tetrahydrofuran-3-yl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0622] To a 5 mL vial fitted with a stir bar were added (3S)-tetrahydrofuran-3-amine (29 mg, 0.336 mmol), 2-(4'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]- 1'-yl)-5-(trifluoromethyl)phenol (30 mg, 0.0841 mmol), Cs 2 CO 3 (137 mg, 0.420 mmol), palladium(II) acetate (1.9 mg, 0.00841 mmol), and (9,9-d
  • EXAMPLE 342 2-((5R,8S)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [0624] EXAMPLE 343: 2-((5S,8R)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [0625] A mixture of (1R,2R)-2-((1-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-4-yl)amino)cyclo
  • reaction mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10 to 30% ACN (0.035% TFA) in water (0.005% TFA).
  • a TFA salt of the title compound of Example 342 was obtained as a white semi-solid (50.0 mg, 45%).
  • EXAMPLE 344 2-(4-(((1R,2R)-2-hydroxycyclobutyl)amino)-6,7,8,9-tetrahydro- 5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [0627] Using a procedure analogous to Example 237, the title compound was obtained as a yellow oil (6.0 mg, 15%).
  • EXAMPLE 345 (3S,4R)-4-((1-(2-hydroxy-4-(trifluoromethyl)phenyl)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol
  • the title compound was obtained as a light-yellow oil (1.0 mg, 2%).
  • EXAMPLE 346 5-(1'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)-2,3-dihydro-1H-inden-4-ol
  • EXAMPLE 347 (R)-2-(4'-((tetrahydrofuran-3-yl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0633] To a 5 mL vial fitted with a stir bar were added R-BINAP (17 mg, 0.0280 mmol), (3R)-oxolan-3-amine hydrochloride (35 mg, 0.280 mmol), 2-(4'-chloro-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol (25 mg, 0.0701 mmol), Cs 2 CO 3 (114 mg, 0.350 mmol), and palladium(II) acetate (3.1 mg
  • EXAMPLE 348 5-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'-dihydrospiro [cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-2,3-dihydro-1H-inden-4-ol
  • a microwave vial was charged with 4'-chloro-1'-(4-(methoxymethoxy)-2,3-dihydro- 1H-inden-5-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (18.3 mg, 0.049 mmol), (1R,2R)-2-aminocyclohexan-1-ol (5.7 mg, 0.049 mmol), Pd 2 (dba) 3 (4.5 mg, 0.005 mmol), (
  • the vial was capped, and a stream of nitrogen was bubbled through the reaction mixture for 15 minutes.
  • the reaction mixture was heated to 100°C in a microwave reactor and stirred for 3 hours.
  • the reaction was quenched with saturated aq NH4Cl and extracted with DCM.
  • the organic phase was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • a solution of TFA in DCM (1:4, 2.5 mL, 0.02 M) was added to the crude mixture and stirred for 1 hour at 30°C.
  • EXAMPLE 349 5-(1'-(((1R,2R)-2-hydroxycyclobutyl)amino)-5',8'-dihydrospiro [cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)-2,3-dihydro-1H-inden-4-ol
  • a microwave vial was charged with 4'-chloro-1'-(4-(methoxymethoxy)-2,3-dihydro- 1H-inden-5-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (16.7 mg, 0.045 mmol), (1R,2R)-2-aminocyclobutanol (3.9 mg, 0.045 mmol), palladium (II) acetate (2.0 mg, 0.009 mmol), (R)-(
  • the vial was capped, and a steam of nitrogen was bubbled through the reaction mixture for 15 minutes.
  • the reaction mixture was heated to 100°C in a microwave reactor and stirred for 3 hours.
  • the reaction was quenched with saturated aq NH4Cl and extracted with DCM.
  • the organic phase was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • a solution of TFA in DCM (1:4, 2.7 mL, 0.02 M) was added to the crude mixture and stirred for 1 hour at 30°C.
  • EXAMPLE 350 5-(4'-(((1R,2R)-2-hydroxycyclobutyl)amino)-5',8'-dihydrospiro [cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-2,3-dihydro-1H-inden-4-ol
  • a microwave vial was charged with 4'-chloro-1'-(4-(methoxymethoxy)-2,3-dihydro- 1H-inden-5-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (20.0 mg, 0.054 mmol), (1R,2R)-2-aminocyclobutanol hydrochloride (26.5 mg, 0.215 mmol), palladium (II) acetate (2.4 mg, 0.011 mmol), (R
  • the vial was capped, and a steam of nitrogen was bubbled through the reaction mixture for 15 minutes.
  • the reaction mixture was heated to 100°C in a microwave reactor and stirred for 3 hours.
  • the reaction was quenched with saturated aq NH4Cl and extracted with DCM.
  • the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • a solution of TFA in DCM (1:4, 2.7 mL, 0.02 M) was added to the crude mixture and stirred for 1 hour at 30°C.
  • EXAMPLE 351 5-(4'-(((1R,2R)-2-hydroxycyclohexyl)oxy)-5',8'-dihydrospiro [cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-2,3-dihydro-1H-inden-4-ol
  • a microwave vial was charged with NaH (4.8 mg, 0.119 mmol), (1R,2R)- cyclohexane-1,2-diol (5.9 mg, 0.119 mmol) and 4'-chloro-1'-(4-(methoxymethoxy)-2,3- dihydro-1H-inden-5-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (12.7 mg, 0.034 mmol) and THF (1.7 mL, 0.02 M
  • the vial was capped, and a steam of nitrogen was bubbled through the reaction mixture for 15 minutes.
  • the reaction mixture was heated to 100°C in a microwave reactor and stirred for 3 hours.
  • the reaction was quenched with saturated aq NH4Cl and extracted with DCM.
  • the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • a solution of TFA in DCM (1:4, 2.7 mL, 0.02 M) was added to the crude mixture and stirred for 1 hour at 30°C.
  • EXAMPLE 352 2-(4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro- 5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [0643] Using a procedure analogous to Example 237 under 0.1 mmol scale, the title compound was obtained as an orange oil (TFA salt, 12.0 mg, 22%).
  • EXAMPLE 353 5-cyclopropyl-3-fluoro-2-(4-(((1R,2R)-2- hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1- yl)phenol [0645] Using a procedure analogous to Example 268 under 0.1 mmol scale, the title compound was obtained as a white semi-solid (3.0 mg, 7%).
  • EXAMPLE 354 rac-2-(4'-(((1R,2S)-3,3-difluoro-2-hydroxycyclopentyl)amino)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5- (trifluoromethyl)phenol [0647] To a 5 mL vial fitted with a stir bar were added R-BINAP (17 mg, 0.0280 mmol), rac-(1R,5S)-5-amino-2,2-difluorocyclopentan-1-ol hydrochloride (49 mg, 0.280 mmol), 2-(4'- chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5- (trifluoromethyl)phenol (25 mg, 0.07
  • EXAMPLE 355 5-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H- spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-2,3-dihydro-1H-inden-4-ol
  • the title compound was prepared using a procedure analogous to Example 318, starting from R-BINAP (17 mg, 0.0267 mmol), 4-chloro-1-[4-(methoxymethoxy)indan-5- yl]spiro[7H-furo[3,4-d]pyridazine-5,3'-tetrahydrofuran] (26 mg, 0.0669 mmol), Cs2CO3 (87 mg, 0.267 mmol), (1R,2R)-2-aminocyclohexanol (30.8 mg, 0.267 mmol), and
  • EXAMPLE 356 5-cyclopropyl-2-(4'-(((1R,2R)-2-hydroxycyclobutyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0651] To a 5 mL vial fitted with a stir bar were added R-BINAP (28 mg, 0.0451 mmol), (1R,2R)-2-aminocyclobutanol hydrochloride (56 mg, 0.451 mmol), 4'-chloro-1'-(4- cyclopropyl-2-(methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazine] (42 mg, 0.113 mmol), Cs2CO3 (184 mg, 0.563
  • the vial was flushed with nitrogen and the reaction mixture was heated to 100°C overnight.
  • the mixture was concentrated under reduced pressure and stirred in DCM (1.9533 mL) and TFA (0.87 mL, 11.3 mmol) for 3 hours.
  • the reaction was concentrated and dissolved in MeOH (1 mL) and DMF (1 mL).
  • the solution was filtered and purified via Shimadzu preparative HPLC using a TFA-containing mobile phase. The title compound was obtained as a TFA salt (0.50 mg, 0.90%).
  • EXAMPLE 357 5-cyclopropyl-2-(4-(((1R,2R)-2-hydroxycyclobutyl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol [0653] Using a procedure analogous to Example 268 under 0.1 mmol scale, the title compound was obtained as a white semi-solid (TFA salt, 5.0 mg, 10%).
  • EXAMPLE 358 5-cyclopropyl-2-(4-(((1R,2R)-2-hydroxycyclopentyl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol [0655] Using a procedure analogous to Example 268 under 0.1 mmol scale, the title compound was obtained as a white semi-solid (TFA salt, 4.0 mg, 8%).
  • EXAMPLE 360 5-((5S,8R)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol
  • STEP 1 (1R,2R)-2-(((5S,8R)-1-(4-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclohexan-1-ol
  • EXAMPLE 361 5-cyclopropyl-2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0667] To a 5 mL vial fitted with a stir bar were added R-BINAP (25 mg, 0.0408 mmol), (1R,2R)-2-aminocyclopentan-1-ol (41 mg, 0.408 mmol), 4'-chloro-1'-(4-cyclopropyl-2- (methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (38 mg, 0.102 mmol), Cs2CO3 (166 mg, 0.510 mmol), and pal
  • EXAMPLE 362 5-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-2,3-dihydro-1H-inden-4-ol
  • a microwave vial was charged with 4'-chloro-1'-(4-(methoxymethoxy)-2,3-dihydro- 1H-inden-5-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (26.6 mg, 0.713 mmol), (1R,2R)-2-aminocyclopentan-1-ol (28.9 mg, 0.285 mmol), palladium (II) acetate (3.2 mg, 0.014 mmol), (R
  • the vial was capped and a stream of nitrogen was bubbled through the reaction mixture for 15 minutes.
  • the reaction mixture was heated at 100°C in a microwave reactor and stirred for 3 hours.
  • the reaction was quenched with saturated aq NH4Cl and extracted with DCM.
  • the organic phase was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the crude material and 2,2'-bipyridine (104 mg, 0.666 mmol) were dissolved in DCM (1.5 mL, 0.05 M) under N2 atmosphere.
  • the mixture was cooled to 0°C and trimethylsilyl trifluoromethane sulfonate (0.08 mL, 0.444 mmol) was added dropwise.
  • the solution was stirred at room temperature until the spot on a TLC plate associated with methoxymethyl ether had disappeared.
  • the reaction mixture was extracted with DCM and the organic phase was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • EXAMPLE 363 5-(difluoromethyl)-2-((5R,8S)-4-(((1R,2R)-2- hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1- yl)phenol [0671] A mixture of or (1R,2R)-2-(((5R,8S)-1-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-4-yl)amino)cyclohexan-1-ol (32 mg, 0.1 mmol), 2-(4- (difluoromethyl)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3-dioxolane (63 mg, 0.200 mmol), and Pd(dppf)Cl 2
  • reaction mixture was concentrated, treated with TFA (1 mL) and DCM (2 mL) and allowed to stir for 1 hour at 50°C.
  • the title compound was obtained as a light-yellow semi- solid (7.0 mg, 16%).
  • EXAMPLE 364 5-(difluoromethyl)-2-((5S,8R)-4-(((1R,2R)-2- hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1- yl)phenol [0673] A mixture of (1R,2R)-2-(((5S,8R)-1-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-4-yl)amino)cyclohexan-1-ol (32 mg, 0.1 mmol), 2-(4- (difluoromethyl)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3-dioxolane (63 mg, 0.200 mmol), and Pd(dppf)Cl 2 .
  • reaction mixture was concentrated, treated with TFA (1 mL) and DCM (2 mL) and allowed to stir for 1 hour at 50°C.
  • the reaction mixture was concentrated and purified by preparative HPLC (Phenomenex Gemini® C18 column) using a 10 to 30% gradient of ACN (0.035% TFA) in water (0.005% TFA).
  • a TFA salt of the title compound was obtained as a light- yellow oil (7.5 mg, 14%).
  • EXAMPLE 365 2-(4'-(((1S,2R)-2-hydroxycyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0675]
  • the title compound was prepared using a procedure analogous to Example 318, starting from R-BINAP (17 mg, 0.0272 mmol), 2-(4'-chloro-5',8'-dihydrospiro[cyclopropane- 1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol (24 mg, 0.0680 mmol), Cs 2 CO 3 (111 mg, 0.340 mmol), (1S,2R)-2-aminocyclopentanol hydrochloride (37.4 mg, 0.272 mmol), and pal
  • EXAMPLE 367 5-chloro-2-(4'-(((1R,2S)-2-hydroxycyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol
  • a mixture of 5-chloro-2-(4'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazin]-1'-yl)phenol 25 mg, 0.0774 mmol
  • (1S,2R)-2-aminocyclopentanol hydrochloride 43 mg, 0.309 mmol
  • palladium(II) acetate 3.5 mg, 0.0155 mmol
  • R-BINAP (19 mg, 0.0309 mmol)
  • Cs2CO3 126 mg, 0.387 mmol
  • the reaction mixture was concentrated via rotary evaporation, diluted with MeOH (1 mL) and DMF (1 mL), filtered through a 0.45 ⁇ m PTFE membrane filter (VWR), rinsed with MeOH (0.5 mL), and purified via preparative HPLC (Shimadzu) using a gradient of 10-100% ACN in H2O (0.05% TFA). The appropriate fractions were combined and concentrated via rotary evaporation at 45°C. The resulting mixture was dried in vacuo to provide a TFA salt of the title compound.
  • the TFA salt was dissolved in MeOH (1 mL), passed through a 100 mg Agilent StratoSpheres SPE cartridge (PL-HCO 3 MP SPE) to remove TFA, and the cartridge was rinsed with MeOH (3 x 1 mL). The filtrate was concentrated via rotary evaporation and dried in vacuo to provide the title compound as a light-yellow solid (4.8 mg, 16%).
  • EXAMPLE 368 5-(difluoromethyl)-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0681] STEP 1: (1R,2R)-2-((1'-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclohexan-1-ol [0682] A mixture of 4'-chloro-1'-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-5',8'- dihydrospiro[cyclo[cyclo[
  • STEP 2 5-(difluoromethyl)-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0684] A mixture of (1R,2R)-2-((1'-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclohexan-1-ol (30 mg, 65.01 ⁇ mol) in TFA (0.3 mL) and DCM (0.9 mL) was degassed and purged with N2 (3 x) and then stirred at 25°C for 3 hours under N 2 atmosphere.
  • EXAMPLE 369 (R)-5-cyclopropyl-2-(4'-((tetrahydrofuran-3-yl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0686] To a 5 mL vial fitted with a stir bar was added R-BINAP (30 mg, 0.0483 mmol), (3R)-oxolan-3-amine hydrochloride (60 mg, 0.483 mmol), 4'-chloro-1'-(4-cyclopropyl-2- (methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (45 mg, 0.121 mmol), Cs2CO3 (197 mg, 0.603 mmol), and palladium(I
  • EXAMPLE 371 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H- spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-3-methyl-5-(trifluoromethyl)phenol [0690] Using a procedure analogous to Example 268 at 0.1 mmol scale, the title compound was obtained as a colorless oil (TFA salt, 14.0 mg, 24%).
  • EXAMPLE 372 5-chloro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5- dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-3-methylphenol [0692] Using a procedure analogous to Example 268 at 0.1 mmol scale, the title compound was obtained as a colorless oil (TFA salt, 7.0 mg, 13%).
  • EXAMPLE 373 5-cyclopropyl-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0694] STEP 1: (1R,2R)-2-((1'-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclohexan-1-ol [0695] To a solution of 4'-chloro-1'-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyr
  • STEP 2 5-cyclopropyl-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0697] To a solution of (1R,2R)-2-((1'-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclohexan-1-ol (47 mg, 104.08 ⁇ mol) in DCM (0.4 mL) was added TFA (240.48 mg, 2.11 mmol, 156.67 ⁇ L).
  • EXAMPLE 374 5-((5R,8S)-4-(((1R,2R)-2-hydroxycyclobutyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol [0699]
  • the title compound was prepared like Example 268 under 0.1 mmol scale. Two diastereomers were isolated by preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10 to 30% ACN (0.035% TFA) in water (0.005% TFA) before the deprotection of methoxymethyl-group.
  • the first-eluting isomer was added to a solution of TFA (2 mL) and DCM (10 mL) and stirred for 1 hour at 60°C.
  • the title compound was obtained as a light-yellow oil (2.2 mg, 4%).
  • EXAMPLE 375 5-(difluoromethyl)-2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0701] STEP 1: (1R,2R)-2-((1'-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclopentan-1-ol [0702] A mixture of 4'-chloro-1'-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-5',8'- dihydrospiro[cyclopropan
  • EXAMPLE 376 5-cyclopropyl-2-(4'-(((1R,2S)-2-hydroxycyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol
  • R-BINAP 20 mg, 0.0322 mmol
  • (1S,2R)-2-aminocyclopentanol hydrochloride 44 mg, 0.322 mmol
  • 4'-chloro-1'-(4- cyclopropyl-2-(methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazine] (30 mg, 0.0805 mmol)
  • Cs2CO3 131 mg, 0.402 m
  • EXAMPLE 379 5-(4'-(((1R,2R,3R,4S)-3-hydroxybicyclo[2.2.1]heptan-2-yl) amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-2,3-dihydro-1H- inden-4-ol
  • a microwave vial was charged with a mixture of 4'-chloro-1'-(4- (methoxymethoxy)-2,3-dihydro-1H-inden-5-yl)-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazine] (10.9 mg, 0.029 mmol), (1S,2R,3R,4R)-3-aminonorbornan-2-ol hydrochloride (9.6 mg, 0.058
  • the reaction mixture was heated to 100°C in a microwave reactor and stirred for 3 hours.
  • the reaction mixture was quenched with saturated aq NaHCO 3 and extracted with DCM.
  • the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • the concentrate was taken up in a solution of DCM and toluene (1.5 mL, 0.02 M).
  • Trifluoroacetic acid 23 ⁇ L, 0.292 mmol was added, and the solution was stirred for 1 hour at 40°C. After the completion of reaction was observed by LC-MS, the reaction was quenched with saturated aq NaHCO 3 and extracted with DCM.
  • EXAMPLE 380 3-fluoro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5- dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0714]
  • the title compound was synthesized from starting material (1R,2R)-2- aminocyclohexan-1-ol and 4'-chloro-1'-(2-fluoro-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazine] using a procedure analogous to Example 254.
  • EXAMPLE 381 (3S,4R)-4-((1'-(2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)- 4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-4'-yl)amino)tetrahydro-2H-pyran- 3-ol
  • the title compound was synthesized from starting materials (3S,4R)-4- aminotetrahydro-2H-pyran-3-ol and 4'-chloro-1'-(2-fluoro-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazine] using a procedure analogous to Example 254; 1 H NMR (400 MHz, CD3OD) ⁇ ppm 1.63
  • EXAMPLE 382 rel-5-(4'-(((1R,2R,3R)-2-hydroxy-3-methylcyclohexyl)amino)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-2,3-dihydro-1H-inden-4- ol
  • a microwave vial was charged with a mixture of 4'-chloro-1'-(4- (methoxymethoxy)-2,3-dihydro-1H-inden-5-yl)-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazine] (11.4 mg, 0.031 mmol), (1R,2R,6R)-2-amino-6-methyl- cyclohexanol hydrochloride (10.1 mg, 0.061 m
  • the reaction mixture was heated to 120°C in a microwave reactor and stirred for 1 hour.
  • the reaction mixture was then quenched with saturated aq NaHCO3 and extracted with DCM.
  • the organic phase was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the concentrate was dissolved in DCM (1.5 mL, 0.02 M), and TFA (24 ⁇ L, 0.306 mmol) was added. The solution was stirred for 1 hour at 40°C. After the completion of reaction was observed by LC-MS, the reaction was quenched with saturated aq NaHCO3 and the mixture extracted with DCM.
  • EXAMPLE 383 3-fluoro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-7'H- spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0720]
  • the title compound was prepared from starting materials (1R,2R)-2- aminocyclohexan-1-ol and 4'-chloro-1'-(2-fluoro-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazine] using a procedure analogous to Example 254.
  • EXAMPLE 384 5-chloro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-7'H- spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin]-1'-yl)phenol [0722]
  • the title compound was prepared from starting materials (1R,2R)-2- aminocyclohexan-1-ol and 4'-chloro-1'-(2-fluoro-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazine] using a procedure analogous to Example 254.
  • EXAMPLE 385 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5'-methyl-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0724] STEP 1: (1R,2R)-2-((1'-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5'- methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'- yl)amino)cyclohexan-1-ol [0725] A mixture of 4'-chloro-1'-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5'- methyl-5',8'-
  • EXAMPLE 386 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5'-methyl-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0729] STEP 1: (1R,2R)-2-((1'-(2-(methoxymethoxy)-4-methylphenyl)-5'-methyl-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclohexan-1-ol [0730] To a solution of 4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-5'-methyl-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano
  • STEP 2 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5'-methyl-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0732] To a solution of (1R,2R)-2-((1'-(2-(methoxymethoxy)-4-methylphenyl)-5'-methyl- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclohexan-1-ol (60 mg, 136.50 ⁇ mol) in DCM (0.7 mL) was added TFA (3.37 mmol, 0.25 mL).
  • EXAMPLE 387 5-chloro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5'-methyl- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0734] STEP 1: (1R,2R)-2-((1'-(4-chloro-2-(methoxymethoxy)phenyl)-5'-methyl-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclohexan-1-ol [0735] A mixture of 4'-chloro-1'-(4-chloro-2-(methoxymethoxy)phenyl)-5'-methyl-5',8'- dihydrospiro[cyclopropane
  • EXAMPLE 388 4-fluoro-2-((5R,8S)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [0739] STEP 1: (1R,2R)-2-(((5R,8S)-1-(5-fluoro-2-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4- yl)amino)cyclohexan-1-ol [0740] A mixture of (1R,2R)-2-(((5R,8S)-1-chloro-6,7,8,9-tetrahydro-5H-5,8-
  • STEP 2 4-fluoro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0747] A mixture of (1R,2R)-2-((1'-(5-fluoro-2-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'- yl)amino)cyclohexan-1-ol (57 mg, 108.57 ⁇ mol) in DCM (2 mL) and TFA (0.5 mL) was stirred at 21°C for 1.5 hours.
  • EXAMPLE 390 4-fluoro-2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0749] STEP 1: (1R,2R)-2-((1'-(5-fluoro-2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclopentan-1-ol [0750] To a mixture of (1R,2R)-2-((1'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'---phenyl
  • STEP 2 4-fluoro-2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0752] A mixture of (1R,2R)-2-((1'-(5-fluoro-2-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'- yl)amino)cyclopentan-1-ol (38 mg, 68.51 ⁇ mol) in DCM (2 mL) and TFA (0.5 mL) was stirred at 27°C for 1 hour.
  • EXAMPLE 391 4-fluoro-2-((5S,8R)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [0754] STEP 1: (1R,2R)-2-(((5S,8R)-1-(5-fluoro-2-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4- yl)amino)cyclohexan-1-ol [0755] A mixture of (1R,2R)-2-(((5S,8R)-1-chloro-6,7,8,9-tetrahydro-5H-5,8-
  • EXAMPLE 392 (3S,4R)-4-((1'-(4-chloro-2-hydroxyphenyl)-7'H- spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin]-4'-yl)amino)tetrahydro-2H-pyran-3-ol
  • the title compound was prepared from starting materials (3S,4R)-4- aminotetrahydro-2H-pyran-3-ol and 4'-chloro-1'-(2-fluoro-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazine] using a procedure analogous to Example 254.
  • EXAMPLE 393 5-(4'-(((1R,2S,3S,4S)-3-hydroxybicyclo[2.2.1]heptan-2-yl) amino)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-2,3-dihydro-1H-inden-4- ol
  • a microwave vial was charged with 4'-chloro-1'-(4-(methoxymethoxy)-2,3-dihydro- 1H-inden-5-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (13.4 mg, 0.036 mmol), (1S,2S,3S,4R)-3-aminonorbornan-2-ol hydrochloride (11.8 mg, 0.072 mmol),
  • the reaction mixture was heated to 120°C in a microwave reactor and stirred for 1 hour.
  • the reaction mixture was quenched with saturated aq NaHCO 3 and extracted with DCM.
  • the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • the crude mixture was dissolved in DCM (1.8 mL, 0.02 M) and TFA (28 ⁇ L, 0.359 mmol) was added. The solution was stirred for 1 hour at 40°C. After the completion of reaction was observed by LC-MS, the reaction was quenched with saturated aq NaHCO3 and extracted with DCM.
  • the organic phase was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the title compound was obtained as a light- yellow powder (4.7 mg, 31%).
  • EXAMPLE 394 2-((R)-4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5'-methyl-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0763] STEP 1: (1R,2R)-2-((1'-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5'- methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'- yl)amino)cyclopentan-1-ol [0764] To a solution of 4'-chloro-1'-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5'- methyl-5',
  • EXAMPLE 395 5-chloro-2-((R)-4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5'- methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0768] STEP 1: (1R,2R)-2-((1'-(4-chloro-2-(methoxymethoxy)phenyl)-5'-methyl-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclopentan-1-ol [0769] A mixture of 4'-chloro-1'-(4-chloro-2-(methoxymethoxy)phenyl)-5'-methyl-5',8'- dihydrospiro[cyclopropan
  • STEP 2 5-chloro-2-((R)-4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5'-methyl-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0771] To (1R,2R)-2-((1'-(4-chloro-2-(methoxymethoxy)phenyl)-5'-methyl-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclopentan-1-ol (30 mg, 67.27 ⁇ mol) was added TFA (0.2 mL) in DCM (0.6 mL).
  • EXAMPLE 396 5-(4'-(((1R,2S)-2-hydroxycyclobutyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-2,3-dihydro-1H-inden-4-ol
  • a microwave vial was charged with 4'-chloro-1'-(4-(methoxymethoxy)-2,3-dihydro- 1H-inden-5-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (11.8 mg, 0.032 mmol), (1S,2R)-2-aminocyclobutanol hydrochloride (7.8 mg, 0.063 mmol), palladium (II) acetate (1.4 mg, 0.006 mmol), (
  • the reaction mixture was heated to 120°C in a microwave reactor and stirred for 5 hours.
  • the reaction was quenched with saturated aq NaHCO3 and the mixture extracted with DCM.
  • the organic phase was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the crude mixture was dissolved in DCM (1.6 mL, 0.02 M).
  • TFA 49 ⁇ L, 0.633 mmol was added and the solution was stirred for 1 hour at 40°C. After the completion of reaction was observed by LC- MS, the reaction was quenched with saturated aq NaHCO3 and extracted with DCM.
  • the organic phase was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the reaction mixture was heated to 120°C in a microwave reactor and stirred for 3 hours.
  • the reaction was quenched with saturated aq NaHCO 3 and the mixture extracted with DCM.
  • the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • the crude mixture was dissolved in DCM (1.9 mL, 0.02 M), and TFA (57 ⁇ L, 0.74 mmol) was added. The solution was stirred for 1 hour at 40°C. After the completion of reaction was observed by LC-MS, the reaction was quenched with saturated aq NaHCO3 and the mixture extracted with DCM.
  • the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • the title compound was obtained as a white powder (4.0 mg, 0.01 mmol, 30%).
  • EXAMPLE 398 3-fluoro-2-((3R*)-4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5- dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0777]
  • the title compound was prepared from starting material (1R,2R)-2- aminocyclohexan-1-ol hydrochloride using a procedure analogous to Example 381.
  • EXAMPLE 400 3-fluoro-2-(4'-(((R)-tetrahydrofuran-3-yl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0781] To a 5 mL vial fitted with a stir bar were added R-BINAP (13 mg, 0.0213 mmol), (3R)-oxolan-3-amine hydrochloride (16 mg, 0.133 mmol), 2-(4-chlorospiro[5,8- dihydropyrano[3,4-d]pyridazine-7,1'-cyclopropane]-1-yl)-3-fluoro-5-(trifluoromethyl)phenol (20 mg, 0.0534 mmol), Cs2CO3 (52 mg, 0.160 mmol), and palladium(II) a
  • EXAMPLE 401 (3S,4R)-4-(((3R*)-1'-(2-fluoro-6-hydroxy-4-methylphenyl)-4,5- dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-4'-yl)amino)tetrahydro-2H-pyran-3-ol [0783]
  • the title compound was prepared from starting material (3R,4S)-4-aminooxan-3-ol hydrochloride using a procedure analogous to Example 381.
  • EXAMPLE 402 (3S,4R)-4-((1'-(2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)- 7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin]-4'-yl)amino)tetrahydro-2H-pyran-3-ol
  • the title compound was prepared from starting material (3R,4S)-4-aminooxan-3-ol hydrochloride using a procedure analogous to Example 381.
  • EXAMPLE 403 2-(4'-(((1R,2R)-2-methoxycyclobutyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0787] A mixture of 2-(4'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol (25 mg, 0.0701 mmol), (1R,2R)-2- methoxycyclobutan-1-amine (19 mg, 0.14 mmol), sodium tert-butoxide (24 mg, 0.245 mmol), rac-BINAP Pd G3 (7.0 mg, 0.007 mmol), and toluene (1 mL) was
  • the mixture was diluted with DMSO (1 mL), filtered, and purified by HPLC (Gemini 30 mm x 150 mm column) using a 10-70% gradient of ACN (0.035% TFA) in water (0.05% TFA) followed by SFC (Waters, IC-5 ⁇ m, 21 mm x 250 mm column) using a mobile phase of CO2 and 10 to 35% MeOH (with 0.05% NH3OH) to give the title compound (0.6 mg, 2.03%).
  • EXAMPLE 404 3-fluoro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-7'H- spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0789]
  • the title compound was prepared from starting material (1R,2R)-2- aminocyclohexan-1-ol hydrochloride using a procedure analogous to Example 381.
  • EXAMPLE 405 3-fluoro-2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0791] STEP 1 (1R,2R)-2-((1'-(2-fluoro-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclopentan-1-ol [0792] A mixture of (1R,2R)-2-((1'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,
  • EXAMPLE 406 3-fluoro-2-((3R*)-4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5- dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0796]
  • the title compound was prepared from starting material (1R,2R)-2- aminocyclohexan-1-ol hydrochloride using a procedure analogous to Example 381.
  • EXAMPLE 407 (R)-2-(4'-((3,3-difluorocyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0798] To a 5 mL vial fitted with a stir bar were added R-BINAP (17 mg, 0.0280 mmol), (1R)-3,3-difluorocyclopentanamine hydrochloride (44 mg, 0.280 mmol), 2-(4'-chloro-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol (25 mg, 0.0701 mmol), Cs2CO3 (114 mg, 0.350 mmol), and palladium(I
  • EXAMPLE 408 rac-2-(4'-(((3R,4R)-4-methyltetrahydrofuran-3-yl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0800] To a 5 mL vial fitted with a stir bar were added R-BINAP (17 mg, 0.0280 mmol), rac-(3R,4R)-4-methyltetrahydrofuran-3-amine;hydrochloride (39 mg, 0.280 mmol), 2-(4'- chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5- (trifluoromethyl)phenol (25 mg, 0.0701 mmol), Cs2CO3 (114
  • the reaction mixture was concentrated and diluted with MeOH (3 mL) and filtered using a syringe filter.
  • EXAMPLE 410 5-chloro-3-fluoro-2-(7'-(((1R,2R)-2-hydroxycyclohexyl)amino)- 3'H-spiro[cyclopropane-1,1'-isobenzofuran]-4'-yl)phenol [0804] The title compound was prepared from starting material (1R,2R)-2- aminocyclohexan-1-ol hydrochloride using a procedure analogous to Example 254.
  • EXAMPLE 411 2-(4'-(((1R,2R)-2-methoxycyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0806] To a 5 mL vial fitted with a stir bar were added R-BINAP (21 mg, 0.0329 mmol), (1R,2R)-2-methoxycyclopentan-1-amine hydrochloride (50 mg, 0.329 mmol), 4'-chloro-1'-(2- (methoxymethoxy)-4-(trifluoromethyl)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazine] (33 mg, 0.0823 mmol), Cs2CO3 (134
  • EXAMPLE 412 5-(1-fluorocyclopropyl)-2-((5S*,8R*)-4-(((1R,2R)-2- hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1- yl)phenol
  • a mixture of (1R,2R)-2-(((5S,8R)-1-chloro-6,7,8,9-tetrahydro-5H-5,8- epoxycyclohepta[d]pyridazin-4-yl)amino)cyclopentan-1-ol (30 mg, 0.100 mmol), 2-(4-(1- fluorocyclopropyl)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (64 mg, 0.200 mmol), and Pd(d
  • EXAMPLE 413 5-ethyl-3-fluoro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)- 7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin]-1'-yl)phenol [0810] The title compound was prepared from starting material (1R,2R)-2- aminocyclohexan-1-ol hydrochloride using a procedure analogous to Example 254.
  • EXAMPLE 414 (3S,4R)-4-(((3R*)-1'-(4-ethyl-2-fluoro-6-hydroxyphenyl)-4,5- dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-4'-yl)amino)tetrahydro-2H-pyran-3-ol
  • the title compound was prepared from starting material (3R,4S)-4-aminooxan-3-ol hydrochloride using a procedure analogous to Example 381.
  • EXAMPLE 415 (3S,4R)-4-(((3R*)-1'-(4-chloro-2-fluoro-6-hydroxyphenyl)-4,5- dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-4'-yl)amino)tetrahydro-2H-pyran-3-ol
  • the title compound was prepared from starting material (3R,4S)-4-aminooxan-3-ol hydrochloride using a procedure analogous to Example 381.
  • EXAMPLE 416 5-chloro-3-fluoro-2-((3R*)-4'-(((1R,2R)-2- hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'- yl)phenol [0816] The title compound was prepared from starting material (1R,2R)-2- aminocyclohexan-1-ol using a procedure analogous to Example 381.
  • EXAMPLE 417 3-fluoro-2-(4'-(((1R,2R)-2-methoxycyclohexyl)amino)-4,5- dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0818] STEP 1: 1'-(2-fluoro-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-N-((1R,2R)- 2-methoxycyclohexyl)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-4'-amine [0819] A mixture of 4'-chloro-1'-(2-fluoro-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-4,5-dihydr
  • EXAMPLE 418 3-fluoro-2-(4'-(((1R,2R)-2-methoxycyclopentyl)amino)-4,5- dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0823] Using a procedure analogous to Example 417, the title compound was obtained as a light-yellow film (5.5 mg, 13%). ESI-MS [M+H] + calc'd for C22H23F4N3O4, 469.2; found, 470.2.
  • EXAMPLE 419 5-(4'-(cyclobutylamino)-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazin]-1'-yl)-2,3-dihydro-1H-inden-4-ol [0825] Using a procedure analogous to Example 417, the title compound was obtained as a yellow solid (2.9 mg, 29%). ESI-MS [M+H] + calc'd for C22H25N3O2, 363.2; found, 364.2.
  • EXAMPLE 420 5-(4'-(cyclopentylamino)-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazin]-1'-yl)-2,3-dihydro-1H-inden-4-ol [0827] Using a procedure analogous to Example 417, the title compound was obtained as an orange solid (2.4 mg, 24%).
  • EXAMPLE 421 5-cyclopropyl-2-(4-(((1R,2R)-2-methoxycyclopentyl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol
  • the title compound was prepared using a procedure analogous to Example 268 under 0.1 mmol scale.
  • the title compound was obtained as a yellow oil (5.0 mg, 12%).
  • EXAMPLE 422 2-(4'-(cyclopentylamino)-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0831] To a 5 mL vial fitted with a stir bar were added R-BINAP (21 mg, 0.0336 mmol), cyclopentylamine (29 mg, 0.336 mmol), 2-(4'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'- pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol (30 mg, 0.0841 mmol), Cs2CO3 (137 mg, 0.420 mmol), and palladium(II) acetate (3.8 mg, 0.0168 mmol) in DMA (3 mL).
  • EXAMPLE 423 (S)-2-(4'-((3,3-difluorocyclopentyl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0833] To a 5 mL vial fitted with a stir bar were added R-BINAP (21 mg, 0.0336 mmol), (1S)-3,3-difluorocyclopentanamine hydrochloride (53 mg, 0.336 mmol), 2-(4'-chloro-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol (30 mg, 0.0841 mmol), Cs2CO3 (137 mg, 0.420 mmol), and palladium(
  • EXAMPLE 424 (R)-5-(1-fluorocyclopropyl)-2-(4'-((tetrahydrofuran-3-yl)amino)- 5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0835] To a 5 mL vial were added (R)-1'-chloro-N-(tetrahydrofuran-3-yl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-amine (30 mg, 0.106 mmol), 2- (4-(1-fluorocyclopropyl)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (34 mg, 0.106 mmol), XPhos Palla
  • the vial was flushed with nitrogen and the reaction mixture was heated at 70°C for 3 hours. The mixture was allowed to cool to room temperature and extracted with EtOAc (2 mL) and brine (2 mL). The organics were concentrated, dissolved in DCM (2 mL) and trifluoroacetic acid (0.25 mL, 3.19 mmol), and allowed to stir at room temperature for 4 hours. The solution was concentrated and extracted with saturated aq NaHCO3 (2 mL) and EtOAc (2 mL). The organics were concentrated via rotary evaporation, dissolved in MeOH (1 mL) and DMF (1 mL), and purified by basic preparative HPLC to give the title compound (5.4 mg, 13%).
  • EXAMPLE 425 5-cyclopropyl-2-((5S*,8R*)-4-(((1R,2R)-2- methoxycyclobutyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1- yl)phenol
  • the title compound was prepared using a procedure analogous to Example 268 under 0.1 mmol scale.
  • the diastereomers were purified via preparative SFC (Waters, ChiralTech IC column-5 ⁇ m, 21 mm x 150 mm) using a gradient of 35 to 50% MeOH (with 0.1% NH4OH) in CO2.
  • the title compound was obtained as a light-yellow semi-solid (7.0 mg, 18%).
  • the diastereomers were purified via preparative SFC (Waters, ChiralTech IC column-5 ⁇ m, 21 mm x 150 mm) using a gradient of 25 to 50% MeOH (with 0.1% NH 4 OH) in CO 2 .
  • the title compound was obtained as a light-yellow semi-solid (2.5 mg, 6%).
  • EXAMPLE 428 5-(difluoromethyl)-3-fluoro-2-((3R*)-4'-(((1R,2R)-2- hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'- yl)phenol [0843] The title compound was prepared from starting material (1R,2R)-2- aminocyclohexan-1-ol using a procedure analogous to Example 381.
  • EXAMPLE 429 3-fluoro-2-((3R*)-4'-(((1R,2R)-2-methoxycyclopentyl)amino)-4,5- dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0845]
  • the title compound was prepared from starting material (1R,2R)-2- methoxycyclopentan-1-amine hydrochloride using a procedure analogous to Example 381.
  • EXAMPLE 430 3-fluoro-2-((3R*)-4'-(((1R,2R)-2-methoxycyclobutyl)amino)-4,5- dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0847]
  • the title compound was prepared from starting material trans-(1R,2R)-2- methoxycyclobutanamine hydrochloride using a procedure analogous to Example 381.
  • EXAMPLE 431 3-fluoro-2-((3R*)-4'-(((3S,4R)-3-methoxytetrahydro-2H-pyran-4- yl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-5-methylphenol [0849]
  • the title compound was prepared from starting material (3S,4R)-3- methoxytetrahydro-2H-pyran-4-amine using a procedure analogous to Example 381.
  • EXAMPLE 432 3-fluoro-2-((3R*)-4'-(((3S,4R)-3-methoxytetrahydro-2H-pyran-4- yl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-5- (trifluoromethyl)phenol [0851] The title compound was prepared from starting material (3S,4R)-3- methoxytetrahydro-2H-pyran-4-amine using a procedure analogous to Example 381.
  • EXAMPLE 433 5-(1,1-difluoroethyl)-3-fluoro-2-((3R*)-4'-(((3S,4R)-3- methoxytetrahydro-2H-pyran-4-yl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4- d]pyridazin]-1'-yl)phenol [0853] The title compound was prepared from starting material (3S,4R)-3- methoxytetrahydro-2H-pyran-4-amine using a procedure analogous to Example 381.
  • EXAMPLE 434 2-((R*)-4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5'-methyl-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [0855] To a 5 mL vial fitted with a stir bar were added rel-(R)-4'-chloro-1'-(2- (methoxymethoxy)-4-(trifluoromethyl)phenyl)-5'-methyl-5',8'-dihydrospiro[cyclopropane- 1,7'-pyrano[3,4-d]pyridazine] (66 mg, 0.159 mmol), (1R,2R)-2-aminocyclopentan-1-ol hydrochloride (66 mg, 0.477 mmol), Cs2CO3 (207 mg,
  • EXAMPLE 435 2-(4-(((1R,2S)-2-methoxycyclobutyl)amino)-6,7,8,9-tetrahydro- 5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol
  • the title compound was prepared using a procedure analogous to Example 268 under 0.1 mmol scale.
  • the title compound was obtained as a light-yellow semi-solid (14.0 mg, 33%).
  • EXAMPLE 436 1-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-N-((1R,2R)-2- methoxycyclobutyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-amine [0859] A mixture of Pd 2 (dba) 3 (7.5 mg, 0.00818 mmol), Cs 2 CO 3 (107 mg, 0.327 mmol), R- BINAP (0.010 mL, 0.0164 mmol), trans-(1R,2R)-2-methoxycyclobutanamine hydrochloride (23 mg, 0.164 mmol) and 4-chloro-1-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta
  • the reaction mixture was concentrated and 3 mL of MeOH was added to dissolve the mixture.
  • the title compound was obtained as an orange semi-solid (16.0 mg, )45%).
  • EXAMPLE 437 1'-(4-cyclopropyl-2,6-difluorophenyl)-N-((1R,2R)-2- methoxycyclobutyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-amine
  • R-BINAP 39 mg, 0.0619 mmol
  • the vial was flushed with nitrogen and the reaction mixture was heated in a Biotage microwave reactor at 130°C for 30 minutes. The mixture was extracted with EtOAc (5 mL) and brine (5 mL). The organics were separated and dried with MgSO 4 . The solution was concentrated and purified via flash chromatography (amine column) using a gradient of 10 to 50% EtOAc in heptane. The mixture was separated via SFC to give the title compound as the second eluting peak (3.6 mg, 5.6%).
  • EXAMPLE 438 1'-(4-cyclopropyl-2-fluorophenyl)-N-((1R,2R)-2- methoxycyclopentyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-amine
  • R-BINAP 45 mg, 0.0726 mmol
  • the vial was flushed with nitrogen and the reaction mixture was heated in a Biotage microwave reactor at 130°C for 30 minutes.
  • the reaction was extracted with EtOAc (2 x 5 mL) and brine (5 mL).
  • the organics were dried with MgSO 4 , filtered, concentrated.
  • the crude material was purified via flash chromatography (amine column) using a gradient of 10 to 50% EtOAc in heptane. Both isomers were isolated as a single peak.
  • the mixture was purified via SFC to give the title compound as the second eluting peak (2.3 mg, 6.2%).
  • EXAMPLE 439 5-chloro-2-((S*)-4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5'- methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0865] The title compound is obtained like Example 395.
  • EXAMPLE 440 (S)-5-methyl-2-(4'-((tetrahydrofuran-3-yl)amino)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)phenol [0867] The title compound was prepared using a procedure analogous to Example 313. ESI-MS [M+H] + calc'd for C20H23N3O3, 353.2; found, 354.1.
  • EXAMPLE 441 (1R,2R)-2-(((5S*,8R*)-1-(4-cyclopropyl-2,6-difluorophenyl)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclopentan-1-ol
  • the title compound was prepared like Example 343 and was obtained as a colorless oil (TFA salt, 20.0 mg, 38%).
  • EXAMPLE 442 2-((5S,8R)-4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [0871] EXAMPLE 443: 2-((5R,8S)-4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [0872] The title compounds were prepared using a procedure analogous to Example 342 and Example 343 under 0.1 mmol scale.
  • Example 442 The title compound of Example 442 was obtained as a light-yellow solid (TFA salt, 37.0 mg, 69 %).
  • 1 H NMR 400 MHz, CD 3 OD
  • Example 443 was obtained as a light-yellow semi-solid (TFA salt, 37.0 mg, 69%).
  • 1 H NMR 400 MHz, CD3OD
  • EXAMPLE 445 5-((5R,8S)-4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol
  • EXAMPLE 446 5-((5S,8R)-4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9- tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol
  • the title compounds were prepared using a procedure analogous to Example 363 and Example 364 under 0.1 mmol scale.
  • Example 445 was obtained as a colorless semi-solid (3.5 mg, 9%).
  • Example 446 The title compound of Example 446 was obtained as a colorless semi-solid (17.0 mg, 43%).
  • 1 H NMR 400 MHz, CD 3 OD
  • EXAMPLE 447 5-cyclopropyl-2-((5S*,8R*)-4-(((1R,2R)-2- hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1- yl)phenol [0879] Using a procedure analogous to Example 364 under 0.1 mmol scale, the title compound was obtained as a brown oil (9.0 mg, 23%).
  • EXAMPLE 448 3-fluoro-2-((5S*,8R*)-4-(((1R,2R)-2-hydroxycyclopentyl)amino)- 6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [0881] Using a procedure analogous to Example 364 under 0.1 mmol scale, the title compound was obtained as a light-yellow semi-solid (9.0 mg, 20%).
  • EXAMPLE 449 (3S,4R)-4-((1'-(2-hydroxy-4-(trifluoromethyl)phenyl)-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)tetrahydro-2H-pyran-3- ol
  • R-BINAP 21 mg, 0.0336 mmol
  • (3R,4S)-4-aminooxan-3-ol hydrochloride 52 mg, 0.336 mmol
  • 2-(4'-chloro-5',8'- dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol (30 mg, 0.0841 mmol)
  • Cs2CO3 137 mg, 0.
  • EXAMPLE 450 1'-(2-fluoro-4-(1-fluorocyclopropyl)phenyl)-N-((1R,2R)-2- methoxycyclopentyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-amine
  • EXAMPLE 451 1'-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-N-((1R,2R)-2- methoxycyclopentyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-amine
  • EXAMPLE 452 1'-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-N-((1R,2R)-2- methoxycyclobutyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-amine
  • 1-chloro-N-[(1R,2R)-2- methoxycyclobutyl]spiro[5,8-dihydropyrano[3,4-d]pyridazine-7,1'-cyclopropane]-4-amine 25 mg, 0.0845 mmol
  • EXAMPLE 453 1'-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-N-((3S,4R)-3- methoxytetrahydro-2H-pyran-4-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazin]-4'-amine
  • EXAMPLE 454 (5R,8S)-1-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-N- ((1R,2R)-2-methoxycyclobutyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4- amine
  • EXAMPLE 455 (5S,8R)-1-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-N- ((1R,2R)-2-methoxycyclobutyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4- amine
  • the reaction mixture was concentrated and dispersed in MeOH (10 mL).
  • the resulting suspension was filtered through a syringe filter and the filtrate was purified by preparative HPLC (basic-ACCQ-prep) using a gradient of 10 to100% ACN in water (with NH4HCO3).
  • the product-containing fractions were collected, concentrated and dried in vacuo.
  • the mixture components were separated by preparative SFC (Waters, Phenomenex Cellulose-2 column) using a gradient of 5 to 30% MeOH (modified with 0.1% NH4OH) in CO2.
  • the first eluting product was dried in vacuo to give the title compound of Example 454 as a white semi-solid (40.7 mg, 23%).
  • EXAMPLE 456 (1R,2R)-2-(((5R,8S)-1-(2,6-difluoro-4-(1- fluorocyclopropyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4- yl)amino)cyclobutan-1-ol
  • EXAMPLE 457 (1R,2R)-2-(((5S,8R)-1-(2,6-difluoro-4-(1- fluorocyclopropyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4- yl)amino)cyclobutan-1-ol [
  • the reaction mixture was concentrated and dispersed in MeOH (10 mL).
  • the resulting suspension was filtered through a syringe filter and the filtrate was purified by preparative HPLC (basic-ACCQ-prep,) using a gradient of 10 to 100% ACN in water (with NH 4 HCO 3 ).
  • the product-containing fractions were collected, concentrated and dried in vacuo.
  • the mixture components were separated by preparative SFC (Waters, Phenomenex i-Amylose-3 column) using a gradient of 25 to 50% MeOH (modified with 0.1% NH 4 OH) in CO 2 .
  • the first eluting product was dried in vacuo to give the title compound of Example 456 as a light-yellow semi-solid (27 mg, 16%).
  • EXAMPLE 458 1'-(4-cyclopropyl-2-fluorophenyl)-N-((3S,4R)-3- methoxytetrahydro-2H-pyran-4-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4- d]pyridazin]-4'-amine
  • R-BINAP 27 mg, 0.0441 mmol
  • (3R,4S)-3-methoxyoxan-4-amine hydrochloride 55 mg, 0.331 mmol
  • Table 5 lists in vitro biological assay data (IL-1 ⁇ and TNF- ⁇ ) for some of the compounds shown in the examples. These assays are described in the section entitled Biological Activity, above. [0903] TABLE 5: Biological Assay Data Example No. IL-1 ⁇ IC 50 TNF- ⁇ IC 50 (nM) (nM) 233 15.6 10000 234 163.4 10000 235 81.4 10000 Example No.
  • IL-1 ⁇ IC 50 TNF- ⁇ IC 50 (nM) (nM) 360 13.2 361 21.4 362 22.3 363 70.8 364 53.9 365 21.1 366 35.6 367 99.6 368 43.4 369 47.2 370 69.6 371 36.0 372 42.8 373 24.8 374 53.9 375 56.9 376 48.8 377 74.3 378 90.0 379 68.0 10000 380 16.1 381 48.3 382 25.1 383 18.4 384 86.4 385 37.9 386 41.4 387 38.8 388 60.5 389 26.0 390 56.3
  • IL-1 ⁇ IC 50 TNF- ⁇ IC 50 (nM) (nM) 391 95.1 392 36.0 393 7.3 394 33.4 395 46.7 396 39.3 397 28.3 398 14.6 399 22.2 400 42.8 401 32.5 402 31.8 403 14.9 404 25.0 405 27.1 406 11.2 407 20.5 408 29.0 409 30.1 410 24.5 411 10.7 412 22.0 413 19.7 414 49.6 415 27.2 416 17.1 417 30.8 418 37.2 419 31.5 420 26.1 421 23.8

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Abstract

L'invention concerne des composés de formule 1, (1) et des sels pharmaceutiquement acceptables de ceux-ci, α, β, m, R5, R6, R7, R9, R10, R11, Ra, Rb, X1, X2, X3, X4 et X8 étant définis dans la description. La présente invention concerne également des matériaux et des procédés de préparation de composés de formule 1, des compositions pharmaceutiques qui les contiennent, et leur utilisation pour traiter des maladies, des troubles et des états associés à NLRP3.
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991011172A1 (fr) 1990-01-23 1991-08-08 The University Of Kansas Derives de cyclodextrines presentant une solubilite aqueuse amelioree et utilisation de ceux-ci
WO1994002518A1 (fr) 1992-07-27 1994-02-03 The University Of Kansas Derives de cyclodextrines ayant une meilleure solubilite aqueuse et leur utilisation
WO1998055148A1 (fr) 1997-06-05 1998-12-10 Janssen Pharmaceutica N.V. Compositions pharmaceutiques comprenant des cyclodextrines
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO2022135567A1 (fr) * 2020-12-25 2022-06-30 上海拓界生物医药科技有限公司 Composé contenant de la pyridazine et son utilisation médicinale
WO2022253326A1 (fr) * 2021-06-05 2022-12-08 药捷安康(南京)科技股份有限公司 Inhibiteur de l'inflammasome nlrp3 et son utilisation
WO2023003002A1 (fr) * 2021-07-21 2023-01-26 アステラス製薬株式会社 Composé de pyridazine annelé
WO2023131277A1 (fr) * 2022-01-07 2023-07-13 药捷安康(南京)科技股份有限公司 Inhibiteur de l'inflammasome nlrp3 et utilisations associées

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991011172A1 (fr) 1990-01-23 1991-08-08 The University Of Kansas Derives de cyclodextrines presentant une solubilite aqueuse amelioree et utilisation de ceux-ci
WO1994002518A1 (fr) 1992-07-27 1994-02-03 The University Of Kansas Derives de cyclodextrines ayant une meilleure solubilite aqueuse et leur utilisation
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO1998055148A1 (fr) 1997-06-05 1998-12-10 Janssen Pharmaceutica N.V. Compositions pharmaceutiques comprenant des cyclodextrines
WO2022135567A1 (fr) * 2020-12-25 2022-06-30 上海拓界生物医药科技有限公司 Composé contenant de la pyridazine et son utilisation médicinale
WO2022253326A1 (fr) * 2021-06-05 2022-12-08 药捷安康(南京)科技股份有限公司 Inhibiteur de l'inflammasome nlrp3 et son utilisation
WO2023003002A1 (fr) * 2021-07-21 2023-01-26 アステラス製薬株式会社 Composé de pyridazine annelé
WO2023131277A1 (fr) * 2022-01-07 2023-07-13 药捷安康(南京)科技股份有限公司 Inhibiteur de l'inflammasome nlrp3 et utilisations associées

Non-Patent Citations (44)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987
"Compendium of Organic Synthetic Methods", 1974
"Pharmaceutical Dosage Forms: Tablets", vol. 1-3, 1990
"Remington: The Science and Practice of Pharmacy", 2000
"Stahl and Wermuth", 2002, HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION, AND USE
A. ALBONID. CERVIAS. SUGAMA ET AL.: "Interleukin 18 in the CNS", J NEUROINFLAMMATION, vol. 7, no. 9, 2010
A. LUV. G MAGUPALLIJ. RUAN ET AL.: "Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes", CELL, vol. 156, no. 6, 2014, pages 1193 - 1206, XP028632821, DOI: 10.1016/j.cell.2014.02.008
ANN RHEUM DIS, vol. 71, no. 7, 2012, pages 1264
B. N. DUGGERD. W. DICKSON: "Pathology of Neurodegenerative Diseases", COLD SPRING HARBOR PERSPECT BIOL, vol. 9, no. 7, 2017, pages a028035
COLLJ. R. HILLC. J. DAY ET AL.: "MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition", NAT CHEM BIOL, vol. 15, no. 6, 2019, pages 556 - 559
D. K. PARIKH, C. K.PARIKH, HANDBOOK OF PHARMACEUTICAL GRANULATION TECHNOLOGY, vol. 81, 1997
D. ZHENGT. LIWINSKIE. ELINAV: "Inflammasome activation and regulation: toward a better understanding of complex mechanisms", CELL DISCOV, vol. 6, no. 36, 2020
E. L. ELIELS. H. WILEN, STEREOCHEMISTRY OF ORGANIC COMPOUNDS, 1994
F. SHIY. YANGM. KOUADIR M ET AL.: "Inhibition of phagocytosis and lysosomal acidification suppresses neurotoxic prion peptide-induced NALP3 inflammasome activation in BV2 microglia", JNEUROIMMUNOL, vol. 260, no. 1-2, 2013, pages 121 - 5, XP028562013, DOI: 10.1016/j.jneuroim.2013.04.016
FINNINMORGAN, J. PHARM. SCI., vol. 88, no. 10, 1999, pages 955 - 958
H. BUNDGAAR, DESIGN OF PRODRUGS, 1985
I. FERNANDEZ-CRUZE. REYNAUD: "Proteasome Subunits Involved in Neurodegenerative Diseases", ARCH MED RES, vol. 52, no. 1, 2021, pages 1 - 14, XP086465928, DOI: 10.1016/j.arcmed.2020.09.007
J. K. HALEBLIAN, J. PHARM. SCI., vol. 64, no. 8, 1975, pages 1269 - 88
J. YANGZ. LIUT. S. XIAO: "Post-translational regulation of inflammasomes", CELL MOL IMMUNOL, vol. 14, no. 1, 2017, pages 65 - 79
JIANGM. LIF. HE ET AL.: "Inhibition of NLRP3 inflammasome attenuates spinal cord injury-induced lung injury in mice", J CELLPHYSIOL, vol. 234, no. 5, 2019, pages 6012 - 6022, XP071328795, DOI: 10.1002/jcp.27233
K. R. MORRIS: "Polymorphism in Pharmaceutical Solids", 1995
L. CUISSETI. JERUB. DUMONT ET AL.: "Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France", ANN RHEUM DIS, vol. 70, no. 3, 2011, pages 495 - 9, XP093129522, DOI: 10.1136/ard.2010.138420
L. I. LABZINM. T. HENEKAE. LATZ: "Innate Immunity and Neurodegeneration", ANNU REV MED, vol. 69, 2018, pages 437 - 449
L. M. BOOSHEHRIH. M. HOFFMAN: "CAPS and NLRP3", J CLIN IMMUNOL, vol. 39, no. 3, 2019, pages 277 - 286
LIANGCHEN, EXPERT OPINION IN THERAPEUTIC PATENTS, vol. 11, no. 6, 2001, pages 981 - 986
M. LAMKANFIV. M. DIXIT: "Mechanisms and functions of inflammasomes", CELL, vol. 157, no. 5, 2014, pages 1013 - 22
N. H. HARTSHORNEA. STUART, CRYSTALS AND THE POLARIZING MICROSCOPE, 1970
N. KELLEYD. JELTEMAY. DUAN ET AL.: "The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation", INT J MOL SCI, vol. 20, no. 13, 2019, pages 3328
O. ALMARSSONM. J. ZAWOROTKO, CHEM. COMMUN., vol. 17, 2004, pages 1889 - 1896
P. BROZV. M. DIXIT: "Inflammasomes: mechanism of assembly, regulation and signaling", NAT REV IMMUNOL, vol. 16, no. 7, 2016, pages 407 - 20, XP037923191, DOI: 10.1038/nri.2016.58
P. KOCIENSKI, PROTECTIVE GROUPS, 2000
R. C. COLL, A. A. ROBERTSON, J.J. CHAE: "A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases", NAT MED, vol. 21, no. 3, 2015, pages 248 - 55, XP055745537, DOI: 10.1038/nm.3806
R. CAORSIL. LEPOREF. ZULIAN ET AL.: "The schedule of administration of canakinumab in cryopyrin associated periodic syndrome is driven by the phenotype severity rather than the age", ARTHRITIS RES THER, vol. 15, no. 1, 2013, pages R33, XP021147715, DOI: 10.1186/ar4184
R. M. RANSOHOFFM. A. BROWN: "Innate immunity in the central nervous system", J CLIN INVEST, vol. 122, no. 4, 2012, pages 1164 - 71
RICHARD LAROCK, COMPREHENSIVE ORGANIC TRANSFORMATIONS, 1999
S. AMORF. PUENTESD. BAKER ET AL.: "Inflammation in neurodegenerative diseases", IMMUNOLOGY, vol. 129, no. 2, 2010, pages 154 - 69
S. E. CORCORANR. HALAIM. A. COOPER: "Pharmacological Inhibition of the Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome with MCC950", PHARMACOL REV, vol. 73, no. 3, 2021, pages 968 - 1000
S. L. FINKB. T COOKSON: "Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages", CELL MICROBIOL, vol. 8, no. 11, 2006, pages 1812 - 25
S. M ALLANP. J. TYRRELLN. J. ROTHWELL: "Interleukin-1 and neuronal injury", NAT REV IMMUNOL,, vol. 5, no. 8, 2005, pages 629 - 40
S. M. BERGE ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
S. URIENC. BARDINB. BADER-MEUNIER ET AL.: "Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes", BMC PHARMACOL TOXICOL, vol. 14, 2013, pages 40, XP021162617, DOI: 10.1186/2050-6511-14-40
T. HIGUCHIV. STELLA: "Pro-drugs as Novel Delivery Systems", ACS SYMPOSIUM SERIES, 1975, pages 14
T. W. GREENEP. G. WUTS, PROTECTING GROUPS IN ORGANIC CHEMISTRY, 1999
VERMA ET AL., PHARMACEUTICAL TECHNOLOGY ON-LINE, vol. 25, no. 2, 2001, pages 1 - 14

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