WO2025240835A2 - Inhibiteurs de jak2 et leur utilisation en tant que produits pharmaceutiques - Google Patents

Inhibiteurs de jak2 et leur utilisation en tant que produits pharmaceutiques

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Publication number
WO2025240835A2
WO2025240835A2 PCT/US2025/029716 US2025029716W WO2025240835A2 WO 2025240835 A2 WO2025240835 A2 WO 2025240835A2 US 2025029716 W US2025029716 W US 2025029716W WO 2025240835 A2 WO2025240835 A2 WO 2025240835A2
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Prior art keywords
formula
compound
amino
methyl
oxo
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PCT/US2025/029716
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WO2025240835A3 (fr
Inventor
Xiaowei Wu
Andrew Combs
John Rose
Song MEI
Klare Lazor BERSCH
Danielle Roth
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Prelude Therapeutics Inc
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Prelude Therapeutics Inc
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Publication of WO2025240835A2 publication Critical patent/WO2025240835A2/fr
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Pending legal-status Critical Current
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the disclosure is directed to JAK2 inhibitors and methods of their use.
  • JAK Janus kinase family of kinases
  • JAK1, JAK2, JAK3, and TYK2 are a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals.
  • JAKs are in the cell selectively associated with the cytoplasmic domains of various cytokine receptors.
  • Receptor-associated JAKs are activated in a ligand-dependent manner. Upon binding of the ligand and subsequent activation, JAKs can phosphorylate another JAK protein on the paired receptor and the intracellular tail of the receptors to which the JAKs are bound.
  • phosphorylated peptides serve as docking sites for a family of transcription factors, the signal transducers and activators of transcription (STAT).
  • STAT signal transducers and activators of transcription
  • the STATs Upon binding of the STATs to the activated receptor-JAK complex, the STATs are phosphorylated, dimerize, and then are translocated to the nucleus where the binding of DNA and regulate gene expression occurs.
  • Alterations in JAK2 signaling can occur through point mutations/deletions/insertions or chromosomal translocations. These JAK2 alterations drive diseases that are primarily characterized by abnormal proliferation of terminally differentiated myeloid cells.
  • Examples of disease with JAK2 alterations are essential thrombocytosis or essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), primary myelofibrosis (PMF), and secondary myelofibrosis (SMF).
  • EGF essential thrombocytosis
  • PV polycythemia vera
  • MF myelofibrosis
  • PMF primary myelofibrosis
  • SMF secondary myelofibrosis
  • Clinical features of these diseases include progressive anemia, splenomegaly, and constitutional symptoms (cough, fatigue, puritus, and bone pain).
  • B 1 is CR B1 ;
  • B 2 is CR B2 or N
  • B 3 is CR B3 or N
  • B 4 is CR B4 or N
  • R B1 , R B2 , R B3 , and R B4 are each independently H, D, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, - O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -C 3 -C 8 cycloalkyl, -C 3 -C 10 cycloalkenyl, C 6 -C 1 o aryl, C 3 -C 10 heteroaryl, C 3 -C 10 heterocycloalkyl, C 3 -C 10 heterocycloalkenyl, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b
  • substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • C 1 -C 6 alkyl is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C 6 alkyl.
  • Co alkyl refers to a covalent bond.
  • the compounds of the invention are stable.
  • “stable” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
  • certain features of the invention which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub-combination.
  • alkyl when used alone or as part of a substituent group, refers to a straighter branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C1-C12”), preferably 1 to 6 carbons atoms (“C 1 -C 6 ”), in the group.
  • alkyl groups include methyl (Me, C 1 alkyl), ethyl (Et, C 2 alkyl), n-propyl (C 3 alkyl), isopropyl (C 3 alkyl), butyl (C4alkyl), isobutyl (C4alkyl), sec-butyl (C4alkyl), tert-butyl (C4alkyl), pentyl (C 3 alkyl), isopentyl (C 3 alkyl), tertpentyl (C 3 alkyl), hexyl (C 6 alkyl), isohexyl (C 6 alkyl), and the like. Alkyl groups may be optionally substituted.
  • the alkyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 - C 6 haloalkoxy, -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , -OC(O)NH(C 1 -C 6 alkyl), - OC(O)N(C 1 -C 6 alkyl)2, -S(O)2NH(C 1 -C 6 alkyl), and -S(O)2N(C 1 -C 6 alkyl)2.
  • substituents independently selected from -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and
  • the alkyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d ; or the alkyl group is optionally substituted by 1-6 R f groups.
  • halo or halogen refers to chloro, fluoro, bromo, or iodo.
  • cycloalkyl when used alone or as part of a substituent group refers to cyclic- containing, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms (“C 3 -C 10 ”), preferably from 3 to 6 carbon atoms (“C 3 .C 6 ”).
  • Cycloalkyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one multicyclic cycloalkyl group, the cyclic groups can share one common atom (i.e., spirocyclic).
  • the cyclic groups share two common atoms (e.g., fused or bridged).
  • cycloalkyl groups include, for example, cyclopropyl (C3), cyclobutyl (C4), cyclopropylmethyl (C4), cyclopentyl (C5), cyclohexyl (C 6 ), 1 -methylcyclopropyl (C4), 2-m ethylcyclopentyl (C4), adamantanyl (C10), spiro[3.3]heptanyl, bicyclo[3.3.0]octanyl, and the like.
  • Cycloalkyl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the cycloalkyl group is substituted, the cycloalkyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 - C 6 haloalkyl, and C 1 -C 6 haloalkoxy, -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , -OC(O)NH(C 1 - C 6 alkyl), -OC(O)N(C 1 -C 6 alkyl) 2 , -S(O) 2 NH(C 1 -C 6 alkyl), and -S(O) 2 N(C 1 -C 6 alkyl) 2 .
  • the cycloalkyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d ; or the cycloalkyl group is optionally substituted by 1-6 R f groups.
  • cycloalkenyl when used alone or as part of a substituent group refers to monocyclic or multi cyclic, partially saturated ring structure having from 3 to 10 carbon atoms (“C 3 -C 10 ”), preferably from 3 to 6 carbon atoms (“Cs-C 6 ”).
  • Cycloalkenyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one multicyclic cycloalkenyl group, the cyclic groups can share one common atom (z.e., spirocyclic).
  • the cyclic groups share two common atoms (e.g., fused or bridged).
  • the term -C3-C6 cycloalkenyl refers to a cycloalkenyl group having between three and six carbon atoms.
  • the cycloalkenyl group may be attached at any carbon atom of the partially saturated ring such that the result is a stable structure.
  • Cycloalkenyl groups include groups in which the partially saturated ring is fused to an aryl group.
  • cycloalkenyl groups include, for example, cyclopropenyl (C3), cyclobutenyl (C4), cyclopropenylmethyl (C4), cyclopentenyl (C5), cyclohexenyl (C 6 ), 1 -methylcyclopropenyl (C4), 2-m ethylcyclopentenyl (C4), adamantenyl (C10), spiro[3.3]heptenyl, bicyclo[3.3.0]octenyl, indanyl, and the like.
  • Cycloalkenyl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the cycloalkenyl group is substituted, the cycloalkenyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy, -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 - C 6 alkyl) 2 , -OC(O)NH(C 1 -C 6 alkyl), -OC(O)N(C 1 -C 6 alkyl) 2 , -S(O) 2 NH(C 1 -C 6 alkyl), and - S(O) 2 N(C 1 -C 6 alkyl) 2 .
  • the cycloalkenyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d ; or the cycloalkenyl group is optionally substituted by 1-6 R f groups.
  • heterocycloalkyl when used alone or as part of a substituent group refers to any three to twelve membered monocyclic or multicyclic, saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S.
  • Heterocycloalkyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups.
  • the cyclic groups can share one common atom (z.e., spirocyclic).
  • the cyclic groups share two common atoms (e.g., fused or bridged).
  • -C3-C6 heterocycloalkyl refers to a heterocycloalkyl group having between three and six carbon ring atoms.
  • the heterocycloalkyl group may be attached at any heteroatom or carbon atom of the group such that the result is a stable structure.
  • heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, azepanyl, diazepanyl, oxepanyl, dioxepanyl, azocanyl diazocanyl, oxocanyl, dioxocanyl, azaspiro[2.2]pentanyl, oxaazaspiro[3.3]heptanyl, p o
  • Heteroycloalkyl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the heterocycloalkyl group is substituted, the heterocycloalkyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy, - C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , -OC(O)NH(C 1 -C 6 alkyl), -OC(O)N(C 1 -C 6 alkyl) 2 , - S(O) 2 NH(C 1 -C 6 alkyl), and -S(O) 2 N(C 1 -C 6 alkyl) 2 .
  • substituents independently selected from
  • the heterocycloalkyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , - SR a , -NR a R d , or NR c R d ; or the heterocycloalkyl group is optionally substituted by 1-6 R f groups.
  • 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , - SR a , -NR a R d , or NR c R d ; or the heterocycloalkyl group is optionally substituted by 1-6 R f groups.
  • heterocycloalkenyl when used alone or as part of a substituent group refers to any three to twelve membered monocyclic or multicyclic, partially saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S.
  • Heterocycloalkenyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups.
  • the cyclic groups can share one common atom (z.e., spirocyclic).
  • the cyclic groups share two common atoms (e.g., fused or bridged).
  • the term -C3-C6 heterocycloalkenyl refers to a heterocycloalkenyl group having between three and six carbon atoms.
  • heterocycloalkenyl group may be attached at any heteroatom or carbon atom of ring system such that the result is a stable structure.
  • Heterocycloalkenyl groups include groups in which the partially saturated ring is fused to an aryl group, such as, for example isoindoline, , or for example a dihydroisoquinolinone such as 3,4-dihydroisoquinolin-l(2H)- one, which the partially saturated ring is fused to a heteroaryl group, such as, for example, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, wherein represents a point of attachment.
  • Heteroycloalkenyl groups of the disclosure are optionally substituted.
  • the heterocycloalkenyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy, -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , -OC(O)NH(C 1 -C 6 alkyl), - OC(O)N(C 1 -C 6 alkyl)2, -S(O)2NH(C 1 -C 6 alkyl), and -S(O)2N(C 1 -C 6 alkyl)2.
  • the heterocycloalkenyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d ; or the heterocycloalkenyl group is optionally substituted by 1-6 R f groups.
  • heterocyclic group when used alone or as part of a substituent group, refers to a heterocycloalkyl group or a heterocycloalkenyl group.
  • heteroaryl when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic ring structure including carbon atoms as well as up to five heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings can include a total of 5, 6, 7, 8, 9, or 10 ring atoms.
  • heteroaryl groups include but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, and the like.
  • Heteroaryl groups of the disclosure are optionally substituted.
  • the heteroaryl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 - C 6 haloalkoxy, -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , -OC(O)NH(C 1 -C 6 alkyl), - OC(O)N(C 1 -C 6 alkyl) 2 , -S(O) 2 NH(C 1 -C 6 alkyl), and -S(O) 2 N(C 1 -C 6 alkyl)2.
  • the heteroaryl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d ; or the heteroaryl group is optionally substituted by 1-6 R f groups.
  • aryl when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic carbon ring structure.
  • Aryl rings can include a total of 5, 6, 7, 8, 9, or 10 ring atoms. Examples of aryl groups include but are not limited to, phenyl, napthyl, and the like. Aryl groups of the disclosure are optionally substituted.
  • the aryl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 - C 6 haloalkyl, and C 1 -C 6 haloalkoxy, -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , -OC(O)NH(C 1 - C 6 alkyl), -OC(O)N(C 1 -C 6 alkyl) 2 , -S(O) 2 NH(C 1 -C 6 alkyl), and -S(O) 2 N(C 1 -C 6 alkyl) 2 .
  • the aryl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d ; or the aryl group is optionally substituted by 1-6 R f groups.
  • bicyclyl refers to a bicyclic ring system, i.e., a moiety that has two joined rings.
  • Bicyclyl groups include fused rings (i.e., the two rings share two adjacent atoms), spirocyclic rings (i.e., the two rings share one common atom) and bridged rings (i.e., the two rings share three or more common atoms).
  • the rings that comprise the bicyclyl group may be cycloalkyl, heterocycloalkyl, cycloakenyl, heterocycloalkenyl, aryl, heteroaryl, or any combination thereof.
  • the bicyclyl group is substituted.
  • the bicyclyl group is substituted by one of more of the groups described herein.
  • C 1 -C 6 when a range of carbon atoms is used herein, for example, C 1 -C 6 , all ranges, as well as individual numbers of carbon atoms are encompassed, for example, “C1-3” includes C1-3, C 1 - 2 , C 2 . 3, C 1 , C 2 , and C3.
  • C 1 -ealk refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, -CH 2 -, -CH(CHs)-, -CH(CH3)-CH 2 -, and -C(CH3) 2 -.
  • -Coalk- refers to a bond.
  • Co-C 6 alk when used alone or as part of a substituent group refers to an aliphatic linker having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.
  • -C 1 alk- for example, refers to a -CH 2 -.
  • -Coalk- refers to a bond.
  • the -C 1 -C 6 alkyl, -C 1 - C10 alkyl, -C 1 -C 8 alkoxide, -C 2 -C 6 alkenyl, -C 2 -C 10 alkenyl, -C 2 -C 6 alkynyl, -C 2 -C 1 oalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, and heterocycloalkyl groups are optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , - NR a R d , or NR c R d ; or the -C 1 -C 6 alkyl, -C1-C10 alkyl, -C 1 -C 8 alkoxide, -C2-C 6 alkenyl, -C2- C
  • alkoxy refers to an -O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • hydroxylalkyl refers to an alkyl group substituted by OH.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.
  • Geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • Compounds of the invention may also include tautomeric forms. All tautomeric forms are encompassed.
  • the compounds of the present invention may exist as rotational isomers. In some embodiments, the compounds of the present invention exist as mixtures of rotational isomers in any proportion. In other embodiments, the compounds of the present invention exist as particular rotational isomers, substantially free of other rotational isomers. [0030] Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. [0031] In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington ’s Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 1 (1977) p. 1-19, each of which is incorporated herein by reference in its entirety.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • a “solvate” refers to a physical association of a compound of Formula I with one or more solvent molecules.
  • “Subject” includes humans.
  • the terms “human,” “patient,” and “subject” are used interchangeably herein.
  • “Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treating” or “treatment” refers to delaying the onset of the disease or disorder.
  • Compounds of the present disclosure are meant to embrace compounds of Formula I as described herein, as well as its subgenera, which expression includes the stereoisomers (e.g., entaniomers, diastereomers) and constitutional isomers (e.g., tautomers) of compounds of Formula I as well as the pharmaceutically acceptable salts, where the context so permits.
  • stereoisomers e.g., entaniomers, diastereomers
  • constitutional isomers e.g., tautomers
  • isotopic variant refers to a compound that contains proportions of isotopes at one or more of the atoms that constitute such compound that is greater than natural abundance.
  • an “isotopic variant” of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non -radioactive isotopes such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • any hydrogen may be 2 H/D
  • any carbon may be 13 C
  • any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • stereoisomers compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers,” for example, diastereomers, enantiomers, and atropisomers.
  • the compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (A')- stereoisomers at each asymmetric center, or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include all stereoisomers and mixtures, racemic or otherwise, thereof.
  • a 2 is CR A2 or N;
  • a 3 is CR A3 or N
  • a 4 is O, S or NR A4 ;
  • a 5 is CR A5 or N
  • B 1 is CR B1 ;
  • B 2 is CR B2 or N
  • B 3 is CR B3 or N
  • B 4 is CR B4 or N
  • R B1 , R B2 , R B3 , and R B4 are each independently H, D, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, - O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -C 3 -C 8 cycloalkyl, -C 3 -C 10 cycloalkenyl, C 6 -C 1 o aryl, C 3 -C 10 heteroaryl, C 3 -C 10 heterocycloalkyl, C 3 -C 10 heterocycloalkenyl, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b
  • a 1 in Cy A in Formula (I) is CR A1 or N. In some embodiments, A 1 in Cy A in Formula (I) is CR A1 . In other embodiments, A 1 in Cy A in Formula (I) is N.
  • a 2 in Cy A in Formula (I) is CR A2 or N. In some embodiments, A 2 in Cy A in Formula (I) is CR A2 . In other embodiments, A 2 in Cy A in Formula (I) is N.
  • a 3 in Cy A in Formula (I) is CR A3 or N. In some embodiments, A 3 in Cy A in Formula (I) is CR A3 . In other embodiments, A 3 in Cy A in Formula (I) is N. [0046] In some embodiments, A 4 in Cy A in Formula (I) is O, S or NR A4 . In some embodiments, A 4 in Cy A in Formula (I) is NR A4 . In other embodiments, A 4 in Cy A in Formula (I) is O. In other embodiments, A 4 in Cy A in Formula (I) is S.
  • a 5 in Cy A in Formula (I) is CR A5 or N. In some embodiments, A 5 in Cy A in Formula (I) is CR A5 . In other embodiments, A 5 in Cy A in Formula (I) is N.
  • R 1 in Cy A in Formula (I) is H. In some embodiments, R 1 in Cy A in Formula (I) is OH. In some embodiments, R 1 in Cy A in Formula (I) is NH 2 . In some embodiments, R 1 in Cy A in Formula (I) is -NR c R d . In some embodiments, R 1 in Cy A in Formula (I) is -C(O)OR b . In some embodiments, R 1 in Cy A in Formula (I) is -C(O)NR c R d . In some embodiments, R 1 in Cy A in Formula (I) is -S(O)R b .
  • R 1 in Cy A in Formula (I) is -OC 1 -C 6 alkyl. In other embodiments, R 1 in Cy A in Formula (I) is C 1 -C 6 alkyl. In other embodiments, R 1 in Cy A in Formula (I) is C 1 -C 6 haloalkyl. In other embodiments, R 1 in Cy A in Formula (I) is -C 3 -C 8 cycloalkyl. In other embodiments, R 1 in Cy A in Formula (I) is -C3- C10 cycloalkenyl. In other embodiments, R 1 in Cy A in Formula (I) is C 6 -C 1 o aryl.
  • R 1 in Cy A in Formula (I) is C 3 -C 10 heteroaryl. In yet other embodiments, R 1 in Cy A in Formula (I) is C 3 -C 10 heterocycloalkyl. In yet other embodiments, R 1 in Cy A in Formula (I) is C 3 -C 10 hetero-cycloalkenyl.
  • the -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 - C 6 haloalkyl, C 3 -C 8 cycloalkyl, -C 3 -C 10 cycloalkenyl, aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl are optionally substituted by 1-6 R f groups.
  • R 20 in Cy A in Formula (I) is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 10 cycloalkenyl, C 6 -C 1 o aryl, C 3 -C 10 heteroaryl, C 3 -C 10 heterocycloalkyl, or C3- C10 heterocycloalkenyl, wherein said -C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 10 cycloalkenyl, C 6 -C 1 o aryl, C 3 -C 10 heteroaryl, C 3 -C 10 heterocycloalkyl, or C 3 -C 10 heterocycloalkenyl, are optionally substituted by 1-6 R f groups.
  • R 20 in Cy A in Formula (I) is C 1 -C 6 alkyl. In some embodiments, R 20 in Cy A in Formula (I) is C 1 -C 6 haloalkyl. In some embodiments, R 20 in Cy A in Formula (I) is -C 3 -C 8 cycloalkyl. In other embodiments, R 20 in Cy A in Formula (I) is -C 3 -C 10 cycloalkenyl. In other embodiments, R 20 in Cy A in Formula (I) is C 6 -C 1 o aryl. In other embodiments, R 20 in Cy A in Formula (I) is C 3 -C 10 heteroaryl.
  • R 20 in Cy A in Formula (I) is C3- C10 heterocycloalkyl. In yet other embodiments, R 20 in Cy A in Formula (I) is C 3 -C 10 heterocycloalkenyl. In yet other embodiments, the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C3- C10 cycloalkenyl, C 6 -C 1 o aryl, C3-C 10 heteroaryl, C3-C 10 heterocycloalkyl, or C 3 -C 10 heterocycloalkenyl, are optionally substituted by 1-6 R f groups.
  • R 20 in Cy A in Formula (I) is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C3- Cs cycloalkyl, wherein said - C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, is optionally substituted by 1-6 R f groups.
  • R 20 in Cy A in Formula (I) is C 1 -C 6 alkyl optionally substituted by 1-6 R f groups.
  • R 20 in Cy A in Formula (I) is C 1 - C 6 haloalkyl optionally substituted by 1-6 R f groups.
  • R 20 in Cy A in Formula (I) is C 3 -C 8 cycloalkyl optionally substituted by 1-6 R f groups.
  • R 20 in Cy A in Formula (I) is a C 3 -C 8 cycloalkyl group. In some embodiments, R 20 in Cy A in Formula (I) is a cyclopropyl group. In other embodiments, R 20 in Cy A in Formula (I) is a cyclobutyl group.
  • R 1 in Cy A in Formula (I) is
  • Cy A in Formula (I) is In some embodiments, R 1 in Cy A in Formula (I) is In some embodiments, R 1 in Cy A in Formula (I) is In some embodiments, R 1 in Cy A in Formula (I) is In other embodiments, R 1 in Cy A in
  • Formula (I) is in other embodiments, R 1 in Cy A in Formula (I) is . In other embodiments, R 1 in Cy A in Formula (I) is . In other embodiments, R 1 in Cy A in
  • Formula (I) is in other embodiments, R 1 in Cy A in Formula (I) is . In other embodiments, R 1 in Cy A in Formula (I) is . In yet other embodiments, R 1 in
  • Cy A in Formula (I) is .
  • R 1 in Cy A in Formula (I) is
  • R 1 in Cy A in Formula (I) is .
  • R 1 in Cy A in Formula (I) is .
  • R 1 in Cy A in . , y embodiments, R 1 in Cy A in Formula (I) In other embodiments, R 1 in Cy A in
  • R 1 in Cy A in Formula (I) is optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, or optionally substituted pyrazolyl. In some embodiments, R 1 in Cy A in Formula (I) is optionally substituted pyridinyl. In other embodiments, R 1 in Cy A in Formula (I) is optionally substituted pyrimidinyl. In other embodiments, R 1 in Cy A in Formula (I) is optionally substituted pyridazinyl. In other embodiments, R 1 in Cy A in Formula (I) is optionally substituted pyrazolyl.
  • R 1 in Cy A in Formula (I) is
  • R 1 in Cy A in Formula (I) is . In some embodiments, R 1 in Cy A in Formula (I) is In other embodiments, R 1 in Cy A in Formula (I) is
  • R 1 in Cy A in Formula ( yet other embodiments, R 1 in Cy A in Formula (I) is In yet other embodiments, R 1 in Cy A in Formula (I) is In yet other embodiments, R 1 in Cy A in Formula (I) is In yet other embodiments, R 1 in Cy A in Formula (I).
  • R A1 in Cy A in Formula (I) is H. In some embodiments, R A1 in Cy A in Formula (I) is D. In some embodiments, R A1 in Cy A in Formula (I) is halo. In some embodiments, R A1 in Cy A in Formula (I) is C 1 -C 6 alkyl. In some embodiments, R A1 in Cy A in Formula (I) is -OC 1 -C 6 alkyl. In some embodiments, R A1 in Cy A in Formula (I) is C 1 -C 6 haloalkyl. In some embodiments, R A1 in Cy A in Formula (I) is C 3 -C 8 cycloalkyl.
  • R A1 in Cy A in Formula (I) is -C2-C6 alkenyl. In other embodiments, R A1 in Cy A in Formula (I) is -C2-C6 alkynyl. In other embodiments, R A1 in Cy A in Formula (I) is -OR a . In other embodiments, R A1 in Cy A in Formula (I) is -SR a . In other embodiments, R A1 in Cy A in Formula (I) is -NR c R d . In other embodiments, R A1 in Cy A in Formula (I) is -NR a R c . In other embodiments, R A1 in Cy A in Formula (I) is -C(O)R b .
  • R A1 in Cy A in Formula (I) is -C(O)NR b OR b . In yet other embodiments, R A1 in Cy A in Formula (I) is S(O)2OR b . In yet other embodiments, R A1 in Cy A in Formula (I) is -OS(O)2OR b . In yet other embodiments, R A1 in Cy A in Formula (I) is -OPO(OR b )(OR b ).
  • R A2 in Cy A in Formula (I) is H. In some embodiments, R A2 in Cy A in Formula (I) is D. In some embodiments, R A2 in Cy A in Formula (I) is halo. In some embodiments, R A2 in Cy A in Formula (I) is C 1 -C 6 alkyl. In some embodiments, R A2 in Cy A in Formula (I) is -OC 1 -C 6 alkyl. In some embodiments, R A2 in Cy A in Formula (I) is C 1 -C 6 haloalkyl. In some embodiments, R A2 in Cy A in Formula (I) is C 3 -C 8 cycloalkyl.
  • R A2 in Cy A in Formula (I) is -C2-C6 alkenyl. In other embodiments, R A2 in Cy A in Formula (I) is -C2-C6 alkynyl. In other embodiments, R A2 in Cy A in Formula (I) is -OR a . In other embodiments, R A1 in Cy A in Formula (I) is -SR a . In other embodiments, R A2 in Cy A in Formula (I) is -NR c R d . In other embodiments, R A2 in Cy A in Formula (I) is -NR a R c . In other embodiments, R A2 in Cy A in Formula (I) is -C(O)R b .
  • R A2 in Cy A in Formula (I) is -C(O)NR b OR b . In yet other embodiments, R A2 in Cy A in Formula (I) is S(O)2OR b . In yet other embodiments, R A2 in Cy A in Formula (I) is -OS(O)2OR b . In yet other embodiments, R A2 in Cy A in Formula (I) is -OPO(OR b )(OR b ).
  • R A3 in Cy A in Formula (I) is H. In some embodiments, R A3 in Cy A in Formula (I) is D. In some embodiments, R A3 in Cy A in Formula (I) is halo. In some embodiments, R A3 in Cy A in Formula (I) is C 1 -C 6 alkyl. In some embodiments, R A3 in Cy A in Formula (I) is -OC 1 -C 6 alkyl. In some embodiments, R A3 in Cy A in Formula (I) is C 1 -C 6 haloalkyl. In some embodiments, R A3 in Cy A in Formula (I) is C 3 -C 8 cycloalkyl.
  • R A3 in Cy A in Formula (I) is -C2-C6 alkenyl. In other embodiments, R A3 in Cy A in Formula (I) is -C2-C6 alkynyl. In other embodiments, R A3 in Cy A in Formula (I) is -OR a . In other embodiments, R A3 in Cy A in Formula (I) is -SR a . In other embodiments, R A3 in Cy A in Formula (I) is -NR c R d . In other embodiments, R A3 in Cy A in Formula (I) is -NR a R c . In other embodiments, R A3 in Cy A in Formula (I) is -C(O)R b .
  • R A3 in Cy A in Formula (I) is -C(O)NR b OR b . In yet other embodiments, R A3 in Cy A in Formula (I) is S(O)2OR b . In yet other embodiments, R A3 in Cy A in Formula (I) is -OS(O)2OR b . In yet other embodiments, R A3 in Cy A in Formula (I) is -OPO(OR b )(OR b ).
  • At least one of R A1 , R A2 , or R A3 in Cy A in Formula (I) is H. In some embodiments, each of R A1 , R A2 , or R A3 in Cy A in Formula (I) is H. In other embodiments, at least one of R A1 , R A2 , or R A4 in Cy A in Formula (I) is H. In other embodiments, each of R A1 , R A2 , or R A4 in Cy A in Formula (I) is H. In yet other embodiments, at least one of R A1 , R A2 , R A3 or R A5 in Cy A in Formula (I) is H. In yet other embodiments, each of R A1 , R A2 , R A3 or R A5 in Cy A in Formula (I) is H.
  • R A4 in Cy A in Formula (I) is H. In some embodiments, R A4 in Cy A in Formula (I) is D. In some embodiments, R A4 in Cy A in Formula (I) is halo. In some embodiments, R A4 in Cy A in Formula (I) is C 1 -C 6 alkyl. In some embodiments, R A4 in Cy A in Formula (I) is -OC 1 -C 6 alkyl. In some embodiments, R A4 in Cy A in Formula (I) is C 1 -C 6 haloalkyl. In some embodiments, R A4 in Cy A in Formula (I) is C 3 -C 8 cycloalkyl.
  • R A4 in Cy A in Formula (I) is -C2-C6 alkenyl. In other embodiments, R A4 in Cy A in Formula (I) is -C2-C6 alkynyl. In other embodiments, R A4 in Cy A in Formula (I) is -OR a . In other embodiments, R A4 in Cy A in Formula (I) is -SR a . In other embodiments, R A4 in Cy A in Formula (I) is -NR c R d . In other embodiments, R A4 in Cy A in Formula (I) is -NR a R c . In other embodiments, R A4 in Cy A in Formula (I) is -C(O)R b .
  • R A4 in Cy A in Formula (I) is -C(O)NR b OR b . In yet other embodiments, R A4 in Cy A in Formula (I) is S(O)2OR b . In yet other embodiments, R A4 in Cy A in Formula (I) is -OS(O)2OR b . In yet other embodiments, R A4 in Cy A in Formula (I) is -OPO(OR b )(OR b ).
  • R A5 in Cy A in Formula (I) is H. In some embodiments, R A5 in Cy A in Formula (I) is D. In some embodiments, R A5 in Cy A in Formula (I) is halo. In some embodiments, R A5 in Cy A in Formula (I) is C 1 -C 6 alkyl. In some embodiments, R A5 in Cy A in Formula (I) is -OC 1 -C 6 alkyl. In some embodiments, R A5 in Cy A in Formula (I) is C 1 -C 6 haloalkyl. In some embodiments, R A5 in Cy A in Formula (I) is C 3 -C 8 cycloalkyl.
  • R A5 in Cy A in Formula (I) is -C2-C6 alkenyl. In other embodiments, R A5 in Cy A in Formula (I) is -C2-C6 alkynyl. In other embodiments, R A5 in Cy A in Formula (I) is -OR a . In other embodiments, R A5 in Cy A in Formula (I) is -SR a . In other embodiments, R A5 in Cy A in Formula (I) is -NR c R d . In other embodiments, R A5 in Cy A in Formula (I) is -NR a R c . In other embodiments, R A5 in Cy A in Formula (I) is -C(O)R b .
  • R A5 in Cy A in Formula (I) is -C(O)NR b OR b . In yet other embodiments, R A5 in Cy A in Formula (I) is S(O)2OR b . In yet other embodiments, R A5 in Cy A in Formula (I) is -OS(O)2OR b . In yet other embodiments, R A5 in Cy A in Formula (I) is -OPO(OR b )(OR b ).
  • B 2 in Cy B in Formula (I) is CR B2 or N. In some embodiments, B 2 in Cy B in Formula (I) is CR B2 . In other embodiments, B 2 in Cy B in Formula (I) is N.
  • B 3 in Cy B in Formula (I) is CR B3 or N. In some embodiments, B 3 in Cy B in Formula (I) is CR B3 . In other embodiments, B 3 in Cy B in Formula (I) is N.
  • B 4 in Cy B in Formula (I) is CR B4 or N. In some embodiments, B 4 in Cy B in Formula (I) is CR B4 . In other embodiments, B 4 in Cy B in Formula (I) is N.
  • R B1 in Cy B in Formula (I) is H, D, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -C 3 -C 8 cycloalkyl, -C 3 -C 10 cycloalkenyl, C 6 -C 1 o aryl, C3-C 10 heteroaryl, C 3 -C 10 heterocycloalkyl, C3-C 10 heterocycloalkenyl, -OH, -CN, -NO2, - C2-C6 alkenyl, -C2-C6 alkynyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C
  • R B1 in Cy B in Formula (I) is H. In some embodiments, R B1 in Cy B in Formula (I) is D. In some embodiments, R B1 in Cy B in Formula (I) is halo. In some embodiments, R B1 in Cy B in Formula (I) is C 1 -C 6 alkyl. In some embodiments, R B1 in Cy B in Formula (I) is C 1 -C 6 haloalkyl. In some embodiments, R B1 in Cy B in Formula (I) is -O-C 1 -C 6 alkyl. In some embodiments, R B1 in Cy B in Formula (I) is -O-C 1 -C 6 haloalkoxyl.
  • R B1 in Cy B in Formula (I) is -C 3 -C 8 cycloalkyl. In some embodiments, R B1 in Cy B in Formula (I) is -C 3 -C 10 cycloalkenyl. In some embodiments, R B1 in Cy B in Formula (I) is C 6 - C10 aryl. In some embodiments, R B1 in Cy B in Formula (I) is C 3 -C 10 heteroaryl. In some embodiments, R B1 in Cy B in Formula (I) is C 3 -C 10 heterocycloalkyl. In other embodiments, R B1 in Cy B in Formula (I) is C 3 -C 10 heterocycloalkenyl.
  • R B1 in Cy B in Formula (I) is -OH. In other embodiments, R B1 in Cy B in Formula (I) is -CN. In other embodiments, R B1 in Cy B in Formula (I) is -NO2. In other embodiments, R B1 in Cy B in Formula (I) is -C2-C6 alkenyl. In other embodiments, R B1 in Cy B in Formula (I) is -C2-C6 alkynyl. In other embodiments, R B1 in Cy B in Formula (I) is -OR a . In other embodiments, R B1 in Cy B in Formula (I) is -SR a .
  • R B1 in Cy B in Formula (I) is -NR c R d . In other embodiments, R B1 in Cy B in Formula (I) is -NR a R c . In other embodiments, R B1 in Cy B in Formula (I) is -C(O)R b . In other embodiments, R B1 in Cy B in Formula (I) is -OC(O)R b . In other embodiments, R B1 in Cy B in Formula (I) is -C(O)OR b . In other embodiments, R B1 in Cy B in Formula (I) is -C(O)NR c R d .
  • R B1 in Cy B in Formula (I) is -P(O)(OR b )(OR b ). In yet other embodiments, R B1 in Cy B in Formula (I) is - B(OR c )(OR d ). In yet other embodiments, R B1 in Cy B in Formula (I) is -S(O)2R b . In yet other embodiments, R B1 in Cy B in Formula (I) is -C(O)NR b OR b . In yet other embodiments, R B1 in Cy B in Formula (I) is -S(O)2OR b . In yet other embodiments, R B1 in Cy B in Formula (I) is - OS(O)2OR b .
  • R B1 in Cy B in Formula (I) is -OPO(OR b )(OR b ).
  • R B2 in Cy B in Formula (I) is H, D, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -C 3 -C 8 cycloalkyl, -C 3 -C 10 cycloalkenyl, C 6 -C 1 o aryl, C3-C 10 heteroaryl, C 3 -C 10 heterocycloalkyl, C3-C 10 heterocycloalkenyl, -OH, -CN, -NO2, - C2-C6 alkenyl, -C2-C6 alkynyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C
  • R B2 in Cy B in Formula (I) is H. In some embodiments, R B1 in Cy B in Formula (I) is D. In some embodiments, R B2 in Cy B in Formula (I) is halo. In some embodiments, R B2 in Cy B in Formula (I) is C 1 -C 6 alkyl. In some embodiments, R B2 in Cy B in Formula (I) is C 1 -C 6 haloalkyl. In some embodiments, R B2 in Cy B in Formula (I) is -O-C 1 -C 6 alkyl. In some embodiments, R B2 in Cy B in Formula (I) is -O-C 1 -C 6 haloalkoxyl.
  • R B2 in Cy B in Formula (I) is -C 3 -C 8 cycloalkyl. In some embodiments, R B2 in Cy B in Formula (I) is -C 3 -C 10 cycloalkenyl. In some embodiments, R B2 in Cy B in Formula (I) is C 6 - C10 aryl. In some embodiments, R B2 in Cy B in Formula (I) is C 3 -C 10 heteroaryl. In some embodiments, R B2 in Cy B in Formula (I) is C 3 -C 10 heterocycloalkyl. In other embodiments, R B2 in Cy B in Formula (I) is C 3 -C 10 heterocycloalkenyl.
  • R B2 in Cy B in Formula (I) is -OH. In other embodiments, R B2 in Cy B in Formula (I) is -CN. In other embodiments, R B2 in Cy B in Formula (I) is -NO2. In other embodiments, R B2 in Cy B in Formula (I) is -C2-C6 alkenyl. In other embodiments, R B2 in Cy B in Formula (I) is -C2-C6 alkynyl. In other embodiments, R B2 in Cy B in Formula (I) is -OR a . In other embodiments, R B2 in Cy B in Formula (I) is -SR a .
  • R B2 in Cy B in Formula (I) is -NR c R d . In other embodiments, R B2 in Cy B in Formula (I) is -NR a R c . In other embodiments, R B2 in Cy B in Formula (I) is -C(O)R b . In other embodiments, R B2 in Cy B in Formula (I) is -OC(O)R b . In other embodiments, R B2 in Cy B in Formula (I) is -C(O)OR b . In other embodiments, R B2 in Cy B in Formula (I) is -C(O)NR c R d .
  • R B2 in Cy B in Formula (I) is -P(O)(OR b )(OR b ). In yet other embodiments, R B2 in Cy B in Formula (I) is - B(OR c )(OR d ). In yet other embodiments, R B2 in Cy B in Formula (I) is -S(O)2R b . In yet other embodiments, R B2 in Cy B in Formula (I) is -C(O)NR b OR b . In yet other embodiments, R B2 in Cy B in Formula (I) is -S(O)2OR b . In yet other embodiments, R B2 in Cy B in Formula (I) is - OS(O)2OR b .
  • R B2 in Cy B in Formula (I) is -OPO(OR b )(OR b ).
  • R B3 in Cy B in Formula (I) is H, D, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -C 3 -C 8 cycloalkyl, -C 3 -C 10 cycloalkenyl, C 6 -C 1 o aryl, C3-C 10 heteroaryl, C 3 -C 10 heterocycloalkyl, C3-C 10 heterocycloalkenyl, -OH, -CN, -NO2, - C2-C6 alkenyl, -C2-C6 alkynyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C
  • R B3 in Cy B in Formula (I) is H. In some embodiments, R B3 in Cy B in Formula (I) is D. In some embodiments, R B3 in Cy B in Formula (I) is halo. In some embodiments, R B3 in Cy B in Formula (I) is C 1 -C 6 alkyl. In some embodiments, R B3 in Cy B in Formula (I) is C 1 -C 6 haloalkyl. In some embodiments, R B3 in Cy B in Formula (I) is -O-C 1 -C 6 alkyl. In some embodiments, R B3 in Cy B in Formula (I) is -O-C 1 -C 6 haloalkoxyl.
  • R B3 in Cy B in Formula (I) is -C 3 -C 8 cycloalkyl. In some embodiments, R B3 in Cy B in Formula (I) is -C 3 -C 10 cycloalkenyl. In some embodiments, R B3 in Cy B in Formula (I) is C 6 - C10 aryl. In some embodiments, R B3 in Cy B in Formula (I) is C 3 -C 10 heteroaryl. In some embodiments, R B3 in Cy B in Formula (I) is C 3 -C 10 heterocycloalkyl. In other embodiments, R B3 in Cy B in Formula (I) is C 3 -C 10 heterocycloalkenyl.
  • R B3 in Cy B in Formula (I) is -OH. In other embodiments, R B3 in Cy B in Formula (I) is -CN. In other embodiments, R B3 in Cy B in Formula (I) is -NO2. In other embodiments, R B3 in Cy B in Formula (I) is -C2-C6 alkenyl. In other embodiments, R B3 in Cy B in Formula (I) is -C2-C6 alkynyl. In other embodiments, R B3 in Cy B in Formula (I) is -OR a . In other embodiments, R B3 in Cy B in Formula (I) is -SR a .
  • R B3 in Cy B in Formula (I) is -NR c R d . In other embodiments, R B3 in Cy B in Formula (I) is -NR a R c . In other embodiments, R B3 in Cy B in Formula (I) is -C(O)R b . In other embodiments, R B3 in Cy B in Formula (I) is -OC(O)R b . In other embodiments, R B3 in Cy B in Formula (I) is -C(O)OR b . In other embodiments, R B3 in Cy B in Formula (I) is -C(O)NR c R d .
  • R B3 in Cy B in Formula (I) is -P(O)(OR b )(OR b ). In yet other embodiments, R B3 in Cy B in Formula (I) is - B(OR c )(OR d ). In yet other embodiments, R B3 in Cy B in Formula (I) is -S(O)2R b . In yet other embodiments, R B3 in Cy B in Formula (I) is -C(O)NR b OR b . In yet other embodiments, R B3 in Cy B in Formula (I) is -S(O)2OR b . In yet other embodiments, R B3 in Cy B in Formula (I) is - OS(O)2OR b .
  • R B3 in Cy B in Formula (I) is -OPO(OR b )(OR b ).
  • R B4 in Cy B in Formula (I) is H, D, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -C 3 -C 8 cycloalkyl, -C 3 -C 10 cycloalkenyl, C 6 -C 1 o aryl, C3-C 10 heteroaryl, C 3 -C 10 heterocycloalkyl, C3-C 10 heterocycloalkenyl, -OH, -CN, -NO2, - C2-C6 alkenyl, -C2-C6 alkynyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C
  • R B4 in Cy B in Formula (I) is H. In some embodiments, R B4 in Cy B in Formula (I) is D. In some embodiments, R B4 in Cy B in Formula (I) is halo. In some embodiments, R B4 in Cy B in Formula (I) is C 1 -C 6 alkyl. In some embodiments, R B4 in Cy B in Formula (I) is C 1 -C 6 haloalkyl. In some embodiments, R B4 in Cy B in Formula (I) is -O-C 1 -C 6 alkyl. In some embodiments, R B4 in Cy B in Formula (I) is -O-C 1 -C 6 haloalkoxyl.
  • R B4 in Cy B in Formula (I) is -C 3 -C 8 cycloalkyl. In some embodiments, R B4 in Cy B in Formula (I) is -C 3 -C 10 cycloalkenyl. In some embodiments, R B4 in Cy B in Formula (I) is C 6 - C10 aryl. In some embodiments, R B4 in Cy B in Formula (I) is C 3 -C 10 heteroaryl. In some embodiments, R B4 in Cy B in Formula (I) is C 3 -C 10 heterocycloalkyl. In other embodiments, R B4 in Cy B in Formula (I) is C 3 -C 10 heterocycloalkenyl.
  • R B4 in Cy B in Formula (I) is -OH. In other embodiments, R B4 in Cy B in Formula (I) is -CN. In other embodiments, R B4 in Cy B in Formula (I) is -NO2. In other embodiments, R B4 in Cy B in Formula (I) is -C2-C6 alkenyl. In other embodiments, R B4 in Cy B in Formula (I) is -C2-C6 alkynyl. In other embodiments, R B4 in Cy B in Formula (I) is -OR a . In other embodiments, R B4 in Cy B in Formula (I) is -SR a .
  • R B4 in Cy B in Formula (I) is -NR c R d . In other embodiments, R B4 in Cy B in Formula (I) is -NR a R c . In other embodiments, R B4 in Cy B in Formula (I) is -C(O)R b . In other embodiments, R 64 in Cy B in Formula (I) is -OC(O)R b . In other embodiments, R B4 in Cy B in Formula (I) is -C(O)OR b . In other embodiments, R B4 in Cy B in Formula (I) is -C(O)NR c R d .
  • R B4 in Cy B in Formula (I) is -P(O)(OR b )(OR b ). In yet other embodiments, R B4 in Cy B in Formula (I) is - B(OR c )(OR d ). In yet other embodiments, R B4 in Cy B in Formula (I) is -S(O)2R b . In yet other embodiments, R B4 in Cy B in Formula (I) is -C(O)NR b OR b . In yet other embodiments, R B4 in Cy B in Formula (I) is -S(O)2OR b . In yet other embodiments, R B4 in Cy B in Formula (I) is - OS(O)2OR b .
  • R B4 in Cy B in Formula (I) is -OPO(OR b )(OR b ).
  • R B2 and R B3 in Cy B in Formula (I) may, together with the carbon atoms to which they are attached, form a ring structure; or R B3 and R B4 in Cy B in Formula (I), may, together with the carbon atoms to which they are attached, form a ring structure; in Cy B in Formula (I), together with the carbon atoms to which they are attached, can form a ring structure.
  • R B2 and R B3 together with the carbon atoms to which they are attached, form a ring structure.
  • R B3 and R B4 in Cy B in Formula (I) together with the carbon atoms to which they are attached, form a ring structure.
  • R f in Formula (I) is H. In some embodiments, R f in Formula (I) is D. In some embodiments, R f in Formula (I) is oxo. In some embodiments, R f in Formula (I) is halogen. In some embodiments, R f in Formula (I) is -OC 1 -C 8 alkyl. In some embodiments, R f in Formula (I) is C 1 -C 8 alkyl.
  • the C 1 -C 8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d .
  • R f in Formula I is haloalkyl.
  • R f in Formula (I) is -OH.
  • R f in Formula (I) is -CN.
  • R f in Formula (I) is -NO2.
  • R f in Formula (I) is -C2-C6 alkenyl.
  • R f in Formula (I) is -C2-C6 alkynyl. In some embodiments, R f in Formula (I) is aryl. In some embodiments, R f in Formula (I) is heteroaryl. In some embodiments, R f in Formula (I) is cycloalkyl. In other embodiments, R f in Formula (I) is cycloalkenyl. In other embodiments, R f in Formula (I) is heterocycloalkyl. In other embodiments, R f in Formula (I) is heterocycloalkenyl. In other embodiments, R f in Formula (I) is -OR a . In other embodiments, R f in Formula (I) is -SR a .
  • R f in Formula (I) is -NR c R d . In other embodiments, R f in Formula (I) is - NR a R c . In other embodiments, R f in Formula (I) is -C(O)R b . In other embodiments, R f in Formula (I) is -OC(O)R b . In other embodiments, R f in Formula (I) is -C(O)OR b . In other embodiments, R f in Formula (I) is -C(O)NR c R d . In yet other embodiments, R f in Formula (I) is - S(O)R b .
  • R f in Formula (I) is -S(O)2R b . In yet other embodiments, R f in Formula (I) is - C(O)NR b OR b . In yet other embodiments, R f in Formula (I) is -S(O)2OR b . In yet other embodiments, R f in Formula (I) is -OS(O)2OR b . In yet other embodiments, R f in Formula (I) is - OPO(OR b )(OR b ).
  • each R a in Formula (I) is independently H, D, -C(O)R b , - R C ) 2 , - -C 1 oalkyl, - C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl.
  • R a in Formula (I) is -P(OR C )2, -P(O)R c R b , -P(O)OR c OR b , - S(O)R b , -S(O)NR c R d , -S(O)2R b , -S(O)2NR c R d , SiR b 3, and the like.
  • R a in Formula (I) is -C 1 -C 1 oalkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, and the like.
  • each R b in Formula (I) is independently H, D, -C 1 -C 6 alkyl, -C2- C 6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl.
  • R b in Formula (I) is H. In some embodiments, R b in Formula (I) is D. In some embodiments, R b in Formula (I) is -C 1 -C 6 alkyl. In some embodiments, R b in Formula (I) is -C2-C6 alkenyl. In some embodiments, R b in Formula (I) is -C2-C6 alkynyl. In other embodiments, R b in Formula (I) is aryl. In other embodiments, R b in Formula (I) is cycloalkyl. In other embodiments, R b in Formula (I) is cycloalkenyl. In other embodiments, R b in Formula (I) is heteroaryl. In other embodiments, R b in Formula (I) is heterocycloalkyl. In other embodiments, R b in Formula (I) is heterocycloalkenyl.
  • each R c or R d in Formula (I) is independently H, D, -C 1 -C 6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl.
  • R c or R d in Formula (I) is H. In some embodiments, R c or R d in Formula (I) is D. In some embodiments, R c or R d in Formula (I) is -C1-C10 alkyl. In some embodiments, R c or R d in Formula (I) is -C2-C6 alkenyl. In some embodiments, R c or R d in Formula (I) is -C2-C6 alkynyl. In other embodiments, R c or R d in Formula (I) is -OC 1 -C 6 alkyl. In other embodiments, R c or R d in Formula (I) is -O-cycloalkyl.
  • R c or R d in Formula (I) is aryl. In other embodiments, R c or R d in Formula (I) is cycloalkyl. In other embodiments, R c or R d in Formula (I) is cycloalkenyl. In other embodiments, R c or R d in Formula (I) is heteroaryl. In other embodiments, R c or R d in Formula (I) is heterocycloalkyl. In other embodiments, R c or R d in Formula (I) is heterocycloalkenyl.
  • R c and R d in Formula (I) form a monocyclic heterocycloalkyl.
  • R c and R d in Formula (I) form a multicyclic heterocycloalkyl.
  • R c and R d in Formula (I) form a monocyclic heterocyclo-alkenyl group.
  • R c and R d in Formula (I) form a multicyclic heterocyclo-alkenyl group.
  • Cy c in Formula (I) is a substituted bicyclyl.
  • the bicyclyl is substituted with -T-A-R, wherein T, A, and R have the meanings described herein.
  • the compound of Formula (I) is a compound of Formula (la): or a pharmaceutically acceptable salt or solvate thereof; wherein fused bicyclic group (/.c. , rings Cl and C2 share two atoms and the bonds between those atoms) wherein, ring Cl is an optionally substituted 5-6 membered aryl group or an optionally substituted 5-6 membered heteroaryl group; and ring C2 is a substituted 5-8 membered heterocyclyl group or a substituted 5-8 membered heteroaryl group.
  • ring Cl in Formula (la) is an optionally substituted 5-6 membered aryl group or an optionally substituted 5-6 membered heteroaryl group. In some embodiments, ring Cl in Formula (la) is an optionally substituted 5-6 membered aryl group. In other embodiments, ring Cl in Formula (la)is an optionally substituted 5-6 membered heteroaryl group.
  • ring C2 in Formula (la) is a substituted 5-8 membered heterocyclyl group or a substituted 5-8 membered heteroaryl group. In some embodiments, ring C2 in Formula (la) is a substituted 5-8 membered heterocyclyl group. In other embodiments, ring C2 in Formula (la) is a substituted 5-8 membered heteroaryl group.
  • X 1 is CR X1 or N
  • X 2 is CR X2 or N;
  • X 3 is CR X3 or N
  • X 4 is CR X4 or N
  • X 5 is CR X5 or N
  • X 6 is CR X6 or N
  • X 7 is O, S, C(R X7 ) 2 or NR X7 ;
  • X 8 is O, S, C(R X8 ) 2 or NR X8 ;
  • X 9 is O, S or NR X9 ; p is 0, 1 or 2; q is 0, 1 or 2; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • R 2 is -T-A-R
  • A is absent, an optionally substituted 5-6 membere
  • embodiments, in Formula (la) is other in Formula other embodiments, other embodi ments, in Formula in Formula other embodiments, yet other embodiments, in Formula yet other embodiments, yet other embodiments, in
  • X 1 in Formula (la) is CR X1 or N. In some embodiments, X 1 in Formula (la) is CR X1 . In other embodiments, X 1 in Formula (la) is N.
  • X 2 in Formula (la) is CR X2 or N. In some embodiments, X 2 in Formula (la) is CR X2 . In other embodiments, X 2 in Formula (la) is N.
  • X 3 in Formula (la) is CR X3 or N. In some embodiments, X 3 in Formula (la) is CR X3 . In other embodiments, X 3 in Formula (la) is N.
  • X 4 in Formula (la) is CR X4 or N. In some embodiments, X 4 in Formula (la) is CR X4 . In other embodiments, X 4 in Formula (la) is N.
  • X 5 in Formula (la) is CR X5 or N. In some embodiments, X 5 in Formula (la) is CR X5 . In other embodiments, X 5 in Formula (la) is N.
  • X 6 in Formula (la) is CR X6 or N. In some embodiments, X 6 in Formula (la) is CR X6 . In other embodiments, X 6 in Formula (la) is N.
  • X 7 in Formula (la) is O, S, C(R X7 )2 or NR X7 . In some embodiments, X 7 in Formula (la) is C(R X7 )2. In some embodiments, X 7 in Formula (la) is NR X7 . In other embodiments, X 7 in Formula (la) is O. In other embodiments, X 7 in Formula (la) is S.
  • X 8 in Formula (la) is O, S, C(R X8 )2 or NR X8 . In some embodiments, X 8 in Formula (la) is C(R X8 )2. In some embodiments, X 8 in Formula (la) is NR X8 . In other embodiments, X 8 in Formula (la) is O. In other embodiments, X 8 in Formula (la) is S.
  • X 9 in Formula (la) is O, S, or NR X9 . In some embodiments, X 9 in Formula (la) is O. In other embodiments, X 9 in Formula (la) is S. In other embodiments, X 9 in Formula (la) is NR X9 .
  • p in Formula (la) is 0, 1 or 2. In some embodiments, p in Formula (la) is 0. In other embodiments, p in Formula (la) is 1. In other embodiments, p in Formula (la) is 2.
  • q in Formula (la) is 0, 1 or 2. In some embodiments, q in Formula (la) is 0. In other embodiments, q in Formula (la) is 1. In other embodiments, q in Formula (la) is 2.
  • n in Formula (la) is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. In some embodiments, n in Formula (la) is 1. In some embodiments, n in Formula (la) is 2. In some embodiments, n in Formula (la) is 3. In some embodiments, n in Formula (la) is 4. In other embodiments, n in Formula (la) is 5. In other embodiments, n in Formula (la) is 6. In other embodiments, n in Formula (la) is 7. In other embodiments, n in Formula (la) is 8. In yet other embodiments, n in Formula (la) is 9. In yet other embodiments, n in Formula (la) is 10. In yet other embodiments, n in Formula (la) is 11. In yet other embodiments, n in Formula (la) is 12.
  • R 2 in Formula (la) is -T-A-R. In some embodiments, R 2 in Formula (la) is -Co-C 6 alk-A-R or -Co-C 6 alk-(CO)-Co-C 6 alk-A-R. In some embodiments, R 2 in Formula (la) is -Co-C 6 alk-A-R. In other embodiments, R 2 in Formula (la) is -CH2-A-R. In other embodiments, R 2 in Formula (la) is -Co-C 6 alk-(CO)-Co-C 6 alk-A-R. In other embodiments, R 2 in Formula (la) is -CH2-A-C(O)NR c R d . In yet other embodiments, R 2 in Formula (la) is -CH2-A- C(O)N(CH3)2. In yet other embodiments, R 2 in Formula (la) is -C(O)-A-R.
  • T is absent. In some embodiments, T is optionally substituted C1-6 alkyl. In some embodiments, T is -Co-C 6 alk-. In some embodiments, T is -Co-C 6 alk-C(O)- Co-C 6 alk-. In some embodiments, T is -Co-C 6 alk-O-Co-C 6 alk-. In some embodiments, T is -Co- C 6 alk-NR b -Co-C 6 alk-. In other embodiments, T is optionally substituted C3-12 cycloalkyl. In other embodiments, T is optionally substituted C3-12 heterocycloalkyl. In other embodiments, T is -C(O)-.
  • A is absent, an optionally substituted 5-6 membered aryl group, an optionally substituted 5-6 membered heteroaryl group, an optionally substituted 5-6 membered heterocycloalkyl group or an optionally substituted 5-6 membered heterocycloalkenyl group. In some embodiments, A is absent. In some embodiments, A is an optionally substituted 5-6 membered aryl group. In other embodiments, A is an optionally substituted 5-6 membered heteroaryl group. In other embodiments, A is an optionally substituted 5-6 heterocycloalkyl group. In other embodiments, A is an optionally substituted 5-6 membered heterocycloalkenyl group.
  • A is an optionally substituted 5-6 membered cycloalkyl group. In yet other embodiments, A is an optionally substituted 5-6 membered cycloalkenyl group. [00116] In some embodiments, A is an optionally substituted 6-membered heteroaryl group. In other embodiments, A is an optionally substituted pyridinyl. [00117] In some embodiments, A is an optionally substituted 5-membered heteroaryl group. In other embodiments, A is an optionally substituted pyrazolyl or thiazolyl. In other embodiments, A is an optionally substituted pyrazolyl. In other embodiments, A is an optionally substituted thiazolyl.
  • A is an optionally substituted 6-membered heterocycloalkyl group. In other embodiments, A is an optionally substituted piperidinyl.
  • A is an optionally substituted 5-membered heterocycloalkyl group. In other embodiments, A is an optionally substituted pyrrolidinyl.
  • A is an optionally substituted 6-membered cycloalkyl group. In other embodiments, A is an optionally substituted cyclohexyl group.
  • A is an optionally substituted 5-membered cycloalkyl group. In other embodiments, A is an optionally substituted cyclopentyl group.
  • A is an optionally substituted 6-membered heterocycloalkenyl group. In other embodiments, A is an optionally substituted 5-membered heterocycloalkenyl group.
  • A is an optionally substituted 6-membered cycloalkenyl group. In other embodiments, A is an optionally substituted 5-membered cycloalkenyl group.
  • R is -P(O)R c R b . In other embodiments, R is -P(O)OR c OR b . In other embodiments, R is -S(O)R b . In other embodiments, R is -S(O)NR c R d . In other embodiments, R is -S(O) 2 R b . In other embodiments, R is -S(O) 2 NR c R d . In other embodiments, R is SiR b 3. In other embodiments, R is -C 1 -C 1 oalkyl. In other embodiments, R is -C2-C10 alkenyl.
  • R is -C2-C10 alkynyl. In yet other embodiments, R is aryl. In yet other embodiments, R is cycloalkyl. In yet other embodiments, R is cycloalkenyl. In yet other embodiments, R is heteroaryl. In yet other embodiments, R is heterocycloalkyl. In yet other embodiments, R is heterocycloalkenyl. [00125] In some embodiments, R is H, -CN, -C(O)R b , -C(O)NR c R d , -S(O)2R b , or -C 1 -C 1 oalkyl, wherein:
  • R b is H or -C 1 -C 6 alkyl; each R c or R d is independently H or -C1-C10 alkyl, or R c and R d , together with the atom to which they are both attached, form a monocyclic heterocycloalkyl ring that is optionally substituted with 1-3 C 1 -C 6 alkyl or fluoro groups.
  • R c and R d are -CH3.
  • R 2 is -CH2-A-C(O)NR c R d , wherein each R c or R d is independently H or -C1-C10 alkyl, or R c and R d , together with the atom to which they are both attached, form a monocyclic heterocycloalkyl ring that is optionally substituted with 1-3 C 1 -C 6 alkyl or fluoro groups.
  • R c and R d are -CH3.
  • R 2 is , other embodiments, R 2 is
  • R 2 is In other embodiments, R 2 is In yet other embodiments, R 2 is In yet other embodiments, yet other embodiments, [00128] In some embodiments, some embodiments, R 2 is ,
  • each R 3 in Formula (la) is H. In some embodiments, each R 3 in Formula (la) is D. In some embodiments, each R 3 in Formula (la) is halo. In some embodiments, each R 3 in Formula (la) is C 1 -C 6 alkyl. In some embodiments, each R 3 in Formula (la) is -OC 1 -C 6 alkyl. In some embodiments, each R 3 in Formula (la) is C 1 -C 6 haloalkyl. In some embodiments, each R 3 in Formula (la) is C 3 -C 8 cycloalkyl. In some embodiments, each R 3 in Formula (la) is -C2-C6 alkenyl.
  • each R 3 in Formula (la) is -C2-C6 alkynyl. In other embodiments, each R 3 in Formula (la) is -OR a . In other embodiments, each R 3 in Formula (la) is -SR a . In other embodiments, each R 3 in Formula (la) is -NR c R d . In other embodiments, each R 3 in Formula (la) is -NR a R c . In other embodiments, each R 3 in Formula (la) is -C(O)R b . In other embodiments, each R 3 in Formula (la) is -C(O)OR b .
  • each R 3 in Formula (la) is -P(O)R b R b . In yet other embodiments, each R 3 in Formula (la) is -P(O)(OR b )(OR b ). In yet other embodiments, each R 3 in Formula (la) is - B(OR c )(OR d ). In yet other embodiments, each R 3 in Formula (la) is -S(O)2R b . In yet other embodiments, each R 3 in Formula (la) is -C(O)NR b OR b . In yet other embodiments, each R 3 in Formula (la) is S(O) 2 OR b . In yet other embodiments, each R 3 in Formula (la) is -OS(O) 2 OR b . In yet other embodiments, each R 3 in Formula (la) is -OPO(OR b )(OR b ).
  • At least one R 3 in Formula (la) is H. In some embodiments, at least one R 3 in Formula (la) is D. In some embodiments, at least one R 3 in Formula (la) is halo. In some embodiments, at least one R 3 in Formula (la) is C 1 -C 6 alkyl. In some embodiments, at least one R 3 in Formula (la) is -OC 1 -C 6 alkyl. In some embodiments, at least one R 3 in Formula (la) is C 1 -C 6 haloalkyl. In some embodiments, at least one R 3 in Formula (la) is C 3 -C 8 cycloalkyl.
  • At least one R 3 in Formula (la) is -C2-C6 alkenyl. In other embodiments, at least one R 3 in Formula (la) is -C2-C6 alkynyl. In other embodiments, at least one R 3 in Formula (la) is -OR a . In other embodiments, at least one R 3 in Formula (la) is -SR a . In other embodiments, at least one R 3 in Formula (la) is -NR c R d . In other embodiments, at least one R 3 in Formula (la) is -NR a R c . In other embodiments, at least one R 3 in Formula (la) is - C(O)R b .
  • At least one R 3 in Formula (la) is S(O)2OR b . In yet other embodiments, at least one R 3 in Formula (la) is -OS(O)2OR b . In yet other embodiments, at least one R 3 in Formula (la) is -OPO(OR b )(OR b ).
  • two R 3 groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cycloalkyl ring, an optionally substituted heterocycloalkyl ring, an optionally substituted cycloalkenyl ring, or an optionally substituted heterocycloalkenyl ring, wherein the ring is optionally substituted by 1-6 R f groups.
  • the spirocyclic ring that is an optionally substituted heterocycloalkyl ring is an optionally substituted cycloalkyl ring.
  • the spirocyclic ring that is an optionally substituted cycloalkenyl ring In other embodiments, the spirocyclic ring that is an optionally substituted heterocycloalkenyl ring.
  • two R 3 groups attached to adjacent carbon atoms, together with those carbon atoms form a ring that is an optionally substituted aryl ring, an optionally substituted heteroaryl ring, an optionally substituted cycloalkyl ring, or an optionally substituted cycloalkenyl ring, an optionally substituted heterocycloalkyl ring, or an optionally substituted heterocycloalkenyl ring; wherein the ring optionally substituted by 1-6 R f groups.
  • the ring is an optionally substituted aryl ring. In some embodiments, the ring is an optionally substituted heteroaryl ring. In other embodiments, the ring that is an optionally substituted cycloalkyl ring. In other embodiments, the ring is an optionally substituted heterocycloalkyl ring. In yet other embodiments, the ring that is an optionally substituted cycloalkenyl ring. In yet other embodiments, the ring is an optionally substituted heterocycloalkenyl ring.
  • two R 3 groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cyclopropyl ring, or any optionally substituted cyclobutyl ring, wherein the ring is optionally substituted by 1-6 R f groups.
  • two R 3 groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cyclopropyl ring, or any optionally substituted cyclobutyl ring, wherein the ring is optionally substituted by 1-2 -F.
  • R X1 in Formula (la) is H. In some embodiments, R X1 in Formula (la) is D. In some embodiments, R X1 in in Formula (la) is halo. In some embodiments, R X1 in Formula (la) is C 1 -C 6 alkyl. In some embodiments, R X1 in in Formula (la) is -OC 1 -C 6 alkyl. In some embodiments, R X1 in Formula (la) is C 1 -C 6 haloalkyl. In some embodiments, R X1 in Formula (la) is C 3 -C 8 cycloalkyl.
  • R X1 in Formula (la) is -C2-C6 alkenyl. In other embodiments, R X1 in Formula (la) is -C2-C6 alkynyl. In other embodiments, R X1 in Formula (la) is -OR a . In other embodiments, R X1 in Formula (la) is -SR a . In other embodiments, R X1 in Formula (la) is -NR c R d . In other embodiments, R X1 in Formula (la) is - NR a R c . In other embodiments, R X1 in Formula (la) is -C(O)R b .
  • R X1 in Formula (la) is S(O)2OR b . In yet other embodiments, R X1 in Formula (la) is -OS(O)2OR b . In yet other embodiments, R X1 in Formula (la) is -OPO(OR b )(OR b ).
  • R X1 in in Formula (la) is H or -OC 1 -C 6 alkyl. In some embodiments, R X1 in in Formula (la) is -OC 1 -C 6 alkyl. In some embodiments, R X1 in in Formula (la) is -OCH3, -OCH2CH3, or -OCH(CH3)2. In some embodiments, R X1 in in Formula (la) is - OCH3. In other embodiments, R X1 in in Formula (la) is -OCH2CH3. In other embodiments, R X1 in in Formula (la) is -OCH(CH3)2.
  • R X2 in Formula (la) is H. In some embodiments, R X2 in Formula (la) is D. In some embodiments, R X2 in in Formula (la) is halo. In some embodiments, R X2 in Formula (la) is C 1 -C 6 alkyl. In some embodiments, R X2 in in Formula (la) is -OC 1 -C 6 alkyl. In some embodiments, R X2 in Formula (la) is C 1 -C 6 haloalkyl. In some embodiments, R X2 in Formula (la) is C 3 -C 8 cycloalkyl.
  • R X2 in Formula (la) is -C2-C6 alkenyl. In other embodiments, R X2 in Formula (la) is -C2-C6 alkynyl. In other embodiments, R X2 in Formula (la) is -OR a . In other embodiments, R X2 in Formula (la) is -SR a . In other embodiments, R X2 in Formula (la) is -NR c R d . In other embodiments, R X2 in Formula (la) is - NR a R c . In other embodiments, R X2 in Formula (la) is -C(O)R b .
  • R X2 in Formula (la) is S(O)2OR b . In yet other embodiments, R X2 in Formula (la) is -OS(O)2OR b . In yet other embodiments, R X2 in Formula (la) is -OPO(OR b )(OR b ).
  • R X3 in Formula (la) is H. In some embodiments, R X3 in Formula (la) is D. In some embodiments, R X3 in in Formula (la) is halo. In some embodiments, R X3 in Formula (la) is C 1 -C 6 alkyl. In some embodiments, R X3 in in Formula (la) is -OC 1 -C 6 alkyl. In some embodiments, R X3 in Formula (la) is C 1 -C 6 haloalkyl. In some embodiments, R X3 in Formula (la) is C 3 -C 8 cycloalkyl.
  • R X3 in Formula (la) is -C2-C6 alkenyl. In other embodiments, R X3 in Formula (la) is -C2-C6 alkynyl. In other embodiments, R X3 in Formula (la) is -OR a . In other embodiments, R X3 in Formula (la) is -SR a . In other embodiments, R X3 in Formula (la) is -NR c R d . In other embodiments, R X3 in Formula (la) is - NR a R c . In other embodiments, R X3 in Formula (la) is -C(O)R b .
  • R X3 in Formula (la) is S(O) 2 OR b . In yet other embodiments, R X3 in Formula (la) is -OS(O) 2 OR b . In yet other embodiments, R X3 in Formula (la) is -OPO(OR b )(OR b ).
  • R X4 in Formula (la) is H. In some embodiments, R X4 in Formula (la) is D. In some embodiments, R X4 in in Formula (la) is halo. In some embodiments, R X4 in Formula (la) is C 1 -C 6 alkyl. In some embodiments, R X4 in in Formula (la) is -OC 1 -C 6 alkyl. In some embodiments, R X4 in Formula (la) is C 1 -C 6 haloalkyl. In some embodiments, R X4 in Formula (la) is C 3 -C 8 cycloalkyl.
  • R X4 in Formula (la) is -C2-C6 alkenyl. In other embodiments, R X4 in Formula (la) is -C2-C6 alkynyl. In other embodiments, R X4 in Formula (la) is -OR a . In other embodiments, R X4 in Formula (la) is -SR a . In other embodiments, R X4 in Formula (la) is -NR c R d . In other embodiments, R X4 in Formula (la) is - NR a R c . In other embodiments, R X4 in Formula (la) is -C(O)R b .
  • R X4 in Formula (la) is S(O)2OR b . In yet other embodiments, R X4 in Formula (la) is -OS(O)2OR b . In yet other embodiments, R X4 in Formula (la) is -OPO(OR b )(OR b ).
  • R X5 in Formula (la) is H. In some embodiments, R X5 in Formula (la) is D. In some embodiments, R X5 in in Formula (la) is halo. In some embodiments, R X5 in Formula (la) is C 1 -C 6 alkyl. In some embodiments, R X5 in in Formula (la) is -OC 1 -C 6 alkyl. In some embodiments, R X5 in Formula (la) is C 1 -C 6 haloalkyl. In some embodiments, R X5 in Formula (la) is C 3 -C 8 cycloalkyl.
  • R X5 in Formula (la) is -C2-C6 alkenyl. In other embodiments, R X5 in Formula (la) is -C2-C6 alkynyl. In other embodiments, R X5 in Formula (la) is -OR a . In other embodiments, R X5 in Formula (la) is -SR a . In other embodiments, R X5 in Formula (la) is -NR c R d . In other embodiments, R X5 in Formula (la) is - NR a R c . In other embodiments, R X5 in Formula (la) is -C(O)R b .
  • R X5 in Formula (la) is S(O)2OR b . In yet other embodiments, R X5 in Formula (la) is -OS(O)2OR b . In yet other embodiments, R X5 in Formula (la) is -OPO(OR b )(OR b ).
  • R X6 in Formula (la) is H. In some embodiments, R X6 in Formula (la) is D. In some embodiments, R X6 in in Formula (la) is halo. In some embodiments, R X6 in Formula (la) is C 1 -C 6 alkyl. In some embodiments, R X6 in in Formula (la) is -OC 1 -C 6 alkyl. In some embodiments, R X6 in Formula (la) is C 1 -C 6 haloalkyl. In some embodiments, R X5 in Formula (la) is C 3 -C 8 cycloalkyl.
  • R X6 in Formula (la) is -C2-C6 alkenyl. In other embodiments, R X6 in Formula (la) is -C2-C6 alkynyl. In other embodiments, R X6 in Formula (la) is -OR a . In other embodiments, R X6 in Formula (la) is -SR a . In other embodiments, R X6 in Formula (la) is -NR c R d . In other embodiments, R X6 in Formula (la) is - NR a R c . In other embodiments, R X6 in Formula (la) is -C(O)R b .
  • R X6 in Formula (la) is S(O)2OR b . In yet other embodiments, R X6 in Formula (la) is -OS(O)2OR b . In yet other embodiments, R X6 in Formula (la) is -OPO(OR b )(OR b ).
  • R X7 in Formula (la) is H. In some embodiments, R X7 in Formula (la) is D. In some embodiments, R X7 in in Formula (la) is halo. In some embodiments, R X7 in Formula (la) is C 1 -C 6 alkyl. In some embodiments, R X7 in in Formula (la) is -OC 1 -C 6 alkyl. In some embodiments, R X7 in Formula (la) is C 1 -C 6 haloalkyl. In some embodiments, R X7 in Formula (la) is C 3 -C 8 cycloalkyl.
  • R X7 in Formula (la) is -C2-C6 alkenyl. In other embodiments, R X7 in Formula (la) is -C2-C6 alkynyl. In other embodiments, R X7 in Formula (la) is -OR a . In other embodiments, R X7 in Formula (la) is -SR a . In other embodiments, R X7 in Formula (la) is -NR c R d . In other embodiments, R X7 in Formula (la) is - NR a R c . In other embodiments, R X7 in Formula (la) is -C(O)R b .
  • R X7 in Formula (la) is S(O) 2 OR b . In yet other embodiments, R X7 in Formula (la) is -OS(O) 2 OR b . In yet other embodiments, R X7 in Formula (la) is -OPO(OR b )(OR b ).
  • two R X7 groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cycloalkyl ring, an optionally substituted heterocycloalkyl ring, an optionally substituted cycloalkenyl ring, or an optionally substituted heterocycloalkenyl ring, wherein the ring is optionally substituted by 1-6 R f groups.
  • the spirocyclic ring that is an optionally substituted heterocycloalkyl ring is an optionally substituted
  • R X8 in Formula (la) is H, D, halo, C 1 -C 6 alkyl or -OC 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OR a , -SR a , -NR c R d , -NR a R c , - C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , -S(O)R b , -S
  • R X8 in Formula (la) is H. In some embodiments, R X8 in Formula (la) is D. In some embodiments, R X8 in in Formula (la) is halo. In some embodiments, R X8 in Formula (la) is C 1 -C 6 alkyl. In some embodiments, R X8 in in Formula (la) is -OC 1 -C 6 alkyl. In some embodiments, R X8 in Formula (la) is C 1 -C 6 haloalkyl. In some embodiments, R X8 in Formula (la) is C 3 -C 8 cycloalkyl.
  • R X8 in Formula (la) is -C2-C6 alkenyl. In other embodiments, R X8 in Formula (la) is -C2-C6 alkynyl. In other embodiments, R X8 in Formula (la) is -OR a . In other embodiments, R X8 in Formula (la) is -SR a . In other embodiments, R X8 in Formula (la) is -NR c R d . In other embodiments, R X8 in Formula (la) is - NR a R c . In other embodiments, R X8 in Formula (la) is -C(O)R b .
  • R X8 in Formula (la) is S(O) 2 OR b . In yet other embodiments, R X8 in Formula (la) is -OS(O) 2 OR b . In yet other embodiments, R X8 in Formula (la) is -OPO(OR b )(OR b ).
  • two R X8 groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cycloalkyl ring, an optionally substituted heterocycloalkyl ring, an optionally substituted cycloalkenyl ring, or an optionally substituted heterocycloalkenyl ring, wherein the ring is optionally substituted by 1-6 R f groups.
  • the spirocyclic ring that is an optionally substituted heterocycloalkyl ring is an optionally substituted
  • R X9 in Formula (la) is H, D, halo, C 1 -C 6 alkyl or -OC 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OR a , -SR a , -NR c R d , -NR a R c , - C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , -S(O)R b , -S
  • R X9 in Formula (la) is H. In some embodiments, R X9 in Formula (la) is D. In some embodiments, R X9 in in Formula (la) is halo. In some embodiments, R X9 in Formula (la) is C 1 -C 6 alkyl. In some embodiments, R X9 in in Formula (la) is -OC 1 -C 6 alkyl. In some embodiments, R X9 in Formula (la) is C 1 -C 6 haloalkyl. In some embodiments, R X9 in Formula (la) is C 3 -C 8 cycloalkyl.
  • R X8 in Formula (la) is -C2-C6 alkenyl.
  • R X9 in Formula (la) is -C2-C6 alkynyl.
  • R X9 in Formula (la) is -OR a .
  • R X9 in Formula (la) is -SR a .
  • R X9 in Formula (la) is -NR c R d .
  • R X9 in Formula (la) is - NR a R c .
  • R X9 in Formula (la) is -C(O)R b .
  • R X9 in Formula (la) is S(O) 2 OR b . In yet other embodiments, R X9 in Formula (la) is -OS(O) 2 OR b . In yet other embodiments, R X9 in Formula (la) is -OPO(OR b )(OR b ). in Formula (la) is in Formula (la) is in Formula (la) is in Formula (la) is yet other embodiments, yet other embodiments,
  • Cy B in Formula (I) or Formula some other embodiments Cy B in Formula (I) or Formula other embodiments, Cy B in Formula (I) or
  • B 1 in Cy B in Formula (I) or Formula (la) is CR B1 .
  • R B1 in Cy B in Formula (I) or Formula (la) is -O-C 1 -C 6 alkyl or -P(O)R b R b , wherein said -O-C 1 -C 6 alkyl is optionally substituted by 1-6 R f groups.
  • R B1 in Cy B in Formula (I) or Formula (la) is -C 1 -C 6 alkyl or - O-C 1 -C 6 alkyl. In some embodiments, R B1 in Cy B in Formula (I) or Formula (la) is -O-C 1 -C 6 alkyl. In other embodiments, R B1 in Cy B in Formula (I) or Formula (la) is -O-CH3.
  • R B1 in Cy B in Formula (I) or Formula (la) is -C 1 -C 6 alkyl. In some embodiments, R B1 in Cy B in Formula (I) or Formula (la) is methyl, trifluoromethyl, ethyl or isopropyl. In other embodiments, R B1 in Cy B in Formula (I) or Formula (la) is methyl. In other embodiments, R B1 in Cy B in Formula (I) or Formula (la) is trifluoromethyl. In other embodiments, R B1 in Cy B in Formula (I) or Formula (la) is ethyl. In other embodiments, R B1 in Cy B in Formula (I) or Formula (la) is isopropyl.
  • Cy B in Formula (I) or Formula In other embodiments, Cy B in Formula (I) or Formula yet other embodiments, Cy B in Formula (I) or Formula ( yet other embodiments,
  • Cy A in Formula (I) or Formula (la) is .
  • Cy A in Formula (I) or Formula (la) is n other embodiments, Cy A in Formula (I) or Formula (la) is .
  • Cy A in Formula (I) or Formula (la) is .
  • Cy A in Formula (I) or Formula (la) is yet other embodiments, Cy A in Formula (I) or Formula (la) is yet other embodiments, Cy A in Formula (I) or Formula (la) is
  • Cy A in Formula (I) or Formula (la) is .
  • Cy A in Formula (I) or Formula (la) is other embodiments, Cy A in Formula (I) or Formula (la) is .
  • Cy A in Formula (I) or Formula (la) is .
  • Cy A in Formula (I) or Formula (la) is yet other embodiments, Cy A in Formula (I) or Formula (la) is yet other embodiments, Cy A in Formula (I) or Formula (la) is
  • Cy A in Formula (I) or Formula ( some embodiments, Cy A in Formula (I) , other embodiments, Cy A in Formula (I) or Formula (la) is . In other embodiments, Cy A in Formula (I) or Formula (la) is other embodiments, Cy A in Formula (I) or Formula (la) is
  • Cy A in Formula (I) or Formula (la) is .
  • Cy A in Formula (I) or Formula (la) is .
  • Cy A in Formula (I) or Formula (la) is yet other embodiments, Cy A in Formula (I) or Formula (la) is
  • Cy A in Formula (I) or Formula (la) is
  • R 1 in Cy A in Formula (I) or Formula (la) is H. In some embodiments, R 1 in Cy A in Formula (I) or Formula (la) is C(O)R 20 . In some embodiments, R 1 in Cy A in Formula (I) or Formula (la) is optionally substituted aryl. In some embodiments, R 1 in Cy A in Formula (I) or Formula (la) is optionally substituted heteroaryl.
  • R 1 in Cy A in Formula (I) or Formula (la) is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 10 heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 10 heterocycloalkyl is optionally substituted by 1-6 R f groups.
  • R 1 in Cy A in Formula (I) or Formula (la) is C 1 -C 6 alkyl optionally substituted by 1-6 R f groups.
  • R 1 in Cy A in Formula (I) or Formula (la) is C 1 -C 6 haloalkyl optionally substituted by 1-6 R f groups. In other embodiments, R 1 in Cy A in Formula (I) or Formula (la) is C 3 -C 10 heterocycloalkyl optionally substituted by 1-6 R f groups.
  • R 20 in Cy A in Formula (I) or Formula (la) is a cycloalkyl group. In some embodiments, R 20 in Cy A in Formula (I) or Formula (la) is a cyclopropyl group.
  • the compounds of Formula (I) are:
  • the disclosure is directed to pharmaceutical compositions comprising compounds of Formula I, or a pharmaceutically acceptable salt or solvate thereof.
  • the subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • the pharmaceutical compositions contain pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • pharmaceutically acceptable excipients including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions.
  • the one or more compounds of the invention and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.
  • the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above)
  • the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 5%,
  • the concentration of one or more compounds of the invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v.
  • the concentration of one or more compounds of the invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.
  • the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009
  • the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g,
  • the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.
  • the compounds according to the invention are effective over a wide dosage range.
  • dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
  • An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • a pharmaceutical composition of the invention typically contains an active ingredient (i.e., a compound of the disclosure) of the present invention or a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including but not limited to inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • an active ingredient i.e., a compound of the disclosure
  • a pharmaceutically acceptable salt and/or coordination complex thereof include but not limited to inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • compositions for Oral Administration are non-limiting exemplary pharmaceutical compositions and methods for preparing the same.
  • Pharmaceutical Compositions for Oral Administration are non-limiting exemplary pharmaceutical compositions and methods for preparing the same.
  • the invention provides a pharmaceutical composition for oral administration containing a compound of the invention, and a pharmaceutical excipient suitable for oral administration.
  • the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration.
  • the composition further contains: (iv) an effective amount of a third agent.
  • the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption.
  • Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion.
  • Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds.
  • water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf- life or the stability of formulations over time.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
  • An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxy-propyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyr
  • suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof.
  • a lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.
  • the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • the tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.
  • a suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10.
  • An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value).
  • HLB hydrophilic-lipophilic balance
  • Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.
  • HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
  • Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycer
  • ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di -glycerides; succinylated mono- and diglycerides; citric acid esters of mono- and di -glycerides; and mixtures thereof.
  • Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl -2 -lacty late, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholyl sarcosine, capro
  • Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene stea,
  • hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyce
  • Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; poly oxy ethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof.
  • preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
  • the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection.
  • a solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
  • solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG ; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone,
  • solubilizers may also be used. Examples include, but not limited to, triacetin, tri ethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • the amount of solubilizer that can be included is not particularly limited.
  • the amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art.
  • the solubilizer can be in a weight ratio of 10%, 25%o, 50%), 100%o, or up to about 200%> by weight, based on the combined weight of the drug, and other excipients.
  • solubilizer may also be used, such as 5%>, 2%>, 1%) or even less.
  • the solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25%> by weight.
  • the composition can further include one or more pharmaceutically acceptable additives and excipients.
  • additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons.
  • pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)-aminomethane (TRIS) and the like.
  • bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids
  • Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
  • the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like.
  • Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
  • Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.
  • suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p- toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.
  • compositions for Injection are provided.
  • the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection.
  • a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection.
  • Components and amounts of agents in the compositions are as described herein.
  • the forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • Aqueous solutions in saline are also conventionally used for injection.
  • Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • certain desirable methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
  • compositions for Topical e.g., Transdermal Delivery.
  • the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.
  • compositions of the present invention can be formulated into preparations in solid, semisolid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions.
  • DMSO dimethylsulfoxide
  • carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients.
  • a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.
  • compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin.
  • suitable solid or gel phase carriers or excipients which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin.
  • penetration- enhancing molecules known to those trained in the art of topical formulation.
  • humectants e.g., urea
  • glycols e.g., propylene glycol
  • alcohols e.g., ethanol
  • fatty acids e.g., oleic acid
  • surfactants e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.glycerol monolaurate, sulfoxides, terpenes (e.g., menthol)
  • amines amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • transdermal delivery devices patches
  • Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, either with or without another agent.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • compositions for Inhalation are provided.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art.
  • Administration of the compounds or pharmaceutical composition of the present invention can be affected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally. [00237] The amount of the compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician.
  • an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day.
  • a compound of the invention is administered in a single dose.
  • administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly.
  • injection e.g., intravenous injection
  • other routes may be used as appropriate.
  • a single dose of a compound of the invention may also be used for treatment of an acute condition.
  • a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary. [00241] Administration of the compounds of the invention may continue as long as necessary.
  • a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
  • An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery -inserted cylindrical polymer.
  • a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty.
  • compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis.
  • a compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent.
  • a compound of the invention is admixed with a matrix.
  • Such a matrix may be a polymeric matrix and may serve to bond the compound to the stent.
  • Polymeric matrices suitable for such use include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g.
  • Compounds of the invention may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip-coating, and/or brush-coating.
  • the compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent.
  • the compound may be located in the body of the stent or graft, for example in microchannels or micropores.
  • stents When implanted, the compound diffuses out of the body of the stent to contact the arterial wall.
  • stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash.
  • compounds of the invention may be covalently linked to a stent or graft.
  • a covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages.
  • Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis.
  • the compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure.
  • the subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • the method typically comprises administering to a subject a therapeutically effective amount of a compound of the invention.
  • the therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein.
  • the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • IC50 refers to the half maximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e., an enzyme, cell, cell receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50% IC, or IC50).
  • IC50 refers to the plasma concentration required for obtaining 50% of a maximum effect in vivo.
  • the present disclosure provides a method of modulating JAK2 activity (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a JAK2 -mediated disorder in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing, to a subject in need thereof.
  • the present disclosure provides a method of treating a JAK2 -mediated disorder in a subject comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof
  • the subject has a mutant JAK2.
  • the subject has JAK2 containing a V617F mutations.
  • the term “JAK2 -mediated” disorders, diseases, and/or conditions means any disease or other deleterious condition in which J AK2 or a mutant thereof is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which JAK2, or a mutant thereof, is known to play a role.
  • Such JA.K2 -mediated disorders include, but are not limited to, cellular proliferative disorders (e g. cancer).
  • the JAK2-mediated disorder is a disorder mediated by a mutant JAK2.
  • the JAK2 -mediated disorder is a disorder mediated by a JAK2 containing a V617F mutations.
  • the present disclosure provides a method for treating a cellular proliferative disease, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing.
  • the present disclosure provides a method for treating a cellular proliferative disease, said method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof.
  • the method of treatmem comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said provided compound in a therapeutically effective amount to treat, suppress and/or prevent the disease state or condition in a subject in need of such treatment.
  • the subject has a mutant JAK2.
  • the subject has JAK2 containing a V617F mutation.
  • the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said composition in a therapeutically effective amount to treat, suppress and/or prevent the disease state or condition in a subject in need of such treatment.
  • the subject has a mutant JAK2.
  • the subject has JAK2 containing a V6I7F mutation.
  • Another aspect of the disclosure provides a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for use in the treatment of a disorder described herein.
  • Another aspect of the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for the treatment of a disorder described herein.
  • the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disorder described herein.
  • the disorder is a cellular proliferative disease.
  • the cellular proliferative disease is cancer.
  • the cancer is a tumor.
  • the cancer is a hematopoietic cancer.
  • the cancer is a solid tumor.
  • the cellular proliferative disease is a tumor and/or cancerous cell growth.
  • the cellular proliferative disease is a tumor.
  • the cellular proliferative disease is a solid tumor.
  • the cellular proliferative disease is a cancerous cell growth.
  • the cancer is selected from sarcoma; lung; bronchus; prostate, breast (including sporadic breast cancers and sufferers of Cowvlen disease); pancreas; gastrointestinal; colon; rectum; carcinoma; colon carcinoma; adenoma, colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma; glioblastoma, endometrial; melanoma; kidney; renal pelvis, urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); multiple myeloma; esophagus; a leukemia; acute myelogenous leukemia; acute megakaryocytic leukemia; chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia; T-cell acute lymphoblastic leukemia
  • lymphoma a mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; neck; head; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; ami Waldenstrom macroglobulinemia.
  • the cancer is selected from lung, bronchus; prostate; breast (including sporadic breast cancers and Cowden disease); pancreas; gastrointestinal; colon; rectum; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; endometrial; kidney, renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); esophagus; a leukemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; neck; and head.
  • the cancer is selected from sarcoma; carcinoma; colon carcinoma; adenoma; colorectal adenoma; glioma, glioblastoma; melanoma; multiple myeloma; a carcinoma of the brain; non-Hodgkin lymphoma; villous colon adenoma; a neoplasia, a neoplasia of epithelial character; lymphoma; a mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstrom macroglobulinemia.
  • the cancer is selected from lung; bronchus; prostate; breast (including sporadic breast cancers and Cowden disease); pancreas; gastrointestinal; colon; rectum; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland, stomach; gastric; endometrial; kidney; renal pelvis, urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); esophagus; brain; oral cavity and pharynx; larynx, small intestine; neck; and head.
  • the cancer is a leukemia.
  • the cancer is acute myelogenous leukemia; chronic myelogenous leukemia, lymphocytic leukemia, or myeloid leukemia.
  • the cancer is breast cancer (including sporadic breast cancers and Cowden disease). In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ER+/HER2- breast cancer. In some embodiments, the cancer is ER+/HER2- breast cancer, and the subject is intolerant to, or ineligible for, treatment with alpelisib. In some embodiments, the cancer is sporadic breast cancer. In some embodiments, the cancer is Cowden disease. [00264] In some embodiments, the cellular proliferative disease has mutant JAK2. In some embodiments, the cellular proliferative disease is a myeloproliferative disorder. In some embodiments, the cancer has mutant JAK2. In some embodiments, the hematopoietic cancer has mutant JAK2. In some embodiments, the myeloproliferative disorder has mutant JAK2.
  • the cancer is adenoma; carcinoma, sarcoma, glioma; glioblastoma; melanoma; multiple myeloma; or lymphoma.
  • the cancer is a colorectal adenoma or avillous colon adenoma.
  • die cancer is colon carcinoma; a carcinoma of the brain; a mammary' carcinoma; basal cell carcinoma; or a squamous cell carcinoma.
  • the cancer is a neoplasia or a neoplasia of epithelial character.
  • the cancer is non-Hodgkin lymphoma.
  • the cancer is actinic keratosis; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; or Waldenstrom macroglobulinemia.
  • the cellular proliferative disease displays overexpression or amplification of JAK2, or somatic mutation of JAK2.
  • the JAK2-mediated disorder is selected from the group consisting of: polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, PROS (PI3K-related overgrowth syndrome), venous malformation.
  • Loftier’s syndrome eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonaiy aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophil -related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia greata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, autoimmune haematogical disorders (e.g.
  • haemolytic anaemia haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven -Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine opthalmopathy.
  • haemolytic anaemia aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus polychondritis
  • Wegener granulomatosis dermatomyositis
  • chronic active hepatitis myasthenia gravis
  • Steven -Johnson syndrome idiopathic sprue
  • Graves’ disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.
  • the JAK2-mediated disorder is polycythemia vera, essential thrombocythemia, or myelofibrosis with myeloid metaplasia.
  • the JAK2- mediated disorder is asthma, COPD, ARDS, PROS (PI3K-related overgrowth syndrome), venous malformation, Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), or bronchopulmonary aspergillosis.
  • the JAK2-mediated disorder is polyarteritis nodosa (including Churg- Strauss syndrome), eosinophilic granuloma, eosinophil -related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, or scleroderma.
  • polyarteritis nodosa including Churg- Strauss syndrome
  • eosinophilic granuloma including Churg- Strauss syndrome
  • eosinophil -related disorders affecting the airways occasioned by drug-reaction psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, or scleroderma.
  • the J AK2 -mediated disorder is vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, or autoimmune baematogical disorders (e.g. haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia).
  • autoimmune baematogical disorders e.g. haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia.
  • the JAK2-mediated disorder is systemic lupus erythematosus, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven- Johnson syndrome, idiopathic sprue, or autoimmune inflammatory' bowel disease (e.g. ulcerative colitis and Crohn's disease).
  • the JAK2 -mediated disorder is endocrine opthalmopathy, Graves’ disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, or psoriatic arthritis.
  • the JAK2-mediated disorder is glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, or reperfusion injuries.
  • the JAK2 -mediated disorder is retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.
  • the J.AK2 -mediated disorder is myelofibrosis (MF), polycythemia Vera (PV), essential thrombocythemia (ET), acute megakaryocytic leukemia, T- cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), acute myeloid leukemia (AML), Chronic Myelomonocytic Leukemia (CMML), T-cell large granular lymphocytic leukemia (T-LGL), T-cell prolymphocyiic leukemia (T-PLL), or graft versus host disease (GVHD).
  • MF myelofibrosis
  • PV polycythemia Vera
  • ET essential thrombocythemia
  • acute megakaryocytic leukemia T- cell acute lymphoblastic leukemia
  • T-ALL T- cell acute lymphoblastic leukemia
  • B-ALL B-cell acute lymphoblastic leukemia
  • the reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., J H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., J H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), or mass spectrometry
  • chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • ambient temperature e.g., a reaction temperature
  • room temperature e.g., a temperature from about 20 °C to about 30 °C.
  • the reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ! H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., ! H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), or mass spectrometry
  • HPLC high performance liquid chromatography
  • ambient temperature e.g. a reaction temperature
  • room temperature e.g. a temperature that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.
  • Compounds of Formula (I) can be prepared as shown in Scheme 1.
  • Compounds 1-1 where Y 1 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with compounds 1-2 where M 1 is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal, such as Sn(Bu)s, or ZnCl, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]dichloro-palladium(II) and a base, such as K3PO4), or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0)), or standard Negishi conditions (e.g., in the presence of a palla
  • compounds 1-1 can be coupled with compounds 1-4, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to afford compounds 1-6.
  • a palladium catalyst such as XPhos Pd G3
  • a base such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide
  • Y 1 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs)
  • M 1 is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal, such as Sn(Bu)3, or ZnCl
  • Suzuki conditions e.g., in the presence of a palladium catalyst, such as [1,1'- bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) and a base, such as K3PO4
  • a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(0)
  • Negishi conditions e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)pal
  • Compounds of Formula (IA) can be prepared as shown in Scheme 2.
  • Compounds 2-1 where Y 2 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with compounds 2-2, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)-amide to provide compounds 2-3.
  • a palladium catalyst such as XPhos Pd G3
  • a base such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as lithium bis(trimethylsilyl)-amide to provide compounds 2-3.
  • Coupling of compounds 2-3 where Y 1 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) with compounds 1-2 under standard Suzuki conditions e.g., in the presence of a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]dichloro-palladium(II) and a base, such as K3PO4
  • a palladium catalyst such as [1,1'- bis(diphenylphosphino)ferrocene]dichloro-palladium(II) and a base, such as K3PO4
  • standard Stille conditions e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0)
  • Negishi conditions e.g., in the presence of a palladium catalyst, such as tetrakis(triphenyl
  • a palladium catalyst such as XPhos Pd G3
  • a base such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide
  • a palladium catalyst such as Pd2(dba)3, ligand, such as XantPhos
  • a base such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide
  • Compounds of Formula (IAa) can be prepared as shown in Scheme 3.
  • Compounds 3- 1 where Y 2 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with compounds 2-2, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)-amide) to provide compounds 3-2.
  • a palladium catalyst such as XPhos Pd G3
  • a base such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as lithium bis(trimethylsilyl)-amide
  • Reaction of thioethers 3-2 where R a is alkyl (e.g., methyl, ethyl, isopropyl) under oxidative conditions (e.g., in the presence of an oxidant such as mCPBA) can provide sulfones 3-3.
  • Sulfones 3-3 can react with protected amines 3-4 (e.g., p-methoxybenzyl-amine), under nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to afford compounds 3-5.
  • protected amines 3-4 e.g., p-methoxybenzyl-amine
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide
  • Compounds 3-5 where Y 1 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with compounds 1-2 where M 1 is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal, such as Sn(Bu)3, or ZnCl, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base, such as K3PO4), or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0)), or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)pal
  • Compounds of Formula (IB) and Formula (IBa) can be prepared as shown in Scheme 4.
  • Compounds 4-1 where Y 2 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with compounds 2-2, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to provide compounds 4-2.
  • a palladium catalyst such as XPhos Pd G3
  • a base such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide
  • Compounds 4-2 where Y 3 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with protected amines 3-4 (e.g., p-methoxybenzylamine), under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to provide compounds 4-3.
  • a palladium catalyst such as XPhos Pd G3
  • a base such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide
  • Y 1 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs)
  • M 1 is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal, such as Sn(Bu)3, or ZnCl
  • Suzuki conditions e.g., in the presence of a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base, such as K3PO4
  • a palladium(O) catalyst such as tetrakis(triphenyl- phosphine)palladium(O)
  • Negishi conditions e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphin
  • the deprotection reaction of compounds 4-4 can afford compounds of Formula (IBa).
  • Coupling of amines of Formula (IBa) with acids 4-5 using standard amide coupling conditions e.g., in the presence of a coupling reagent such as HATU, and an optional base such as triethylamine
  • acylation of amines of Formula (IBa) with compounds 4-6 where Y a is halogen (e.g., F, Cl, Br, or I) can afford compounds of Formula (IB).
  • Compounds of Formula (IC) can be prepared as shown in Scheme 5.
  • Compounds 2-2 where Y 1 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with compounds 1-2 where M 1 is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal, such as Sn(Bu)s, or ZnCl, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]dichloro-palladium(II) and a base, such as K3PO4), or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0)), or standard Negishi conditions (e.g., in the presence of a palla
  • Compounds 5- 2 where Y 2 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with amines 5-1, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to provide compounds 5-3.
  • a palladium catalyst such as XPhos Pd G3
  • a base such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide
  • Y 3 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs)
  • Y 3 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs)
  • a palladium catalyst such as XPhos Pd G3
  • a base such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide
  • Compounds of Formula (ID) can be prepared as shown in Scheme 6.
  • Compounds 6-1 where Y 2 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with amines 5-1, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)-amide) to provide compounds 6-2.
  • a palladium catalyst such as XPhos Pd G3
  • a base such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as lithium bis(trimethylsilyl)-amide
  • Y b is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base, such as sodium hydride, can provide compounds 8-6.
  • halogen e.g., F, Cl, Br, or I
  • pseudohalogen e.g., OTf or OMs
  • Compound 8-6 where Y 4 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 8-7 (e.g., M 1 is B(OH)2, Bpin, BF3K, Sn(Bu)3, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [ 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base, such as potassium acetate).
  • a diboron reagent such as bis(pinacolato)diboron
  • a palladium catalyst such as [ 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base, such as potassium acetate.
  • Reduction of nitriles 9-2 where R a is alkyl (e.g., methyl, ethyl, isopropyl) under standard conditions, such as in the presence of a reducing agent (e.g., borane tetrahydrofuran complex), can provide the cyclized product compounds 9-3.
  • a reducing agent e.g., borane tetrahydrofuran complex
  • Alkylation of amides 9-3 with suitable compounds 8-5 where Y b is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base, such as sodium hydride, can provide compounds 9-4.
  • Compound 9-4 where Y 4 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 9-5 (e.g., M 1 is B(OH)2, Bpin, BF3K, Sn(Bu)s, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [l,l'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) and a base, such as potassium acetate).
  • a diboron reagent such as bis(pinacolato)diboron
  • a palladium catalyst such as [l,l'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
  • a base such as potassium
  • Reduction of nitriles 10-4 under standard conditions, such as in the presence of a reducing agent can provide the cyclized product compounds 10-5.
  • a reducing agent e.g., borane tetrahydrofuran complex
  • Compound 11-2 where Y 4 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 11-3 (e.g., M 1 is B(OH)2, Bpin, BF3K, Sn(Bu)s, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [1,1'- bis(diphenylphosphino)-ferrocene]dichloropalladium(II) and a base, such as potassium acetate).
  • a diboron reagent such as bis(pinacolato)diboron
  • a palladium catalyst such as [1,1'- bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
  • a base such as potassium a
  • Compound 12-3 where Y 4 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 12-4 (e.g., M 1 is B(OH)2, Bpin, BF3K, Sn(Bu)s, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [l,l'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) and a base, such as potassium acetate).
  • a diboron reagent such as bis(pinacolato)diboron
  • a palladium catalyst such as [l,l'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
  • a base such as potassium
  • Compound 13-2 where Y 4 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 13-3 (e.g., M 1 is B(OH)2, Bpin, BF3K, Sn(Bu)s, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [l,l'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) and a base, such as potassium acetate).
  • a diboron reagent such as bis(pinacolato)diboron
  • a palladium catalyst such as [l,l'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) and a base, such as potassium
  • Cyclization of compounds 14-4 under standard conditions, such as in the presence of a Lewis acid (e.g., AlCh), can provide the compounds 14-5.
  • Alkylation of amides 14-5 with suitable compounds 8-5 where Y b is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base, such as sodium hydride, can provide compounds 14-6.
  • a base such as sodium hydride
  • Compound 14- 7 where Y 4 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 14-8 (e.g., M 1 is B(OH)2, Bpin, BF3K, Sn(Bu)3, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II) and a base, such as potassium acetate).
  • a diboron reagent such as bis(pinacolato)diboron
  • a palladium catalyst such as [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II) and a base, such
  • Nucleophilic substitution of the compounds 15-2 with a suitable amide bicycle 8-4 in the presence of a base, such as sodium hydride, can furnish tertiary amides 15-3.
  • Hydrolysis of esters 15-3 with a suitable base, such as LiOH, NaOH, or KOH can give carboxylic acids 15-4.
  • Coupling of amines 15-5 with acids 15-4 using standard amide coupling conditions e.g., in the presence of a coupling reagent such as HATU, and an optional base such as triethylamine
  • a coupling reagent such as HATU
  • an optional base such as triethylamine
  • esters 16-3 Hydrolysis of esters 16-3 with a suitable base, such as LiOH, NaOH, or KOH, can give carboxylic acids 16-4.
  • Coupling of amines 15-5 with acids 16-4 using standard amide coupling conditions e.g., in the presence of a coupling reagent such as HATU, and an optional base such as triethylamine) can provide the compounds 16-5.
  • HC1 deprotection of TBS protected alcohols can provide the deprotected alcohols 18-5.
  • Halogenation of alcohols 18-5 in the presence of an electrophilic halogenating, such as thionyl chloride or phosphorus bromide, or sulfonylation reagent, such as methanesulfonyl chloride, can provide compounds 18-6 where Y b is a halogen (e.g. F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs).
  • Y b is a halogen (e.g. F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs).
  • Compounds 19-3 where Y 3 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with amines 2-5 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, a ligand such as BrettPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to provide compounds 19-4.
  • a palladium catalyst such as BrettPhos Pd G3, a ligand such as BrettPhos, and a base, such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide
  • Compounds 20-2 where Y 3 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with protected amines 3-4 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, a ligand such as BrettPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as N,N- diisopropylethylamine at elevated temperatures) to provide the compounds 20-3.
  • a palladium catalyst such as BrettPhos Pd G3, a ligand such as BrettPhos
  • a base such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as N,N- diisopropylethylamine at elevated temperatures
  • TFA deprotection of a PMB or DMB protecting group can furnish the compounds 20-4.
  • Coupling of compounds 20-4 with acids 4-5 using standard amide coupling conditions e.g., in the presence of a coupling reagent such as HATU, and an optional base such as triethylamine
  • acylation of amines 20-4 with compounds 4-6 where Y a is a halogen (e.g., F, Cl, Br, or I) can afford compounds 20-5.
  • tert-butyl carbamate under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as Pd2(dba)s, ligand, such as XantPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to give compounds 21-2.
  • a palladium catalyst such as Pd2(dba)s
  • ligand such as XantPhos
  • base such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide
  • Compounds 21-2 where Y 3 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with amines 2-5 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, a ligand such as BrettPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as N,N- diisopropylethylamine at elevated temperatures) to provide the compounds 21-3.
  • a palladium catalyst such as BrettPhos Pd G3, a ligand such as BrettPhos
  • a base such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as N,N- diisopropylethylamine at elevated temperatures
  • TFA deprotection of a Boc, PMB, or DMB protecting group can furnish the compounds 21-4.
  • Compounds 21-5 where Y c is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with compounds 21-4, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, a ligand such as BrettPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as CS2CO3 at elevated temperatures or lithium bis(trimethylsilyl)amide) to afford compounds 21-6 where Y 1 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs).
  • Y 1 is halogen (e.g., F,
  • Compounds of Formula (ICa) can be prepared as shown in Scheme 22.
  • Compounds 22-1 can be protected with protecting groups such as THP with suitable conditions (e.g., catalytic pyridinium p-toluenesulfonate and 3,4-dihydro-2H-pyran at elevated temperatures) to provide the compounds 22-2.
  • protecting groups such as THP with suitable conditions (e.g., catalytic pyridinium p-toluenesulfonate and 3,4-dihydro-2H-pyran at elevated temperatures) to provide the compounds 22-2.
  • Compounds 22-2 where Y 2 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with amines 5-1, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as Pd2(dba)s, ligand, such as XantPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to give compounds 22-3.
  • a palladium catalyst such as Pd2(dba)s
  • ligand such as XantPhos
  • a base such as CS2CO3 or K3PO4
  • nucleophilic aromatic substitution conditions e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide
  • Y 3 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs)
  • amines 2-5 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as Pd2(dba)3, ligand, such as XantPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as 7 ⁇ (7V-diisopropylethylamine at elevated temperatures or lithium bis(trimethylsilyl)amide) to afford the compounds 22-4.
  • Deprotection of the compounds 22-4 can be performed under suitable conditions (e.g., TFA deprotection of a THP, PMB, or Boc protecting group) to furnish compounds of Formula (ICa).
  • Reaction of compounds 23-3 with appropriate reagent can provide the compounds 23-4 where Y D is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs).
  • Compounds 23-5 can be prepared by treating 23-4 with standard reagent (such as NaCN). Reduction of nitriles 23-5 under standard conditions, such as in the presence of a reducing agent (e.g., borane tetrahydrofuran complex), can provide the amine product compounds 23-6. Reaction of compounds 23-6 with standard reagent (such as triphosgene) can provide the isocyantes 23-7.
  • standard reagent such as triphosgene
  • a Lewis acid e.g., A1CL
  • Y b is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base, such as sodium hydride, can provide compounds 23-9.
  • a base such as sodium hydride
  • Compound 23-9 where Y 4 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 23-10 (e.g., M 1 is B(OH)2, Bpin, BF3K, Sn(Bu)s, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [l,l'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) and a base, such as potassium acetate).
  • a diboron reagent such as bis(pinacolato)diboron
  • a palladium catalyst such as [l,l'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) and a base, such as potassium
  • Compounds 24-4 where Y 4 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 24-5 (e.g., M 1 is B(OH)2, Bpin, BF3K, Sn(Bu)s, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [1,1'- bis(diphenylphosphino)-ferrocene]dichloropalladium(II) and a base, such as potassium acetate).
  • a diboron reagent such as bis(pinacolato)diboron
  • a palladium catalyst such as [1,1'- bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
  • a base such as potassium
  • Step 3 6-((6'-Bromo-r-oxo-rH-spiro[cyclopropane-l ,4'-isoquinolin]-2'(3'H)- yl)methyl)-N,N-dimethylpicolinamide
  • Step 1 6- Chlor o-N-(2-methoxy-3-(4, 4, 5, 5-tetramethyl-l, 3,2-dioxaborolan-2- yl)phenyl)imidazo[ 1, 2-b ]pyridazin-8-amine
  • Step 2 N-( 8-( ( 2-Methoxy-3-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)phenyl)amino) imidazo[ 1, 2-b ]pyridazin-6-yl) cyclopropanecarboxamide
  • Step 1 N-(3-Bromo-2-methoxyphenyl)-2-chloroimidazo[2,l-J] ' [l,2,4]triazin-4-amine
  • Step 2 N 4 -(3-Bromo-2-methoxyphenyl)-2-N-[(2,4- dimethoxyphenyl)methyl ]imidazo[ 2, l-f][ 1, 2, 4 ]triazine-2, 4-diamine
  • Step 1 N 4 -( 3-Bromo-2-methoxyphenyl)imidazo[ 2, l-f][ 1, 2, 4 ]triazine-2, 4-diamine
  • Step 2. 6'-Bromo-2 ', 3 '-dihydro- 1 'H-spiro[ cyclobutane- 1, 4 '-isoquinolin ]-l '-one
  • Step 4 N,N-dimethyl-6-((r-oxo-6'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-rH- spiro[ cyclobutane- 1, 4 '-isoquinolin ]-2 '( 3 'H) -yl)methyl)picolinamide
  • Step 1 (6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)(pyrrolidin-l- yl)methanone
  • HATU (1.54 g, 4.04 mmol) and DIPEA (2.92 mL, 16.8 mmol) were added in sequence to a stirring solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)picolinic acid (900 mg, 3.37 mmol) and pyrrolidine (239 mg, 3.37 mmol) in DMF (9 mL) at room temperature for 2 hours.
  • the product mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried with Na 2 SO 4 , filtered, concentrated, and purified by SiO 2 FCC: 5-50% EtOAc/heptane to obtain the title compound (1.0 g, 93%).
  • Step 4. 6'- bromo-2 '-( ( 6-(pyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-2 ', 3 '-dihydro-
  • Step 5 2'-((6-(pyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-6'-(4,4,5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)-2 ', 3 '-dihydro- 1 'H-spiro[ cyclopropane- 1, 4 '-isoquinolin ]-l '-one
  • a vial was charged with 6'-bromo-2'-((6-(pyrrolidine-l-carbonyl)pyri din-2 - yl)methyl)-2',3'-dihydro-l 7/-spiro[cyclopropane-l,4'-isoquinolin]-l'-one (350 mg, 0.795 mmol), bis(pinacolato)diboron (606 mg, 2.38 mmol), KOAc (234 mg, 2.38 mmol), and Pd(dppf)C12 (57
  • the mixture was dissolved in 1,4-dioxane (7 mL). The reaction mixture was sparged with N2 gas for 5 minutes then sealed. The sealed reaction mixture was heated to 100 °C and stirred for 2 h. The product mixture was diluted with water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (60 mL), dried over Na 2 SO, 4 concentrated, and purified by SiCL FCC eluting with EtOAc to obtain the title compound (360 mg, 93%).
  • Step 1 6-((6'-(3-Amino-2-methoxyphenyl)-r-oxo-rH-spiro[cyclopropane-l,4'- isoquinolin ]-2 '( 3 'H)-yl)methyl)-N,N-dimethylpicolinamide
  • Step 2 6-( (6'-( 3-( f 6-Chloroimidazo[ 1, 2-b ]pyridazin-8-yl)amino)-2-methoxyphenyl)-l oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-N,N-dimethylpicolinamide
  • Step 3 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8- yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane- 1 ,4' -isoquinolin ]-2 '(3'H)- yl)methyl)-N,N-dimethylpicolinamide
  • Example 2 6-((6'-(3-((6-(cyclopropanecarboxamido)-2-methylimidazo[l,2-/>]pyridazin-8- yl)amino)-2-methoxyphenyl)-l'-oxo-l'H-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'Er)- yl)methyl)-7V,7V-dimethylpicolinamide [00359] The title compound was prepared as the TFA salt using procedures analogous to Example 1 Steps 1-3 with 8-bromo-6-chl oro-2 -methylimidazo[l,2-Z>]pyridazine replacing 8- bromo-6-chloroimidazo[l,2-Z>]pyridazine in Step 2.
  • Step 1 6' -Bromo-2',3'-dihydro-l'H-spiro [cyclopropane- 1 ,4'-isoquinoline]
  • Step 3 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8- yl) amino) -2 -methoxyphenyl)-! 'H-spiro[ cyclopropane- 1,4' -isoquinolin ]-2 '( 3 'H)-yl)methyl)-N,N- dimethylpicolinamide
  • Step 1 6-((6'-Bromo-3'-oxospiro[cyclopropane-l,r-isoindolin]-2'-yl)methyl)-N,N- dimethylpicolinamide
  • Step 2 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8- yl)amino)-2-methoxyphenyl)-3'-oxospiro[cyclopropane-l,l'-isoindolin]-2'-yl)methyl)-N,N- dimethylpicolinamide
  • Step 3 6-((7-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8-yl)amino)- 2-methoxyphenyl)-l -oxo-1, 3,4, 5-tetrahydro-2H-benzo[c]azepin-2-yl)methyl)-N,N- dimethylpicolinamide
  • Example 7 6-((6-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l-/] [l,2,4]triazin-4- yl)amino)-2-methoxyphenyl)-3,3-dimethyl-l-oxo-3,4-dihydroisoquinolin-2(lZ7)-yl)methyl)- 7V,7V-dimethylpicolinamide
  • Step 1 6-((6-Bromo-3,3-dimethyl-l-oxo-3,4-dihydroisoquinolin-2(lH)-yl)methyl)-
  • Step 2 6-((3,3-Dimethyl-l-oxo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4- dihydroisoquinolin-2(lH)-yl)methyl)-N,N-dimethylpicolinamide
  • Step 3 6-((6-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l-f] [l,2,4]triazin-4- yl)amino)-2-methoxyphenyl)-3, 3 -dimethyl- 1 -oxo- 3, 4-dihydroisoquinolin-2( lH)-yl)methyl)-N,N- dimethylpicolinamide
  • Examples 8 - 11 are shown below in Table 1. Examples 8 - 11 were prepared as TFA salts using procedures analogous to those used in Example 7 with the appropriate starting materials and commercial reagents.
  • Step 2. 6- bromo-4, 4-difluoro-3-hydroxy-3, 4-dihydroisoquinolin-l(2H)-one
  • a reaction vessel was charged with 4-bromo-A-methoxybenzamide (250 mg, 1.09 mmol), 2,2-difluorovinyl 4-methylbenzenesulfonate (380 pL, 2.17 mmol), NaOAc (178 mg, 2.17 mmol), tris(acetonitrile)pentamethylcyclopentadienylrhodium(III) hexafluoroantimonate (45.2 mg, 0.05 mmol), and finally water (8.7 mL), and it was sealed and stirred at 80 °C overnight. After the reaction mixture cooled, it was filtered, partially condensed, and extracted with EtOAc.
  • Example 14 6-((6'-(3-((2-Aminoimidazo[2,l-/
  • Step 1 6-((6'-(3-((2-((2,4-Dimethoxybenzyl)amino)imidazo[2,l-f][l,2,4]triazin-4- yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane- 1 ,4' -isoquinolin ]-2 '(3'H)- yl)methyl)-N,N-dimethylpicolinamide
  • Step 2 6-((6'-(3-((2-Aminoimidazo[2,l-f][l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-r-oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-N,N- dimethylpicolinamide
  • Step 3 6-((6'-(3-((5-(cyclopropanecarboxamido)pyrazolo[l,5-a]pyrimidin-7- yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane- 1 ,4' -isoquinolin ]-2 '(3'H)- yl)methyl)-N,N-dimethylpicolinamide
  • the remaining boronic ester starting material was turned into boronic acid by adding 1 N HC1 and stirred at rt for 20 mins.
  • the combined organic phase was dried over Na 2 SO 4 , condensed, and purified by prep-HPLC on C18 column (30 x 250 mm, 10 pM, 8- 55% MeCN/H2O (w/ 0.1% TFA)).
  • the desired fractions were collected, concentrated, and freeze- dried to give the title compound (6.0 mg, 12% yield) as white solids as its TFA salt.
  • Step 1 N-( 3-Bromo-2-methoxyphenyl) -2-(methylthio)pyrazolo[ 1, 5 -a ][ 1, 3, 5 ]triazin-4- amine
  • Lithium bis(trimethylsilyl)amide (6.23 mL, 6.23 mmol, 1 M in THF) was added dropwise to a stirring solution of 3 -bromo-2-methoxy aniline (289 pL, 2.20 mmol) and 4-chloro- 2-(methylthio)pyrazolo[l,5-a][l,3,5]triazine (500 mg, 2.49 mmol) in THF (25 mL) at 0 °C. The reaction mixture was allowed to gradually warm to room temperature and stirred overnight at room temperature. The product mixture was diluted with EtOAc (100 mL) and water (100 mL). The diluted product mixture was extracted with EtOAc (3 x 50 mL).
  • meto-Chloroperoxybenzoic acid (283 mg, 1.64 mmol) was added to a stirring solution of 7V-(3-bromo-2-methoxyphenyl)-2-(methylthio)pyrazolo[l,5-a][l,3,5]triazin-4-amine (300 mg, 0.819 mmol) in DCM (5 mL) at 0 °C.
  • the reaction mixture was allowed to gradually warm to rt.
  • the reaction mixture was stirred at rt for 2 h.
  • the product mixture was diluted with EtOAc (20 mL) and water (20 mL).
  • the diluted product mixture was extracted with EtOAc (3 x 20 mL).
  • Step 3 N 4 -( 3-Bromo-2-methoxyphenyl)-N 2 -(2, 4-dimethoxybenzyl)pyrazolo[ 1, 5- a ][ 1, 3, 5 ]triazine-2, 4-diamine
  • DIPEA 115 pL, 0.663 mmol
  • 2,4- dimethoxybenzylamine 145 pL, and 0.964 mmol
  • 7V-(3-bromo-2-methoxyphenyl)-2- (methylsulfonyl)pyrazolo[l,5-a][l,3,5]triazin-4-amine 120 mg, 0.301 mmol
  • 1,4-dioxane 5 mL
  • the reaction mixture was heated to 45 °C and stirred for 5 hours.
  • the product mixture was concentrated under reduced pressure and purified by SiO 2 FCC: 0-5% MeOH/DCM to obtain the title compound (145 mg, 99%).
  • Step 5 6-((6'-(3-((2-Aminopyrazolo[l,5-a][l,3,5]triazin-4-yl)amino)-2- methoxyphenyl)-r-oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-N,N- dimethylpicolinamide
  • Trifluoroacetic acid (1 mL) was added to stirring solution of 6-((6'-(3-((2-((2,4- dimethoxybenzyl)amino)pyrazolo[l,5-a][l,3,5]triazin-4-yl)amino)-2-methoxyphenyl)-r-oxo- rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-7V,7V-dimethylpicolinamide (40 mg, 0.054 mmol) and anisole (100 pL, 0.92 mmol) in DCM (1 mL).
  • Example 18 6-((6'-(3-((5-(Cyclopropanecarboxamido)thiazolo[5,4-d]pyrimidin-7- yl)amino)-2-methoxyphenyl)-l '-oxo-1 '//-spiro [cyclopropane- 1, 4'-isoquinolin ] -2'(3'//)- yl)methyl)- ⁇ ,A-dimethylpicolinamide
  • Step 1 6-((6'-(3-((5-Chlorothiazolo[5,4-d]pyrimidin-7-yl)amino)-2-methoxyphenyl)-
  • Step 1 tert-Butyl(7-( ( 3-(2'-( ( 6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-l '-oxo-2 3 '- dihydro- rH-spiro[cyclopropane-l,4'-isoquinolin]-6'-yl)-2-methoxyphenyl)amino)thiazolo[5, 4- d]pyrimidin-5-yl) carbamate
  • Step 2 6-( (6'-( 3-((5-Aminothiazolo [ 5, 4-d]pyrimidin- 7 -yl) amino) -2 -methoxyphenyl)-! '- oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-N,N-dimethylpicolinamide
  • the title compound as the TFA salt was prepared using a procedure analogous to Example 14 Step 2 using the appropriate intermediates and commercial reagents.
  • Example 20 6-((6'-(3-((5-Aminothiazolo[5,4- ⁇ /]pyrimidin-7-yl)amino)-2-methoxyphenyl)- l'-oxo-ltH-spiro[cyclobutane-l,4'-isoquinolin]-2'(3tH)-yl)methyl)-7V,7V- dimethylpicolinamide
  • Step 1 6-((6'-(3-Amino-2-methoxyphenyl)-r-oxo-rH-spiro[cyclobutane-l,4'- isoquinolin ]-2 '( 3 'H)-yl)methyl)-N,N-dimethylpicolinamide
  • Step 3 6-( (6'-( 3-((5-Aminothiazolo [ 5, 4-d]pyrimidin- 7 -yl) amino) -2 -methoxyphenyl)-! '- oxo-1 'H-spiro[ cyclobutane- 1, 4 '-isoquinolin ]-2 '( 3 'H) -yl)methyl) -N,N-dimethylpicolinamide
  • the title compound as the TFA salt was prepared using a procedure analogous to Example 1 Step 3 using the appropriate intermediates and commercial reagents.
  • Example 21 6-((6'-(3-((2-Aminopyrido[3,2-J
  • Step 1 N-( 3-Bromo-2-methoxyphenyl) -2-chloropyrido[ 3, 2-d]pyrimidin-4-amine
  • Step 2 N 4 -(3-Bromo-2-methoxyphenyl)-N 2 -(2,4-dimethoxybenzyl)pyrido[3,2- d]pyrimidine-2, 4-diamine
  • Step 3 6-((6'-(3-((2-Aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methoxyphenyl)-r- oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-N,N-dimethylpicolinamide
  • the title compound was prepared as the TFA salt using procedures analogous to Example 13 Step 1 and Example 14 Step 2 using the appropriate intermediates and commercial reagents.
  • Example 22 6-((6'-(3-((2-(Cyclopropanecarboxamido)pyrido[3,2-J
  • Example 23 6-((6'-(3-((5-(Cyclopropanecarboxamido)-3Z7-imidazo[4,5-/>]pyridin-7- yl)amino)-2-methoxyphenyl)-l'-oxo-l'H-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'Er)- yl)methyl)-7V,7V-dimethylpicolinamide
  • Step 3 6-((6'-(3-((5-(Cyclopropanecarboxamido)-3-(tetrahydro-2H-pyran-2-yl)-3H- imidazo[ 4, 5-b Jpyridin- 7 -yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane-1, 4 '- isoquinolin ]-2 '( 3 'H)-yl)methyl)-N,N-dimethylpicolinamide
  • Step 4 6-((6'-(3-((5-(Cyclopropanecarboxamido)-3H-imidazo[4,5-b]pyridin-7- yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane- 1 ,4' -isoquinolin ]-2 '(3'H)- yl)methyl)-N,N-dimethylpicolinamide
  • Example 24 7V-(8-((2-Methoxy-3-(2'-((6-(morpholine-4-carbonyl)pyridin-2-yl)methyl)-l'- oxo-2', 3 Mlihydro- l '//-spiro
  • Step 3 6-((6'-Bromo-r-oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)- yl)methyl)picolinic acid
  • Step 4 6'-Bromo-2 '-( 66-(morpholine-4-carbonyl)pyridin-2-yl)methyl)-2 3 '-dihydro-
  • Step 5 N-(8-((2-Methoxy-3-(2'-((6-(morpholine-4-carbonyl)pyridin-2-yl)methyl)-r- oxo-2',3'-dihydro-l'H-spiro[cyclopropane-l,4'-isoquinolin]-6'-yl)phenyl)amino)imidazo[l,2- b]pyridazin-6-yl)cyclopropanecarboxamide
  • Examples 25 - 29 are shown below in Table 2.
  • Examples 8 - 11 were prepared in accordance with the synthetic protocols set forth in Example 24 using the appropriate intermediates, as well as commercial starting materials. The following compounds are TFA salts unless otherwise noted.
  • Example 30 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-/>]pyridazin-8- yl)amino)-2-methoxyphenyl)-l'-oxo-l'ZZ-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'ZZ)- yl)methyl)-7V-ethyl-7V-methylpicolinamide
  • Step 5 6-((6'-Bromo-r-oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)- yl)methyl)-N-ethyl-N-methylpicolinamide
  • Step 6 6-( (6'-( 3-( f 6-(cyclopropanecarboxamido)imidazo[ 1, 2-b ]pyridazin-8-yl)amino)- 2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane- 1,4' -isoquinolin ]-2 '( 3 'H)-yl)methyl)-N-ethyl- N-methylpicolinamide [00467] The title compound as the TFA salt was prepared using the procedure analogous to that described for Example 1 Steps 1-3 with appropriate starting materials and commercial reagents. LCMS calcd.
  • Examples 31 - 33 are shown below in Table 3. Examples 31 - 33 were prepared in accordance with the synthetic protocols set forth in Example 30 using the appropriate intermediates, as well as commercial starting materials. The following compounds are TFA salts unless otherwise noted.
  • Example 34 2-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l-/] [l,2,4]triazin-4- yl)amino)-2-methoxyphenyl)-l'-oxo-l'H-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'ZZ)- yl)methyl)-7V,7V-dimethylthiazole-4-carboxamide [00469] Step 1.
  • Step 2 2-((6'-Bromo-r-oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)- yl)methyl)-N,N-dimethylthiazole-4-carboxamide
  • Step 3 N,N-Dimethyl-2-((l'-oxo-6'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l'H- spiro[ cyclopropane- 1, 4 '-isoquinolin ]-2 '( 3 'H)-yl)methyl) thiazole-4-carboxamide
  • Step 4 2-((6'-(3-((2-((2,4-Dimethoxybenzyl)amino)imidazo[2,l-f][l,2,4]triazin-4- yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane- 1 ,4' -isoquinolin ]-2 '(3'H)- yl)methyl)-N,N-dimethylthiazole-4-carboxamide
  • Step 5 2-((6'-(3-((2-Aminoimidazo[2,l-f][l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-r-oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-N,N- dimethylthiazole-4-carboxamide
  • Step 6 2-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l-f] [l,2,4]triazin-4- yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane- 1 ,4' -isoquinolin ]-2 '(3'H)- yl)methyl)-N,N-dimethylthiazole-4-carboxamide
  • Example 35 6'-(3-((2-Aminoimidazo[2,l-/
  • Example 36 7V-(4-((3-(2'-((l-Acetylpiperidin-3-yl)methyl)-l'-oxo-2',3'-dihydro-177- spiro[cyclopropane-l,4'-isoquinolin]-6'-yl)-2-methoxyphenyl)amino)imidazo[2,l-
  • Step 1 tert-Butyl 3-(( 6' -bromo- 1 '-oxo-1 'H-spiro[ cyclopropane- 1, 4 '-isoquinolin ]- 2' (3 'H)-yl)methyl)piperidine-l -carboxylate
  • Step 2 6'-Bromo-2 '-(piperidin-3-ylmethyl)-2 ', 3 ' -dihydro- 1 'H-spiro [cyclopropane- 1 ,4'- isoquinolin ]-l '-one
  • Step 3 2'-((l-Acetylpiperidin-3-yl)methyl)-6'-bromo-2',3'-dihydro-l'H-spiro[cyclo- propane-1, 4 '-isoquinolin ]-l '-one
  • Step 5 N-(4-((3-(2'-(( l-Acelylpiperidin-3-yl)melhyl)-l'-oxo-2 ⁇ 3'-dihydro-l'H- spiro[cyclopropane-l,4'-isoquinolin]-6'-yl)-2-methoxyphenyl)amino)imidazo[2,l- f][ 1, 2, 4 ] triazin-2 -y I) cyclopropanecarboxamide
  • Example 37 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-/>]pyridazin-8- yl):iiniiio)-2-inetlioxyphenyl)-8'-ethoxy- l'-oxo- l'//-spiro [cyclopropane- 1 ,4'-isoquinolin]- 2'(3IH)-yl)methyl)-A,7V-dimethylpicolinamide
  • Step 4. 6'-Bromo-8 '-ethoxy-2 ', 3 ' -dihydro- 1 'H-spiro[ cyclopropane-1, 4 '-isoquinolin ]-l '- one
  • Step 6 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8- yl)amino)-2-methoxyphenyl)-8'-ethoxy-r-oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)- yl)methyl)-N,N-dimethylpicolinamide
  • Example 38 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-/>]pyridazin-8- yl)amino)-2-methoxyphenyl)-l'-oxo-l'H-spiro[cyclopropane-l,4'-[2,7]naphthyridin]- 2'(3'ET)-yl)methyl)-7V,7V-dimethylpicolinamide
  • Step 5 6-((6'-Chloro-r-oxo-rH-spiro[cyclopropane-l,4'-[2, 7]naphthyridin]-2'(3'H)- yl)methyl)-N,N-dimethylpicolinamide
  • Step 6 6-((6'-(3-((6-(cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8-yl)amino)- 2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane- 1 ,4'-[ 2, 7 Jnaphthyridin ]-2 '( 3 'H)-yl)methyl) ⁇ N,N-dimethylpicolinamide
  • Example 39 6-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l-/] [l,2,4]triazin-4- yl)amino)-2-methoxyphenyl)-5'-fluoro-l'-oxo-l'H-spiro[cyclopropane-l,4'-isoquinolin]- 2'(3tH)-yl)methyl)-7V,7V-dimethylpicolinamide
  • Step 1 4- bromo-2-( 1 -cyanocyclopropyl) -3-fluorobenzoic acid
  • Step 4 (3-((2-(Cyclopropanecarboxamido)imidazo[2,l-f] [ 1 ⁇ jtriazin ⁇ -ytyamino ⁇ - methoxyphenytyboronic acid
  • Tetrahydroxy diboron (41.4 mg, 0.46 mmol)
  • KOAc 90.5 mg, 0.92 mmol
  • polyethylene glycol 1.0 mL, 18.12 mmol
  • P(t-Bu)s Pd G2 (15.8 mg, 0.03 mmol)
  • TV- (4-((3-bromo-2-methoxyphenyl)amino)imidazo[2,l : /][l, 2, 4]tri azin-2- yl)cyclopropanecarboxamide (Intermediate 5) (124 mg, 0.31 mmol) were added in MeOH (1.5 mL) under N2.
  • Step 5 6-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l-f][l,2,4]triazin-4- yl)amino)-2-methoxyphenyl)-5'-fluoro-r-oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)- yl)methyl)-N,N-dimethylpicolinamide
  • Example 40 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-/>]pyridazin-8- yl)amino)-2-methoxyphenyl)-l'-oxo-l'H-spiro[cyclopentane-l,4'-isoquinolin]-2'(3'Er)- yl)methyl)-7V,7V-dimethylpicolinamide
  • Step 1 6-((6'-bromo-r-oxo-rH-spiro[cyclopentane-l,4'-isoquinolin]-2'(3'H)- yl)methyl)-N,N-dimethylpicolinamide
  • Step 2 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8- yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopentane- 1 ,4' -isoquinolin ]-2 '( 3 'H)-yl)methyl) ⁇ N,N-dimethylpicolinamide
  • Example 41 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-/>]pyridazin-8- yl)amino)-2-methoxyphenyl)-l'-oxo-l'Z/-spiro[cyclobutane-l,4'-isoquinolin]-2'(37/)- yl)methyl)-7V,7V-dimethylpicolinamide
  • Example 42 6-((6-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8- yl)amino)-2-methoxyphenyl)-4,4-dimethyl-l-oxo-3,4-dihydroisoquinolin-2(lH)-yl)methyl)-
  • Example 43 6-((6-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-/>]pyridazin-8- yl)amino)-2-methoxyphenyl)- l-oxo-3.4-dihydroisoquinolin-2( 1 //)-yl)methyl)- ⁇ , ⁇ - dimethylpicolinamide [00532]
  • the title compound was prepared as the formate salt using procedures analogous to Intermediate 2 Step 3 and Example 1 Steps 1-3 with 6-bromo-3,4-dihydroisoquinolin-l(2J7)-one replacing 6'-bromo-2',3'-dihydro-17/-spiro[cyclopropane-l,4'-isoquinolin]-l'-one.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule I, des compositions pharmaceutiques comprenant des composés de formule I, ainsi que des procédés d'utilisation et de préparation de ceux-ci.
PCT/US2025/029716 2024-05-17 2025-05-16 Inhibiteurs de jak2 et leur utilisation en tant que produits pharmaceutiques Pending WO2025240835A2 (fr)

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