WO2014143768A1 - Tricyclic heterocycles as bet protein inhibitors - Google Patents

Tricyclic heterocycles as bet protein inhibitors Download PDF

Info

Publication number
WO2014143768A1
WO2014143768A1 PCT/US2014/027872 US2014027872W WO2014143768A1 WO 2014143768 A1 WO2014143768 A1 WO 2014143768A1 US 2014027872 W US2014027872 W US 2014027872W WO 2014143768 A1 WO2014143768 A1 WO 2014143768A1
Authority
WO
WIPO (PCT)
Prior art keywords
dimethylisoxazol
alkyl
dihydroimidazo
benzoxazin
pyridin
Prior art date
Application number
PCT/US2014/027872
Other languages
French (fr)
Inventor
Andrew P. Combs
Richard B. Sparks
Thomas P. Maduskuie Jr.
James D. Rodgers
Original Assignee
Incyte Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP14721642.8A priority Critical patent/EP2970282B1/en
Priority to NZ712453A priority patent/NZ712453A/en
Priority to SG11201506924YA priority patent/SG11201506924YA/en
Priority to CN201480025137.0A priority patent/CN105164131B/en
Priority to EP19189853.5A priority patent/EP3581576B1/en
Priority to AU2014228175A priority patent/AU2014228175B2/en
Priority to CA2903881A priority patent/CA2903881C/en
Priority to EA201591785A priority patent/EA035469B1/en
Priority to BR112015022942-5A priority patent/BR112015022942B1/en
Priority to UAA201510087A priority patent/UA119848C2/en
Priority to JP2016502650A priority patent/JP6243003B2/en
Priority to KR1020157029800A priority patent/KR102216288B1/en
Priority to MX2015013149A priority patent/MX366703B/en
Priority to KR1020217003659A priority patent/KR102355670B1/en
Application filed by Incyte Corporation filed Critical Incyte Corporation
Priority to ES14721642T priority patent/ES2755827T3/en
Publication of WO2014143768A1 publication Critical patent/WO2014143768A1/en
Priority to IL241158A priority patent/IL241158B/en
Priority to PH12015502157A priority patent/PH12015502157A1/en
Priority to CR20150513A priority patent/CR20150513A/en
Priority to ZA2015/07255A priority patent/ZA201507255B/en
Priority to HK16106622.5A priority patent/HK1218650A1/en
Priority to IL267609A priority patent/IL267609B/en
Priority to PH12019502318A priority patent/PH12019502318A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D471/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-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 genomes of eukaryotic organisms are highly organized within the nucleus of the cell.
  • DNA is packaged into chromatin by wrapping around a core of histone proteins to form a nucleosome. These nucleosomes are further compacted by aggregation and folding to form a highly condensed chromatin structure. A range of different states of condensation are possible, and the tightness of this structure varies during the cell cycle, being most compact during the process of cell division.
  • Chromatin structure plays a critical role in regulating gene transcription by regulating protein access to the DNA.
  • the chromatin structure is controlled by a series of post translational modifications to histone proteins, mainly within the tails of histones H3 and H4 that extend beyond the core nucleosome structure. These reversible modifications include acetylation, methylation, phosphorylation, ubiquitination and
  • the BET (Bromodomain and Extra-Terminal) family of bromodomain containing proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-t) that share a conserved structural organization containing tandem N-terminal bromodomains capable of binding to acetylated lysine residues of histones and other proteins.
  • BRD2, BRD3 and BRD4 are ubiquitously expressed while BRD-t is restricted to germ cells.
  • BRD proteins play essential, but non-overlapping roles in regulating gene transcription and controlling cell growth.
  • BET proteins are associated with large protein complexes including Mediator, PAFc and super elongation complex that regulate many aspects of gene transcription.
  • BRD2, BRD3 and BRD4 have been shown to impair the growth and viability of a wide range of hematological and solid tumor cells. Zuber et al., Nature, 2011, 478, 524-528; Delmore et al, Cell, 2011, 146, 904-917. Aside from a role in cancer, BET proteins regulate inflammatory responses to bacterial challenge, and a BRD2 hypomorph mouse model showed dramatically lower levels of inflammatory cytokines and protection from obesity induced diabetes. Wang et ah, Biochem. J., 2009, 425, 71-83;
  • R b6 is independently at each occurrence selected from Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R 20 ; and
  • R 2 is selected from H, halo, CN, OH, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 alkyl-O-, and Ci_6 haloalkyl-O-;
  • R 5 is selected from H, Ci_6 alkyl, C 2 _ 6 alkenyl, C 2 _6 alkynyl, Ci_6 haloalkyl, NR 15a R 15b , phenyl, C 3 -7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R 5 is optionally substituted by 1, 2, 3, or 4 groups independently selected from R 15 ;
  • R a , R c , and R d are independently at each occurrence selected from H and Ci_6 alkyl;
  • R a4 , R b4 , R c4 and R d4 are independently at each occurrence selected from H, Ci_6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, and Ci-6 haloalkyl, wherein said Ci-6 alkyl, C 2 -6 alkenyl, and C 2 -6 alkynyl forming R a , R , R and R are each optionally substituted with 1, 2, or 3 substituents independently selected from R 20 ;
  • R c6 and R d6 together with the nitrogen atom to which they are attached may be combined to form a 4-7 membered heterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2 additional heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R 20 ;
  • Cy 1 is a five membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said five membered heteroaryl of Cy 1 is optionally substituted with 1, 2, or 3 groups independently selected from R 11 ;
  • R 4 is H or Ci-6 alkyl
  • R 6 is selected from H, Ci_6 alkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, and Ci_6 haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R 6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R 16 ;
  • R 13 is independently at each occurrence selected from H, halo, CN, OH, Ci_6 alkyl, C 2 _
  • R 16 is independently at each occurrence selected from halo, CN, OH, OR a6 , SR a6 ,
  • R b is at each occurrence Ci_6 alkyl
  • R c6 and R d6 together with the nitrogen atom to which they are attached may be combined to form a 4-7 membered heterocycloalkyl group comprising carbon and 1 , 2, or 3 heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R 20 ;
  • R b6 is independently at each occurrence selected from Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R 20 ; and
  • R 4 is H or Ci_6 alkyl
  • R 6 is selected from H and Ci_6 alkyl, wherein said alkyl of R 6 is optionally substituted by 1, 2, or 3 groups independently selected R 16 ;
  • R a6 , R c6 and R d6 are independently at each occurrence selected from H and Ci_6 alkyl; alternatively, R c6 and R d6 together with the nitrogen atom to which they are attached may be combined to form a 4-7 membered heterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2 additional heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R 20 ;
  • R 5 0 when C is a single bond
  • R 7 is selected from H, F, CI, Br, methyl, methoxy, ethoxy, CN, phenyl, and pyridinyl;
  • L is CH 2 .
  • R 1 is -CH 2 OH.
  • R 2 is H.
  • R 2 is methyl
  • tetrahydrofuranyl, and piperidinyl of Cy 3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .
  • Cy 3 is selected from phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl, wherein said phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl of Cy 3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .
  • Cy 3 is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 . In some embodiments, Cy 3 is pyridinyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .
  • Cy 3 is oxidopyridinyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .
  • Cy 3 is thiazolyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .
  • Cy 3 is cyclohexyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .
  • Cy 3 is tetrahydrofuranyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .
  • Cy 3 is piperidinyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .
  • R 4 is H.
  • R 5 is pyrrolidinyl, piperidinyl, azetidinyl, or piperazinyl, wherein said pyrrolidinyl, piperidinyl, azetidinyl, or piperazinyl of R 5 is optionally substituted by 1 or 2 groups independently selected from R 15 .
  • R 5 when C ⁇ N is a double bond then R 5 is pyrrolidinyl, wherein said pyrrolidinyl of R 5 is optionally substituted by 1 or 2 groups independently selected from R 15 .
  • R 5 is piperidinyl, wherein said piperidinyl of R 5 is optionally substituted by 1 or 2 groups independently selected from R 15 .
  • R 5 when C is a double bond then R 5 is azetidinyl, wherein said azetidinyl of R 5 is optionally substituted by 1 or 2 groups independently selected from R 15 .
  • R 6 is H, C1-4 alkyl, or C1-4 alkoxy.
  • R 6 is H, methyl, or methoxy.
  • R 6 is H.
  • R 7 is selected from H, halo, CN, NR c R d , Ci_6 alkyl, C2-6 alkenyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 5-6 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, 5-6 membered heteroaryl group, and 5-6 membered heterocycloalkyl group of R 7 are optionally substituted with 1, 2, or 3 groups independently selected from R 17 .
  • R 7 is selected from H, halo, Ci_ 4 alkyl, and CN.
  • R 7 is selected from H, Br, methyl, and CN.
  • R 7 is Br.
  • R 7 is methyl
  • the compound is selected from the following compounds:
  • the compounds listed above contain a chiral center
  • the compounds can be any of the possible stereoisomers.
  • the stereochemistry of the chiral center can be (R) or (S).
  • the stereochemistry of the chiral center can be (R) or (S).
  • the stereochemistry of the chiral center can be (R) or (S).
  • stereochemistry of the chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R) and (R), (R) and (5); (S) and (R), or (S) and (S).
  • the stereochemistry each of the three chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R), (R) and (R); (R), R) and S); (R), (S) and (R); (R), (5) and (S); (S), (R) and (R); (5), (R) and S); (S), (S) and (R); or (S), (5) and (S).
  • substituted means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group.
  • the hydrogen atom is formally removed and replaced by a substituent.
  • a single divalent substituent e.g., oxo
  • optionally substituted means unsubstituted or substituted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency.
  • the term "C n - m " indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, Ci_6, and the like.
  • C n - m alkyl refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons.
  • the alkyl group contains from 1 to 6 carbon atoms or from 1 to 4 carbon atoms, or from 1 to 3 carbon atoms.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, w-propyl, isopropyl, n-butyl, s- butyl, and t-butyl.
  • C n - m alkoxy refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons.
  • Example alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy).
  • the alkyl group has 1 to 3 carbon atoms.
  • alkylene employed alone or in combination with other terms, refers to a divalent alkyl linking group.
  • alkylene groups include, but are not limited to, ethan-1, 2-diyl, propan-1, 3-diyl, propan-1, 2-diyl, butan-1, 4-diyl, butan-1, 3- diyl, butan-1, 2-diyl, 2-methyl-propan-l, 3-diyl, and the like.
  • C n - m alkenyl refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons.
  • the alkenyl moiety contains 2 to 6 or to 2 to 4 carbon atoms.
  • Example alkenyl groups include, but are not limited to, ethenyl, w-propenyl, isopropenyl, n- butenyl, sec-butenyl, and the like.
  • C n - m alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons.
  • Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like.
  • the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.
  • C n - m alkylamino employed alone or in combination with other terms, refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • di-C n - m -alkylamino employed alone or in combination with other terms, refers to a group of formula -N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group
  • thio employed alone or in combination with other terms, refers to a group of formula -SH.
  • C n - m alkylthio employed alone or in combination with other terms, refers to a group of formula -S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • amino employed alone or in combination with other terms, refers to a group of formula -NH 2 .
  • aryl refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like.
  • aryl is Ce-w aryl.
  • the aryl group is a naphthalene ring or phenyl ring.
  • the aryl group is phenyl.
  • arylalkyl employed alone or in combination with other terms, refers to a group of formula -alkylene-aryl.
  • arylalkyl is Ce-w aryl-Ci-3 alkyl.
  • arylalkyl is Ce-w aryl-C 1-4 alkyl.
  • arylalkyl is benzyl.
  • cycloalkyl refers to a non-aromatic cyclic hydrocarbon moiety, which may optionally contain one or more alkenylene groups as part of the ring structure.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems.
  • moieties that have one or more aromatic rings fused (i.e.,, having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclopentene, cyclohexane, and the like.
  • cycloalkyl is C 3 -7 cycloalkyl, which is monocyclic or bicyclic.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkylalkyl refers to a group of formula -alkylene-cycloalkyl.
  • cycloalkylalkyl is C 3 -7 cycloalkyl-Ci-3 alkyl, wherein the cycloalkyl portion is monocyclic or bicyclic.
  • cycloalkylalkyl is C 3 -7 cycloalkyl-Ci-4 alkyl, wherein the cycloalkyl portion is monocyclic or bicyclic.
  • C n - m haloalkoxy refers to a group of formula -O-haloalkyl having n to m carbon atoms.
  • An example haloalkoxy group is OCF 3 .
  • An additional example haloalkoxy group is OCHF2.
  • the haloalkoxy group is fluorinated only.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • the term "halo” employed alone or in combination with other terms, refers to a halogen atom selected from F, CI, I or Br.
  • halo refers to a halogen atom selected from F, CI, or Br.
  • exemplary halo groups are F.
  • C n - m haloalkyl refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms.
  • the haloalkyl group is fluorinated only.
  • the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl.
  • the haloalkyl group is
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • heteroaryl refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen.
  • heteroaryl is 5- to 10-membered C1-9 heteroaryl, which is monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different.
  • the nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides.
  • Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[l,2- &]thiazole, purine, or the like.
  • a five-membered ring heteroaryl is a heteroaryl group having five ring atoms comprising carbon and one or more (e.g., 1, 2, or 3) ring atoms independently selected from N, O, and S.
  • Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,
  • a six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from , O, and S.
  • Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • heteroarylalkyl employed alone or in combination with other terms, refers to a group of formula -alkylene-heteroaryl.
  • heteroarylalkyl is Ci_ 9 heteroaryl-Ci_3 alkyl, wherein the heteroaryl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • heteroarylalkyl is Ci_ 9 heteroaryl-Ci_4 alkyl, wherein the heteroaryl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • heterocycloalkyl refers to non-aromatic ring system, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and oxygen.
  • heterocycloalkyl groups contains more than one heteroatom, the heteroatoms may be the same or different.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spiro systems.
  • heterocycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic ring, for example, 1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran and the like.
  • the carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
  • an amine such as HNR 6
  • tetrakis(triphenylphosphine)palladium(0) and a base e.g., a bicarbonate or carbonate base
  • a base e.g., a bicarbonate or carbonate base
  • standard Negishi conditions e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0), to give a derivative of Formula (I) (vi).
  • Compounds of Formula (I) can be formed as shown in Scheme VI.
  • the sulfide (i) can be reacted with an oxidant, such as mCPBA or H 2 O 2 or dioxirane, to give the sulfoxide (ii) which can be further oxidized with an oxidant, such as mCPBA or H2O2 or dioxirane, to give the sulfone (iii).
  • an oxidant such as mCPBA or H 2 O 2 or dioxirane
  • Halo-ketones intermediate (ii) of Scheme I and Scheme II can be synthesized as shown in Scheme VII.
  • the carboxylic acid (i) can be activated with a coupling agent (e.g., HBTU, HATU or EDC) and then reacted with N, O-dimethylhydroxylamine to give an N- methoxy-N-methylcarboxamide derivative (ii).
  • the halo-ketone (iv) can be transformed using similar methods as shown in Scheme I and Scheme II to afford compounds of Formula (I).
  • 2- Bromoquinoline (i) can be coupled to M-Cy 3 , where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., Cy ⁇ M is Cy 1 -B(OH)2, Cy 1 -Sn(Bu) 4 , or Zn- Cy 1 ), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0), to give compound (ii).
  • M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., Cy ⁇ M is Cy 1 -B(OH)2, Cy 1 -Sn
  • Compound (ii) can be reduced (eg. borane/pyridine or l,4-dihydro-3,5-dicarbethoxy-2,6- dimethylpyridine/diphenyl hydrogen phosphate) to give compound (iii).
  • Compound (iii) can be converted to (iv) using triphosgene/ methoxylamine or 4-nitrophenyl methoxycarbamate. Cyclization of (iv) can be accomplished with [7J-bis(trifluoroacetoxy)iodo]benzene to give (v).
  • the methoxy group of (v) can be removed by hydrogenation (Pd/C) to give (vi).
  • the halo group of (vii) can be coupled to M-Cy 1 , where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., Cy ⁇ M is Cy 1 -B(OH) 2 , Cy 1 -Sn(Bu) 4 , or Zn- Cy 1 ), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0), to give a derivative of Formula (I) (viii).
  • M is a boronic acid, boronic ester or an appropriately substituted metal
  • Cy ⁇ M is Cy 1 -B(OH) 2
  • the general schemes described above can be modified.
  • the products or intermediates can be modified to introduce particular functional groups.
  • the substituents can be modified at any step of the overall synthesis by methods know to one skilled in the art, e.g., as described by Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations (Wiley, 1999); and Katritzky et al. (Ed.), Comprehensive Organic Functional Group Transformations (Pergamon Press 1996).
  • Compounds of the invention are BET protein inhibitors and, thus, are useful in treating diseases and disorders associated with activity of BET proteins.
  • any of the compounds of the invention including any of the embodiments thereof, may be used.
  • the compounds inhibit two or more of the BET proteins, or all of the BET proteins.
  • selectivity can be at least about 5 -fold, at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold or at least about 1000-fold.
  • the compounds of Formula (I) are therefore useful for treating BET protein mediated disorders.
  • BET-mediated refers to any disease or condition in which one or more of the BET proteins, such as BRD2, BRD3, BRD4 and/or BRD-t, or a mutant thereof, plays a role, or where the disease or condition is associated with expression or activity of one or more of the BET proteins.
  • the compounds of the invention can therefore be used to treat or lessen the severity of diseases and conditions where BET proteins, such as BRD2, BRD3, BRD4, and/or BRD-t, or a mutant thereof, are known to play a role.
  • Diseases and conditions treatable using the compounds of Formula (I) include cancer and other proliferative disorders, autoimmune disease, chronic inflammatory diseases, acute inflammatory diseases, sepsis, and viral infection.
  • the diseases can be treated by
  • the cancers can include adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic
  • dysembryoplastic neuroepithelial tumor dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological mal
  • the cancer can be adenocarcinoma, adult T-cell leukemia/lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, ocular cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma,
  • the diseases treatable using the compounds of Formula (I) also include MYC dependent cancers wherein the cancer is associated with at least one of myc RNA expression or MYC protein expression.
  • a patient can be identified for such treatment by determining myc RNA expression or MYC protein expression in the cancerous tissue or cells.
  • proliferative disorders that can be treated with compounds of Formula (I) also include noncancerous proliferative disorders.
  • proliferative disorders include, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.
  • the diseases and conditions that can be treated with the compounds of Formula (I) also include chronic autoimmune and inflammatory conditions.
  • autoimmune and inflammatory conditions include acute, hyperacute or chronic rejection of transplanted organs, acute gout, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia/reperfusion injury), Addison's disease, agammaglobulinemia, allergic rhinitis, allergy, alopecia, Alzheimer's disease, appendicitis, atherosclerosis, asthma, osteoarthritis, , juvenile arthritis, psoriatic arthritis, rheumatoid arthriti, satopic dermatitis, autoimmune alopecia, autoimmune hemolytic and thrombocytopenic states, autoimmune hypopituitarism, autoimmune polyglandular disease, Behcet's disease, bullous skin diseases, cholecystitis, chronic idiopathic thrombocytopenic purpura, chronic obstructive pulmonary disease (COPD), cirris,
  • Parkinson's disease pericarditis, pernicious anemia, pneumonitis, primary biliary sclerosing cholangitis, polyarteritis nodosa, psoriasis, retinitis, scleritis, scleracierma, scleroderma, sinusitis, Sjogren's disease, sepsis, septic shock, sunburn, systemic lupus erythematosus, tissue graft rejection, thyroiditis, type I diabetes, Takayasu's arteritis, urethritis, uveitis, vasculitis, vasculitis including giant cell arteritis, vasculitis with organ involvement such as glomerulonephritis, vitiligo, Waldenstrom macroglobulinemia and Wegener's
  • the diseases for which the compounds of Formula (I) are indicated also include diseases associated with a systemic inflammatory response syndrome, such as sepsis, burns, pancreatitis, major trauma, hemorrhage and ischemia.
  • the compound of Formula (I) can be administered to reduce the incidence of: SIRS, the onset of shock, multi-organ dysfunction syndrome, which includes the onset of acute lung injury, ARDS, acute renal, hepatic, cardiac and gastro-intestinal injury and mortality.
  • the compounds of the invention can be administered prior to surgical or other procedures associated with a high risk of sepsis, hemorrhage, extensive tissue damage, SIRS or MODS.
  • viral infections examples include Epstein-Barr virus, hepatitis B virus, hepatitis C virus, herpes virus, human immunodeficiency virus, human papilloma virus, adenovirus, poxvirus and other episome-based DNA viruses.
  • the compounds can therefore be used to treat disease and conditions such as herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including acute respiratory disease, and poxvirus infections such as cowpox and smallpox and African swine fever virus.
  • disease and conditions such as herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including acute respiratory disease, and poxvirus infections such as cowpox and smallpox and African swine fever virus.
  • the compounds of Formula (I) are indicated for the treatment of human papilloma virus infections of skin or cervical epithelia.
  • the diseases and conditions that can be treated with the compounds of Formula (I) also include conditions that are associated with ischemia-reperfusion injury.
  • conditions that are associated with ischemia-reperfusion injury include, but are not limited to conditions such as myocardial infarction, cerebrovascular ischemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures and pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism.
  • the compounds of Formula (I) are also useful in the treatment of disorders of lipid metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease.
  • the compounds of Formula (I) can also be used for the treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma and cardiac fibrosis.
  • fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma and cardiac fibrosis.
  • the compounds of Formula (I) can also be used to treat ophthalmological indications such as dry eye.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" a BET protein with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having a BET protein, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the BET protein.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • the term “treating” or “treatment” refers to one or more of (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the
  • the compounds of Formula (I) can be used in combination treatments where the compound of the invention is administered in conjunction with other treatment such as the administration of one or more additional therapeutic agents.
  • the additional therapeutic agents are typically those which are normally used to treat the particular condition to be treated.
  • the additional therapeutic agents can include, e.g., chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, FAK, and JAK kinase inhibitors for treatment of BET protein-associated diseases, disorders or conditions.
  • the one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.
  • the compounds of Formula (I) can be used in combination with a therapeutic agent that targets an epigenetic regulator.
  • epigenetic regulators include the histone lysine methyltransferases, histone arginine methyl transferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases.
  • histone deacetylase inhibitors include, e.g., vorinostat.
  • the compounds of the invention can be used in combination with chemotherapeutic agents, or other anti-proliferative agents.
  • the compounds of the invention can also be used in combination with medical therapy such as surgery or radiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes.
  • chemotherapeutic agents include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxe
  • the compounds of formula (I) can be used in combination with ruxolitinib.
  • the compound of Formula (I) can be administered in combination with a corticosteroid such as triamcinolone,
  • dexamethasone fluocinolone, cortisone, prednisolone, or flumetholone.
  • the compound of Formula (I) can be administered in combination with an immune suppressant such as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol, Alcon), or cyclosporine (Restasis®).
  • an immune suppressant such as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol, Alcon), or cyclosporine (Restasis®).
  • the compound of Formula (I) can be administered in combination with one or more additional agents selected from
  • DehydrexTM (Holies Labs), Civamide (Opko), sodium hyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603, Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P) (Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen), 15-(s)- hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine, doxycycline (ALTY-0501, Alacrity), minocycline, iDestrinTM (NP50301, Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali), oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101 (2S,3S,4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino
  • dehydroepiandrosterone anakinra
  • efalizumab mycophenolate sodium
  • etanercept mycophenolate sodium
  • etanercept mycophenolate sodium
  • etanercept mycophenolate sodium
  • etanercept mycophenolate sodium
  • etanercept mycophenolate sodium
  • etanercept mycophenolate sodium
  • etanercept etanercept
  • HGX267 hydroxychloroquine
  • NGX267 TrireyPines Therapeutics
  • thalidomide thalidomide
  • the compound of Formula (I) can be administered in combination with one or more agents selected from an antibiotic, antiviral, antifungal, anesthetic, anti-inflammatory agents including steroidal and non-steroidal anti- inflammatories, and anti-allergic agents.
  • suitable medicaments include aminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin, netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naphthyridine; sulfonamides; polymyxin;
  • chloramphenicol neomycin; paramomycin; colistimethate; bacitracin; vancomycin;
  • rifampins tetracyclines
  • rifampins tetracyclines
  • rifampins tetracyclines
  • cycloserine beta-lactams
  • cephalosporins cephalosporins; amphotericins; fluconazole; flucytosine; natamycin; miconazole;
  • ketoconazole corticosteroids; diclofenac; flurbiprofen; ketorolac; suprofen; cromolyn;
  • lodoxamide lodoxamide; levocabastin; naphazoline; antazoline; pheniramine; or azalide antibiotic.
  • agents one or more of which a compound of Formula (I) may also be combined with include: a treatment for Alzheimer's Disease such as donepezil and rivastigmine; a treatment for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone; a treatment for asthma such as albuterol and montelukast; an agent for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; an anti-inflammatory agent such as a corticosteroid, such as dexamethasone or prednisone, a TNF blocker, IL-1 RA
  • cholestyramine an interferon, and an anti-viral agent
  • an agent for treating blood disorders such as a corticosteroid, an anti-leukemic agent, or a growth factor
  • an agent for treating immunodeficiency disorders such as gamma globulin.
  • the compounds of the invention can be used in combination with one or more therapeutic agents selected from: Janus kinase inhibitors (e.g., ruxolitinib, tofacitinib, baricitinib, CYT387, GLPG0634, lestaurtinib, pacritinib, TG101348), Pirn kinase inhibitors, PI3 kinase inhibitors (including PI3K-delta selective and broad spectrum PI3K inhibitors), MEK inhibitors, cyclin dependent kinase inhibitors, b-RAF inhibitors, mTOR inhibitors, proteasome inhibitors (e.g., bortezomib, carfilzomib), HDAC-inhibitors (e.g., panobinostat, vorinostat), DNA methyl transferase inhibitors, dexamethasone, melphalan, and immunomodulators such as lenolidomide and pomalidom
  • the compounds of Formula (I) can be administered in the form of pharmaceutical compositions.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.
  • topical including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal
  • oral or parenteral e.g., by
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
  • the compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.
  • Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art, e.g., see International App. No. WO 2002/000196.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention contain from about 5 mg to about 50 mg of the active ingredient.
  • the active ingredient contains from about 5 mg to about 50 mg.
  • One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient.
  • the compositions of the invention contain from about 500 mg to about 1, 000 mg of the active ingredient.
  • the active ingredient One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1, 000 mg of the active ingredient.
  • the active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • 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 can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • Topical formulations can contain one or more conventional carriers.
  • ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline, and the like.
  • Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g., glycerinemonostearate, PEG- glycerinemonostearate and cetylstearyl alcohol.
  • Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like.
  • topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt % of the compound of the invention.
  • the topical formulations can be suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration.
  • Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • compositions of the invention can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
  • additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
  • radionuclides that may be incorporated in compounds of the present invention include but are not limited to 3 H (also written as T for tritium), n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 C1, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro BET protein
  • a “radio-labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide.
  • the radionuclide is
  • reaction mixture was deoxygenated with nitrogen and was heated at 100 °C. After heating for 2 h the reaction was complete by LCMS. The reaction mixture was allowed to cool to room temperature, EtOAc was added and the mixture was washed with water, brine, then dried over magnesium sulfate and concentrated to give the crude product.
  • the product was purified on preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 2 with TFA to give 7-(3,5-dimethylisoxazol-4-yl)-4- phenyl-4,5-dihydroimidazo[l, 5, 4-de][l, 4]benzoxazin-2(7H)-one as white solid (0.10 g, 50%).
  • the title compound was prepared by methods analogous to Example 1 but using 2- bromo-l-(pyridin-3-yl)ethanone [Oakwood, cat. # 005885] in Step 1.
  • the product was purified by preparative HPLC on a C- 18 column eluting with water : MeCN gradient buffered pH 2 with TFA to give the TFA salt of the title compound as a white amorphous solid
  • the title compound was prepared by methods analogous to Example 1 but using 2- bromo-l-(2-methoxyphenyl)ethanone [Aldrich, cat. # 100854] in Step 1 and using dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2- yl)(chloro)palladium as catalyst in Step 5.
  • the product was purified by preparative HPLC on a C- 18 column eluting with water : MeCN gradient buffered pH 2 with TFA to give the title compound as a white amorphous solid (0.010 g, 25%).
  • the title compound was prepared by methods analogous to Example 1 but using 2- bromo-l-(2,4-difluorophenyl)ethanone [Aldrich, cat. # 595152] in Step 1 and using dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2- yl)(chloro)palladium as catalyst in Step 5.
  • the product was purified by preparative HPLC on a C- 18 column eluting with water : MeCN gradient buffered pH 2 with TFA to give the title compound as a white amorphous solid (0.018 g, 45%).
  • LCMS calc. for C2 0 H1 6 F2N 3 O 3
  • Step 1 7-Bromo-l-(2-morphoUn-4-ylethyl)-4-phenyl-4, 5-dihydroimidazofl, 5, 4-deJfl, 4 ] benzoxazin-2 (lH)-one
  • Step 2 7-(3, 5-Dimethylisoxazol-4-yl)-l-(2-morpholin-4-ylethyl)-4-phenyl-4, 5- dihydroimidazof 1, 5, 4-de][ 1 4]benzoxazin-2( lH)-one
  • the title compound was prepared by methods analogous to Example 1 but using 2- bromo-l-(pyridin-2-yl)ethanone HBr [Maybridge CC04005DA] in Step 1.
  • the product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 2 with TFA to give the TFA salt of the title compound as a white amorphous solid (0.015 g, 30%).
  • LCMS calc. for CigHnWs (M+H) + : m/z 349.1; found: 349.1.
  • the enantiomers were prepared from racemic 7-(3,5-dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2(7H)-one from Example 13, by chiral column HPLC using a Phenomenex Lux Cellulose-C4 column, 5 micron, 21.2 x 250 mm, eluting with 60% ethanol in hexanes with a flow rate of 18 mL/min., loading approx. 36 mg per injection with UV (220 nm) detection to give peak 1 at: 7.51 min. and peak 2 at: 12.92 min.
  • Methyltrioxorhenium(VII) (2 mg, 0.008 mmol) was added to a solution of 7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)- one (20 mg, 0.06 mmol) from Example 15, in tetrahydrofuran (2 mL) at room temperature and then 3.0 M hydrogen peroxide in water (0.04 mL) was added. The reaction mixture was heated to 80 °C for 20 min. allowed to cool and was diluted with water and EtOAc. The combined organic layers were washed with brine, dried over MgS0 4 , filtered and
  • the title compound was prepared by methods analogous to Example 1 but using 2- bromo-l-cyclohexylethanone from Step 1 above.
  • the product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 2 with TFA to give the title compound as a white amorphous solid (0.010 g, 30%).
  • N-Bromosuccinimide 200 mg, 1 mmol was added to a mixture of 2-(l-ethoxyvinyl)- 5-fluoropyridine (200 mg, 1 mmol) in THF (6 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 15 min., diluted with EtOAc and washed with brine. The combined organic layer was dried with MgS04, filtered and concentrated to give 2-bromo-l- (5-fluoropyridin-2-yl)ethanone as a clear oil, which was used in the next step.
  • the intermediate compound was prepared by methods analogous to Example 1, but using methyl [2-(bromoacetyl)phenoxy]acetate from above, in Step 1 and the ester was found to saponify in Step 5 to give the sub-title compound as a solid residue.
  • LCMS calc. for C 2 2H 2 o 3 0 6 (M+H)+: m/z 422.1; found: 422.1.
  • Step 2 7-(3, 5-Dimethylisoxazol-4-yl)-N-ethyl-2-oxo-4-phenyl-l, 2, 4, 5- tetrahydroimidazof 1, 5, 4-de][ 1, 4 ] benzoxazine-5-carboxamide
  • the title compound was prepared by a method analogous to Example 35, but using 4- chloro-l-methyl-5-(4,4,5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl)-lH-pyrazole.
  • the product was purified by preparative HPLC on a C- 18 column eluting with water : MeCN gradient buffered at pH2 to give the title compound.
  • LCMS calc. for Ci 9 Hi 6 ClN 4 0 2 (M+H) + :

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The present invention relates to tricyclic heterocycles which are inhibitors of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and are useful in the treatment of diseases such as cancer.

Description

TRICYCLIC HETEROCYCLES AS BET PROTEIN INHIBITORS
TECHNICAL FIELD
The present disclosure relates to tricyclic heterocycles which are inhibitors of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and are useful in the treatment of diseases such as cancer.
BACKGROUND
The genomes of eukaryotic organisms are highly organized within the nucleus of the cell. DNA is packaged into chromatin by wrapping around a core of histone proteins to form a nucleosome. These nucleosomes are further compacted by aggregation and folding to form a highly condensed chromatin structure. A range of different states of condensation are possible, and the tightness of this structure varies during the cell cycle, being most compact during the process of cell division. Chromatin structure plays a critical role in regulating gene transcription by regulating protein access to the DNA. The chromatin structure is controlled by a series of post translational modifications to histone proteins, mainly within the tails of histones H3 and H4 that extend beyond the core nucleosome structure. These reversible modifications include acetylation, methylation, phosphorylation, ubiquitination and
SUMOylation. These epigenetic marks are written and erased by specific enzymes that modify specific residues within the histone tail, thereby forming an epigenetic code. Other nuclear proteins bind to these marks and effect outputs specified by this information through the regulation of chromatin structure and gene transcription. Increasing evidence links genetic changes to genes encoding epigenetic modifiers and regulators leading to aberrant histone marks in diseases such as neurodegenerative disorders, metabolic diseases, inflammation and cancer.
Histone acetylation is typically associated with the activation of gene transcription, as the modification weakens the interaction between the DNA and the histone proteins, permitting greater access to DNA by the transcriptional machinery. Specific proteins bind to acetylated lysine residues within histones to "read" the epigenetic code. A highly conserved protein module called the bromodomain binds to acetylated lysine residues on histone and other proteins. There are more than 60 bromodomain-containing proteins in the human genome.
The BET (Bromodomain and Extra-Terminal) family of bromodomain containing proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-t) that share a conserved structural organization containing tandem N-terminal bromodomains capable of binding to acetylated lysine residues of histones and other proteins. BRD2, BRD3 and BRD4 are ubiquitously expressed while BRD-t is restricted to germ cells. BRD proteins play essential, but non-overlapping roles in regulating gene transcription and controlling cell growth. BET proteins are associated with large protein complexes including Mediator, PAFc and super elongation complex that regulate many aspects of gene transcription. BRD2 and BRD4 proteins have been shown to remain in complex with chromosomes during mitosis and are required to promote transcription of critical genes including cyclin D and c-Myc that initiate the cell cycle. Mochizuki et al, J. Biol. Chem. 2008, 283, 9040-9048. BRD4 is essential for recruiting the protein translational elongation factor B complex to the promoters of inducible genes resulting in the phosphorylation of RNA polymerase II and stimulating productive gene transcription and elongation. Jang et al, Mol. Cell, 2005, 19, 523-534. In some instances, a kinase activity of BRD4 may directly phosphorylate and activate RNA polymerase II.
Devaiah et al, Proc. Nat. Acad. Set, USA. 2012, 109, 6927-6932. Cells lacking BRD4 show impaired progression through cell cycle. BRD2 and BRD3 are reported to associate with histones along actively transcribed genes and may be involved in facilitating transcriptional elongation. Leroy et al., Mol. Cell, 2008, 30, 51-60. In addition to acetylated histones, BET proteins have been shown to bind selectively to acetylated transcription factors including the RelA subunit of NF-kB and GATAl thereby directly regulating the transcriptional activity of these proteins to control expression of genes involved in inflammation and hematopoietic differentiation. Huang et al., Mol. Cell Biol., 2009, 29, 1375-1387; Lamonica et al., Proc. Nat. Acad. Sci, USA, 2011, 108, E159-168.
A recurrent translocation involving NUT (nuclear protein in testes) with BRD3 or BRD4 to form a novel fusion oncogene, BRD-NUT, is found in a highly malignant form of epithelial neoplasia. French et al., Cancer Res., 2003, 63, 304-307; French et al., J. Clin. Oncol., 2004, 22, 4135-4139. Selective ablation of this oncogene restores normal cellular differentiation and reverses the tumorigenic phenotype. Filippakopoulos et al., Nature, 2010, 468, 1068-1073. Genetic knockdown of BRD2, BRD3 and BRD4 has been shown to impair the growth and viability of a wide range of hematological and solid tumor cells. Zuber et al., Nature, 2011, 478, 524-528; Delmore et al, Cell, 2011, 146, 904-917. Aside from a role in cancer, BET proteins regulate inflammatory responses to bacterial challenge, and a BRD2 hypomorph mouse model showed dramatically lower levels of inflammatory cytokines and protection from obesity induced diabetes. Wang et ah, Biochem. J., 2009, 425, 71-83;
Belkina et ah, J. Immunol. 102838, online publication before print, February 18, 2013. In addition, some viruses make use of these BET proteins to tether their genomes to the host cell chromatin, as part of the process of viral replication or use BET proteins to facilitate viral gene transcription and repression. You et ah, Cell, 2004, 117, 349-60; Zhu et ah, Cell Reports, 2012, 2, 807-816.
Accordingly, there is a need for compounds that modulate the activity of the BET family of proteins, including BRD2, BRD3, and BRD4, that can be used to treat BET protein- associated diseases such as cancer. The compounds of the invention help meet this need.
SUMMARY
The present disclosure provides, inter alia, a compound of Formula (I):
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof; wherein the variables are as defined below.
The present disclosure also provides a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
The present disclosure also provides methods of treating cancer and other diseases comprising administering to a patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and from the claims.
DETAILED DESCRIPTION
For the terms "e.g. " and "such as," and grammatical equivalents thereof, the phrase "and without limitation" is understood to follow unless explicitly stated otherwise.
The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The term "about" means "approximately" (e.g., plus or minus approximately 10% of the indicated value).
I. COMPOUNDS
The present disclosure relates, inter alia, to a compound of a BET protein-inhibiting compound of Formula (I):
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein:
represents a single bond or a double bond;
L is CR9R9a , 0, S, SO, or S02;
Cy1 is selected from phenyl or a 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said phenyl or 5-6 membered heteroaryl of Cy1 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R11;
R1 and R2 are independently selected from H, halo, CN, OH, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl, C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl, NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl, NRclS(=0)2Rbl and S(=0)2NRclRdl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl of R1 and R2 are optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl,
C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl, NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl, NRclS(=0)2Rbl and S(=0)2NRclRdl; provided neither R1 nor R2 are CI, Br, I, CN, or OH when L is O or S;
alternatively, R1 and R2 together with the carbon atom to which they are attached are combined to form a C3-7 cycloalkyl group, wherein said cycloalkyl group is optionally substituted with 1, 2, 3, or 4 groups independently selected from R20;
Cy3 is selected from phenyl, C3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl, C3_7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13, wherein a ring- forming nitrogen atom of said 5-10 membered heteroaryl group or a ring-forming nitrogen atom of said 4-10 membered heterocycloalkyl group is optionally oxidized;
R4 is H, C(=0)NR14aR14b, C(=0)R14a, C(=0)OR14a, or Ci_6 alkyl optionally substituted by 1, 2, or 3 substituents independently selected from halo, NR14aR14b, OR14a, SR14a, CN, C(=0)R14a, C(=0)NR14aR14b, C(=0)OR14a, OC(=0)R14b, OC(=0)NR14aR14b, NR14aC(=0)R14b, NR14aC(=0)NR14aR14b, NR14aC(=0)OR14b, S(=0)R14a, S(=0)NR14aR14b, S(=0)2R14a, NR14aS(=0)2R14b , and S(=0)2NR14aR14b;
R5 is selected from =0 and =S when C^^ N is a single bond,
alternatively, when C^^ N is a double bond then R5 is selected from H, Ci_6 alkyl, C2_
6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl, NR15aR15b, -C(=0)NR15aR15b, -C(=0)OR15a, phenyl, C3-
7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-10 membered heterocycloalkyl of R5 is optionally substituted by 1, 2, 3, or 4 groups independently selected from R15;
R6 is selected from H, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C e alkoxy, and Ci_6 haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R16;
alternatively, R6 is selected from Ce-w aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said Ce-w aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20;
R7 is selected from H, halo, CN, ORa, NRcRd, SRb, C(=0)NRcRd, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C e haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 4-7 membered heterocycloalkyl group of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17; R8 is selected from H, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd, wherein said Ci_3 alkyl of R8 is optionally substituted with 1, 2, or 3 groups independently selected from R18;
R9 and R9a are independently selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
R11 is independently at each occurrence selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd, wherein said Ci_3 alkyl is optionally substituted by OH;
R13 is independently at each occurrence selected from H, halo, CN, OH, Ci_6 alkyl, C2_ 6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, ORa3, SRa3, C(=0)Rb3, C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3,
NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl of R13 is optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, OR33, SRa3, C(=0)Rb3,
C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3,
NRc3C(=0)NRc3Rd3, NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3;
R15 is independently at each occurrence selected from H, C e alkyl, C3-7 cycloalkyl, 4- 7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, CN, ORa5, SRa5, C(=0)Rb5, C(=0)NRc5Rd5, C(=0)ORa5, OC(=0)Rb5, OC(=0)NRc5Rd5, NRc5Rd5,
NRc5C(=0)Rb5, NRc5C(=0)NRc5Rd5, NRc5C(=0)ORa5, S(=0)Rb5, S(=0)NRc5Rd5, S(=0)2Rb5, NRc5S(=0)2Rb5, and S(=0)2NRc5Rd5, wherein said Ci_6 alkyl, C3_7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa5, SRa5, C(=0)Rb5,
C(=0)NRc5Rd5, C(=0)ORa5, OC(=0)Rb5, OC(=0)NRc5Rd5, NRc5Rd5, NRc5C(=0)Rb5,
NRc5C(=0)NRc5Rd5, NRc5C(=0)ORa5, S(=0)Rb5, S(=0)NRc5Rd5, S(=0)2Rb5, NRc5S(=0)2Rb5, S(=0)2NRc5Rd5, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl, and C3-7 cycloalkyl;
R14a and R14b are independently at each occurrence selected from H and Ci_6 alkyl, wherein said Ci_6 alkyl of R14a and R14b is optionally substituted with 1, 2, or 3 substituents selected from R20;
or R14a and R14b together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents selected from R20; R15a and R15b are independently at each occurrence selected from H and Ci_6 alkyl, wherein said Ci_6 alkyl of R15a and R15b is optionally substituted with 1, 2, or 3 substituents selected from R20;
or R15a and R15b together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents selected from R20;
R16 is independently at each occurrence selected from halo, CN, OH, ORa6, SRa6, C(=0)Rb6, C(=0)NRc6Rd6, C(=0)ORa6, OC(=0)Rb6, OC(=0)NRc6Rd6, NRc6Rd6,
NRc6C(=0)Rb6, NRc6C(=0)NRc6Rd6, NRc6C(=0)ORa6, S(=0)Rb6, S(=0)NRc6Rd6, S(=0)2Rb6, NRc6S(=0)2Rb6 and S(=0)2NRc6Rd6, C6_i0 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R16 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20;
R17 and R18 are independently at each occurrence selected from halo, C1-4 alkyl, CN, ORa, NRcRd, SRb, C(=0)NRcRd, C(=0)ORa, and NRcC(=0)Ra;
Ra, Rc, and Rd are independently at each occurrence selected from H, Ci_6 alkyl, C(0)Re, S(=0)2Rf, C(=0)NRsRh, and phenyl optionally substituted by Ci_4 alkoxy;
Rb is at each occurrence Ci_6 alkyl;
Re is at each occurrence Ci-4 alkyl optionally substituted by a group selected from phenyl, Ci_4 alkoxy, amino, Ci_4 alkylamino, and C2_8 dialkylamino;
Rf is Ci_4 alkyl;
Rs and Rh are independenetly at each occurrence selected from H and Ci_4 alkyl; Ral, Rbl, Rcl and Rdl are independently at each occurrence selected from H, Ci_6 alkyl,
C2_6 alkenyl, C2_6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl forming Ral, Rbl, Rcl and Rdl are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra3, Rb3, Rc3 and Rd3 are independently at each occurrence selected from H, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl forming R33, Rb3, Rc3 and Rd3 are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, ORa4, SRa4, C(=0)RM, C(=0)NRc4Rd4, C(=0)ORa4, OC(=0)RM, OC(=0)NRc4Rd4, NR^R134, NRc4C(=0)RM, NRc4C(=0)NRc4Rd4, NRc4C(=0)0Ra4, S(=0)RM, S(=0)NRc4Rd4, S(=0)2R , NRc4S(=0)2RM and S(=0)2NRc4Rd4;
Ra4, Rb4, Rc4 and Rd4 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra4, Rb4, R04 and Rd4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra5, Rb5, Rc5 and Rd5 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 5-6 membered heterocycloalkyl, and Ci_6 haloalkyl wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra5, Rb5, Rc5 and Rd5 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
or Rc5 and Rd5 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra6, Rc6 and Rd6 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra6, Rc6 and Rd6 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
alternatively, Rc6 and Rd6 together with the nitrogen atom to which they are attached form a 4-7 membered heterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2 additional heteroatoms selected from N, O and S, wherein said 4-7 membered
heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Rb6 is independently at each occurrence selected from Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; and
R20 is at each occurrence independently selected from H, halo, OH, CN, amino, C1-4 alkyl, Ci_4 alkoxy, Ci_4 alkylthio, Ci_4 alkylamino, di(Ci_4 alkyl)amino, Ci_4 haloalkyl, Ci_4 haloalkoxy, Ci_4 alkyl-C(=0)-, Ci_4 alkyl-C(=0)0-, Ci_4 alkyl-OC(=0)-, HOC(=0)-,
H2NC(=0)-, Ci_4 alkyl-NHC(=0)-, di(Ci_4 alkyl)NC(=0)-, Ci_4 alkyl-C(=0)NH-, Ci_4 alkyl-0- C(=0)NH-, Ci-4 alkyl-S(=0)-, H2NS(=0)-, C1-4 alkyl-NHS(=0)-, di(C1-4 alkyl)NS(=0)-, Ci_4 alkyl-S(=0)2-, Ci_4 alkyl-S(=0)2NH-, H2NS(=0)2-, Ci_4 alkyl-NHS(=0)2-, and di(Ci_4 alkyl)NS(=0)2-.
The present disclosure relates, inter alia, to a compound of a BET protein-inhibiting compound of Formula (I):
Figure imgf000010_0001
or a pharmaceutically acceptable salt thereof, wherein:
represents a single bond or a double bond;
L is CR9R9a , 0, S, SO, or S02;
Cy1 is selected from phenyl or a 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said phenyl or 5-6 membered heteroaryl of Cy1 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R11;
R1 and R2 are independently selected from H, halo, CN, OH, C e alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl, C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl, NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl, NRclS(=0)2Rbl and S(=0)2NRclRdl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl of R1 and R2 are optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl,
C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl, NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl, NRclS(=0)2Rbl and S(=0)2NRclRdl; provided neither R1 nor R2 are CI, Br, I, CN, or OH when L is O or S;
alternatively, R1 and R2 together with the carbon atom to which they are attached may be combined to form a C3-7 cycloalkyl group, wherein said cycloalkyl group is optionally substituted with 1, 2, 3, or 4 groups independently selected from R20;
Cy3 is selected from phenyl, C3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R , wherein a ring- forming nitrogen atom of said 5-10 membered heteroaryl group or a ring- forming nitrogen atom of said 4-10 membered heterocycloalkyl group is optionally oxidized;
R4 is H or Ci_6 alkyl;
R5 is selected from =0 and =S when C^^N is a single bond,
alternatively, when C^^N is a double bond then R5 is selected from H, Ci_6 alkyl, C2- 6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, NR15aR15b, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R5 is optionally substituted by 1, 2, 3, or 4 groups independently selected from R15;
R6 is selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R16;
alternatively, R6 is selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20;
R7 is selected from H, halo, CN, ORa, NRcRd, SRb, C(=0)NRcRd, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 4-7 membered heterocycloalkyl group of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17;
R8 is selected from H, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd, wherein said Ci_3 alkyl of R8 is optionally substituted with 1, 2, or 3 groups independently selected from R18;
R9 and R9a are independently selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd; R11 is independently at each occurrence selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
R13 is independently at each occurrence selected from H, halo, CN, OH, C e alkyl, C2_ 6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, ORa3, SRa3, C(=0)Rb3, C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3,
NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl of R13 is optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, OR33, SRa3, C(=0)Rb3,
C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3, NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3;
R15 is independently at each occurrence selected from H, halo, CN, OH, ORa5, SRa5, C(=0)Rb5, C(=0)NRc5Rd5, C(=0)ORa5, OC(=0)Rb5, OC(=0)NRc5Rd5, NRc5Rd5,
NRc5C(=0)Rb5, NRc5C(=0)NRc5Rd5, NRc5C(=0)ORa5, S(=0)Rb5, S(=0)NRc5Rd5, S(=0)2Rb5, NRc5S(=0)2Rb5 and S(=0)2NRc5Rd5;
R15a and R15b are independently selected from H and Ci_6 alkyl, wherein said alkyl of R15a and R15b is optionally substituted with 0, 1, 2, or 3 substituents selected from R20;
R16 is independently at each occurrence selected from halo, CN, OH, ORa6, SRa6, C(=0)Rb6, C(=0)NRc6Rd6, C(=0)ORa6, OC(=0)Rb6, OC(=0)NRc6Rd6, NRc6Rd6,
NRc6C(=0)Rb6, NRc6C(=0)NRc6Rd6, NRc6C(=0)ORa6, S(=0)Rb6, S(=0)NRc6Rd6, S(=0)2Rb6, NRc6S(=0)2Rb6 and S(=0)2NRc6Rd6, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said Ce-w aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R16 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20;
R17 and R18 are independently at each occurrence selected from halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
Ra, Rc, and Rd are independently at each occurrence selected from H and Ci_6 alkyl; Rb is at each occurrence Ci_6 alkyl;
Ral, Rbl, Rcl and Rdl are independently at each occurrence selected from H, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl forming Ral, Rbl, Rcl and Rdl are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; Ra , R , Rc and R are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra3, Rb3, Rc3 and Rd3 are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, ORa4, SRa4, C(=0)RM,
C(=0)NRc4Rd4, C(=0)ORa4, OC(=0)RM, OC(=0)NRc4Rd4, m°*RM, NRc4C(=0)RM,
NRc4C(=0)NRc4Rd4, NRc4C(=0)ORa4, S(=0)RM, S(=0)NRc4Rd4, S(=0)2RM, NRc4S(=0)2RM and S(=0)2NRc4Rd4;
Ra4, Rb4, Rc4 and Rd4 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra4, RM, R04 and Rd4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra5, Rb5, Rc5 and Rd5 are independently at each occurrence selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra5, Rb5, Rc5 and Rd5 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra6, Rc6 and Rd6 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra6, Rc6 and Rd6 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
alternatively, Rc6 and Rd6 together with the nitrogen atom to which they are attached may be combined to form a 4-7 membered heterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2 additional heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Rb6 is independently at each occurrence selected from Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; and
R20 is at each occurrence independently selected from H, halo, OH, CN, amino, C1-4 alkyl, Ci_4 alkoxy, Ci_4 alkylthio, Ci_4 alkylamino, di(Ci_4 alkyl)amino, Ci_4 haloalkyl, Ci_4 haloalkoxy, C1-4 alkyl-C(=0)-, C1-4 alkyl-C(=0)0-, C1-4 alkyl-OC(=0)-, HOC(=0)-, H2NC(=0)-, Ci_4 alkyl-NHC(=0)-, di(Ci_4 alkyl)NC(=0)-, Ci_4 alkyl-C(=0)NH-, Ci_4 alkyl- S(=0)-, H2NS(=0)-, Ci_4 alkyl-NHS(=0)-, di(Ci_4 alkyl)NS(=0)-, Ci_4 alkyl-S(=0)2-, Ci_4 alkyl-S(=0)2NH-, H2NS(=0)2-, Ci_4 alkyl-NHS(=0)2-, and di(Ci_4 alkyl)NS(=0)2-.
In some embodiments of the compounds of Formula (I):
represents a single bond or a double bond;
L is CR9R9a , 0, S, SO, or S02;
Cy1 is selected from phenyl or a 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said phenyl or 5-6 membered heteroaryl of Cy1 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R11;
R1 is selected from H, halo, CN, OH, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl, C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl, NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl, NRclS(=0)2Rbl and S(=0)2NRclRdl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_ 6 alkynyl of R1 and R2 are optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl, C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl, NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl, NRclS(=0)2Rbl and S(=0)2NRclRdl;
R2 is selected from H, halo, CN, OH, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 alkyl-O-, and Ci_6 haloalkyl-O-;
provided neither R1 nor R2 are CI, Br, I, CN, or OH when L is O or S;
Cy3 is selected from phenyl, C3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13; additionally, wherein a ring-forming nitrogen atom of said 5-10 membered heteroaryl group or a ring-forming nitrogen atom of said 4-10 membered heterocycloalkyl group is optionally oxidized;
R4 is H or Ci_6 alkyl;
R5 is selected from =0 and =S when C^^N is a single bond,
alternatively, when C^^N is a double bond then R5 is selected from H, Ci_6 alkyl, C2_ 6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, NR15aR15b, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R5 is optionally substituted by 1, 2, 3, or 4 groups independently selected from R15;
R6 is selected from H, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, and Ci_6 haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R16;
alternatively, R6 is selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20;
R7 is selected from H, halo, CN, ORa, NRcRd, SRb, C(=0)NRcRd, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 4-7 membered heterocycloalkyl group of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17;
R8 is selected from H, halo, CN, OH, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 alkyl-O-, and Ci_6 haloalkyl-O-;
R9 and R9a are independently selected from H and C1-3 alkyl;
R11 is independently at each occurrence selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
R13 is independently at each occurrence selected from H, halo, CN, OH, Ci_6 alkyl, C2_ 6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, ORa3, SRa3, C(=0)Rb3, C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3,
NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl of R13 is optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, OR33, SRa3, C(=0)Rb3,
C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NR C(=0)NR R , NRc3C(=0)OR , S(=0)R , S(=0)NRC3R , S(=0)2R , NRC3S(=0)2RM and S(=0)2NRc3Rd3;
R15 is independently at each occurrence selected from H, halo, CN, OH, ORa5, SRa5, C(=0)Rb5, C(=0)NRc5Rd5, C(=0)ORa5, OC(=0)Rb5, OC(=0)NRc5Rd5, NRc5Rd5,
NRc5C(=0)Rb5, NRc5C(=0)NRc5Rd5, NRc5C(=0)ORa5, S(=0)Rb5, S(=0)NRc5Rd5, S(=0)2Rb5, NRc5S(=0)2Rb5 and S(=0)2NRc5Rd5;
R15a and R15b are independently selected from H and Ci_6 alkyl, wherein said alkyl of R15a and R15b is optionally substituted with 0, 1, 2, or 3 substituents selected from R20;
R16 is independently at each occurrence selected from halo, CN, OH, ORa6, SRa6, C(=0)Rb6, C(=0)NRc6Rd6, C(=0)ORa6, OC(=0)Rb6, OC(=0)NRc6Rd6, NRc6Rd6,
NRc6C(=0)Rb6, NRc6C(=0)NRc6Rd6, NRc6C(=0)ORa6, S(=0)Rb6, S(=0)NRc6Rd6, S(=0)2Rb6, NRc6S(=0)2Rb6 and S(=0)2NRc6Rd6, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R16 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20;
R17 is independently at each occurrence selected from halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
Ra, Rc, and Rd are independently at each occurrence selected from H and Ci_6 alkyl;
Rb is at each occurrence Ci-6 alkyl;
Ral, Rbl, Rcl and Rdl are independently at each occurrence selected from H, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl forming Ral, Rbl, Rcl and Rdl are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra3, Rb3, Rc3 and Rd3 are independently at each occurrence selected from H, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl forming Ra3, Rb3, Rc3 and Rd3 are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, ORa4, SRa4, C(=0)RM,
C(=0)NRc4Rd4, C(=0)ORa4, OC(=0)RM, OC(=0)NRc4Rd4, NR^R134, NRc4C(=0)RM,
NRc4C(=0)NRc4Rd4, NRc4C(=0)ORa4, S(=0)RM, S(=0)NRc4Rd4, S(=0)2RM, NRc4S(=0)2RM and S(=0)2NRc4Rd4;
Ra4, Rb4, Rc4 and Rd4 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra , R , R and R are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra5, Rb5, Rc5 and Rd5 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra5, Rb5, Rc5 and Rd5 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra6, Rc6 and Rd6 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra6, Rc6 and Rd6 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
alternatively, Rc6 and Rd6 together with the nitrogen atom to which they are attached may be combined to form a 4-7 membered heterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2 additional heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Rb6 is independently at each occurrence selected from Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; and
R20 is at each occurrence independently selected from H, halo, OH, CN, amino, C1-4 alkyl, Ci_4 alkoxy, Ci_4 alkylthio, Ci_4 alkylamino, di(Ci_4 alkyl)amino, Ci_4 haloalkyl, Ci_4 haloalkoxy, Ci_4 alkyl-C(=0)-, Ci_4 alkyl-C(=0)0-, Ci_4 alkyl-OC(=0)-, HOC(=0)-,
H2NC(=0)-, Ci_4 alkyl-NHC(=0)-, di(Ci_4 alkyl)NC(=0)-, Ci_4 alkyl-C(=0)NH-, Ci_4 alkyl- S(=0)-, H2NS(=0)-, Ci_4 alkyl-NHS(=0)-, di(Ci_4 alkyl)NS(=0)-, Ci_4 alkyl-S(=0)2-, Ci_4 alkyl-S(=0)2NH-, H2NS(=0)2-, Ci_4 alkyl-NHS(=0)2-, and di(Ci_4 alkyl)NS(=0)2-.
In some embodiments of the compounds of Formula (I):
represents a single bond or a double bond;
L is O; Cy1 is a five membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said five membered heteroaryl of Cy1 is optionally substituted with 1, 2, or 3 groups independently selected from R11;
R1 is selected from H, F, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl, C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl,
NRclC(=0)Rbl, NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl, NRclS(=0)2Rbl and S(=0)2NRclRdl, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2_6 alkynyl of R1 and R2 are optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl, C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl, NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl, NRclS(=0)2Rbl and S(=0)2NRclRdl;
R2 is selected from H, F, and Ci-6 alkyl;
Cy3 is selected from phenyl, C3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said phenyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13; additionally, wherein a ring-forming nitrogen atom of said 5-10 membered heteroaryl group or a ring-forming nitrogen atom of said 4-10 membered heterocycloalkyl group is optionally oxidized;
R4 is H or Ci-6 alkyl;
R5 is selected from =0 and =S when C=^=N is a single bond,
alternatively, when C=^=N is a double bond then R5 is selected from H, Ci_6 alkyl, C2_ 6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, NR15aR15b, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R5 is optionally substituted by 1, 2, 3, or 4 groups independently selected from R15;
R6 is selected from H, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, and Ci_6 haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R16;
R7 is selected from H, halo, CN, ORa, NRcRd, SRb, C(=0)NRcRd, Ci_6 alkyl, C2_6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 4-7 membered heterocycloalkyl group of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17;
R8 is selected from H, halo, CN, OH, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 alkyl-O-, and Ci_6 haloalkyl-O-;
R11 is independently at each occurrence selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
R13 is independently at each occurrence selected from H, halo, CN, OH, Ci_6 alkyl, C2_
6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, ORa3, SRa3, C(=0)Rb3, C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3,
NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl of R13 is optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, OR33, SRa3, C(=0)Rb3,
C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3, NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3;
R15 is independently at each occurrence selected from H, halo, CN, OH, ORa5, SRa5, C(=0)Rb5, C(=0)NRc5Rd5, C(=0)ORa5, OC(=0)Rb5, OC(=0)NRc5Rd5, NRc5Rd5,
NRc5C(=0)Rb5, NRc5C(=0)NRc5Rd5, NRc5C(=0)ORa5, S(=0)Rb5, S(=0)NRc5Rd5, S(=0)2Rb5, NRc5S(=0)2Rb5 and S(=0)2NRc5Rd5;
R15a and R15b are independently selected from H and Ci_6 alkyl, wherein said alkyl of R15a and R15b is optionally substituted with 0, 1, 2, or 3 substituents selected from R20;
R16 is independently at each occurrence selected from halo, CN, OH, ORa6, SRa6,
C(=0)Rb6, C(=0)NRc6Rd6, C(=0)ORa6, OC(=0)Rb6, OC(=0)NRc6Rd6, NRc6Rd6,
NRc6C(=0)Rb6, NRc6C(=0)NRc6Rd6, NRc6C(=0)ORa6, S(=0)Rb6, S(=0)NRc6Rd6, S(=0)2Rb6, NRc6S(=0)2Rb6 and S(=0)2NRc6Rd6, C6_i0 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R16 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20; R17 is independently at each occurrence selected from halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
Ra, Rc, and Rd are independently at each occurrence selected from H and Ci_6 alkyl;
Rb is at each occurrence Ci_6 alkyl;
Ral, Rbl, Rcl and Rdl are independently at each occurrence selected from H, Ci_6 alkyl,
C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ral, Rbl, Rcl and Rdl are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra3, Rb3, Rc3 and Rd3 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra3, Rb3, Rc3 and Rd3 are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, ORa4, SRa4, C(=0)RM,
C(=0)NRc4Rd4, C(=0)ORa4, OC(=0)RM, OC(=0)NRc4Rd4, R^R134, NRc4C(=0)RM, NRc4C(=0)NRc4Rd4, NRc4C(=0)ORa4, S(=0)RM, S(=0)NRc4Rd4, S(=0)2RM, NRc4S(=0)2RM and S(=0)2NRc4Rd4;
Ra4, Rb4, Rc4 and Rd4 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra4, RM, R04 and Rd4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra5, Rb5, Rc5 and Rd5 are independently at each occurrence selected from H, Ci_6 alkyl,
C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra5, Rb5, Rc5 and Rd5 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra6, Rc6 and Rd6 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra6, Rc6 and Rd6 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
alternatively, Rc6 and Rd6 together with the nitrogen atom to which they are attached may be combined to form a 4-7 membered heterocycloalkyl group comprising carbon and 1 , 2, or 3 heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Rb6 is independently at each occurrence selected from Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; and
R20 is at each occurrence independently selected from H, halo, OH, CN, amino, C1-4 alkyl, Ci-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(Ci_4 alkyl)amino, Ci_4 haloalkyl, C1-4 haloalkoxy, Ci_4 alkyl-C(=0)-, Ci_4 alkyl-C(=0)0-, Ci_4 alkyl-OC(=0)-, HOC(=0)-,
H2NC(=0)-, Ci_4 alkyl-NHC(=0)-, di(Ci_4 alkyl)NC(=0)-, Ci_4 alkyl-C(=0)NH-, Ci_4 alkyl- S(=0)-, H2NS(=0)-, Ci_4 alkyl-NHS(=0)-, di(Ci_4 alkyl)NS(=0)-, Ci_4 alkyl-S(=0)2-, Ci_4 alkyl-S(=0)2NH-, H2NS(=0)2-, Ci_4 alkyl-NHS(=0)2-, and di(Ci_4 alkyl)NS(=0)2-.
In some embodiments:
represents a single bond or a double bond;
L is O;
Cy1 is a five membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said five membered heteroaryl of Cy1 is optionally substituted with 1, 2, or 3 groups independently selected from R11;
R1 is selected from H, F, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, ORal, C(=0)Rbl, C(=0)NRclRdl, and C(=0)ORal;
R2 is selected from H, F, and Ci_6 alkyl;
Cy3 is selected from phenyl, C3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said phenyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13; additionally, wherein a ring-forming nitrogen atom of said 5-10 membered heteroaryl group or a ring-forming nitrogen atom of said 4-10 membered heterocycloalkyl group is optionally oxidized;
R4 is H or Ci_6 alkyl;
R5 is selected from =0 and =S when C^^N is a single bond,
alternatively, when C^^N is a double bond then R5 is selected from H, Ci_6 alkyl, C2_ 6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, NR15aR15b, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R5 is optionally substituted by 1, 2, 3, or 4 groups independently selected from R15;
R6 is selected from H and Ci_6 alkyl, wherein said alkyl of R6 is optionally substituted by 1, 2, or 3 groups independently selected R16;
R7 is selected from H, halo, CN, Ci_6 alkyl, Ci_6 alkoxy, phenyl, and 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, or 5-6 membered heteroaryl group, of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17;
R8 is selected from H, halo, CN, OH, and Ci_6 alkyl;
R11 is independently at each occurrence selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
R13 is independently at each occurrence selected from H, halo, CN, OH, Ci_6 alkyl, C2_ 6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, ORa3, SRa3, C(=0)Rb3, C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3,
NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl of R13 is optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, OR33, SRa3, C(=0)Rb3,
C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3, NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3;
R15 is independently at each occurrence selected from H, halo, CN, OH, ORa5, C(=0)Rb5, C(=0)NRc5Rd5, C(=0)ORa5, NRc5Rd5, and NRc5C(=0)Rb5;
R15a and R15b are independently selected from H and Ci_6 alkyl, wherein said alkyl of R15a and R15b is optionally substituted with 0, 1, 2, or 3 substituents selected from R20;
R16 is independently at each occurrence selected from halo, CN, OH, ORa6, C(=0)Rb6, C(=0)NRc6Rd6, C(=0)ORa6, OC(=0)Rb6, NRc6Rd6, NRc6C(=0)Rb6, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl of R16 is optionally substituted by 1, 2, 3, or 4 groups independently selected R20;
R17 is independently at each occurrence selected from halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
Ra, Rc, and Rd are independently at each occurrence selected from H and Ci_6 alkyl; Rb is at each occurrence Ci-6 alkyl; Ral, Rbl, Rcl and Rdl are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ral, Rbl, Rcl and Rdl are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra3, Rb3, Rc3 and Rd3 are independently at each occurrence selected from H and Ci_6 alkyl, wherein said Ci_6 alkyl forming Ra3, Rb3, Rc3 and Rd3 is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, ORa4, SRa4, C(=0)RM,
C(=0)NRc4Rd4, C(=0)ORa4, OC(=0)RM, OC(=0)NRc4Rd4, NR'V4, NRc4C(=0)RM, NRc4C(=0)NRc4Rd4, NRc4C(=0)ORa4, S(=0)RM, S(=0)NRc4Rd4, S(=0)2RM, NRc4S(=0)2RM and S(=0)2NRc4Rd4;
Ra4, Rb4, Rc4 and Rd4 are independently at each occurrence selected from H and Ci_6 alkyl, wherein said Ci-6 alkyl forming Ra4, RM, Rc4 and Rd4 is optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra5, Rb5, Rc5 and Rd5 are independently at each occurrence selected from H and Ci_6 alkyl, wherein said Ci_6 alkyl forming Ra5, Rb5, Rc5 and Rd5 is optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra6, Rc6 and Rd6 are independently at each occurrence selected from H and Ci_6 alkyl; alternatively, Rc6 and Rd6 together with the nitrogen atom to which they are attached may be combined to form a 4-7 membered heterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2 additional heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Rb6 is independently at each occurrence selected from Ci_6 alkyl; and
R20 is at each occurrence independently selected from H, halo, OH, CN, amino, C1-4 alkyl, Ci_4 alkoxy, Ci_4 alkylthio, Ci_4 alkylamino, di(Ci_4 alkyl)amino, Ci_4 haloalkyl, Ci_4 haloalkoxy, Ci_4 alkyl-C(=0)-, Ci_4 alkyl-C(=0)0-, Ci_4 alkyl-OC(=0)-, HOC(=0)-,
H2NC(=0)-, Ci_4 alkyl-NHC(=0)-, di(Ci_4 alkyl)NC(=0)-, Ci_4 alkyl-C(=0)NH-, Ci_4 alkyl- S(=0)-, H2NS(=0)-, Ci_4 alkyl-NHS(=0)-, di(Ci_4 alkyl)NS(=0)-, Ci_4 alkyl-S(=0)2-, Ci_4 alkyl-S(=0)2NH-, H2NS(=0)2-, Ci_4 alkyl-NHS(=0)2-, and di(Ci_4 alkyl)NS(=0)2-.
In some embodiments of the compounds of Formula (I), the compound is a compound of Formula (la):
Figure imgf000024_0001
or a pharmaceutically acceptable salt thereof, wherein:
represents a single bond or a double bond;
Cy1 is selected from isoxazolyl and pyrazolyl, wherein said isoxazolyl and pyrazolyl of Cy1 is optionally substituted with 1 or 2 groups independently selected from R11;
R1 is selected from H, methyl, -C(=0)OCH2CH3, - C(=0)N(H)CH2CH3, -C(=0)N(H)CH2CH2OH, and -C(=0)N(CH3)2;
Cy3 is selected from phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl, wherein said phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13;
R5 is =0 when C is a single bond,
alternatively, when C^^N is a double bond then R5 is H,
methyl, -CH=CH2, -N(H)CH3, -N(H)CH2CH3, -N(H)CH(CH3)2, -N(CH3)2, -N(H)CH2CH2OH
-N(H)CH(CH3)CH2OH, -N(H)CH2CH(OH)CH3, -
N(H)C(CH3)2CH2OH, -N(CH3)CH2CH2OH, morpholinyl, pyrrolidinyl, hydroxypyrrolidinyl, piperidinyl, hydroxypiperidinyl, azetidinyl, hydroxyazetidinyl, piperazinyl,
butoxycarbonylpiperazinyl, and phenyl;
R6 is selected from H, methyl, ethyl, and propyl wherein said methyl, ethyl, and propyl of R6 are each optionally substituted by 1, 2, or 3 groups independently selected R16;
R7 is selected from H, F, CI, Br, methyl, methoxy, ethoxy, CN, phenyl, and pyridinyl;
R11 is independently at each occurrence selected from H, methyl, ethyl, chloro, and methoxy;
R13 is independently at each occurrence selected from H, F, CN, methoxy, -CF3, -OCH2C(=0)OH, -OCH2C(=0)N(H)CH2CH3, -OCH2C(=0)N(H)CH2CH2OH,
and -OCH2C(=0)N(CH3)2; and
R16 is independently at each occurrence selected from H, morpholinyl, and piperidinyl.
In some embodiments of the compounds described above, L is O. In some embodiments, L is S.
In some embodiments, L is CR9R9a .
In some embodiments, L is CH2.
In some embodiments, Cy1 is isoxazolyl substituted with 1 or 2 groups independently selected from R11.
In some embodiments, Cy1 is pyrazolyl substituted with 1 or 2 groups independently selected from R11.
In some embodiments, R1 is selected from H, methyl, -CH2OH, -C(=0)OCH2CH3, -C(=0)N(H)CH2CH3, -C(=0)N(H)CH3, -C(=0)NH2, -C(=0)N(H)CH2CH2OH, and -C(=0)N(CH3)2.
In some embodiments, R1 is selected from H, methyl, -C(=0)OCH2CH3,
-C(=0)N(H)CH2CH3, -C(=0)N(H)CH2CH2OH, and -C(=0)N(CH3)2.
In some embodiments, R1 is H.
In some embodiments, R1 is methyl.
In some embodiments, R1 is -C(=0)OCH2CH3.
In some embodiments, R1 is C(=0)N(H)CH2CH3.
In some embodiments, R1 is C(=0)N(H)CH2CH2OH.
In some embodiments, R1 is -C(=0)N(CH3)2.
In some embodiments, R1 is -C(=0)N(H)CH3.
In some embodiments, R1 is -C(=0)NH2.
In some embodiments, R1 is -CH2OH.
In some embodiments, R2 is H.
In some embodiments, R2 is methyl.
In some embodiments, Cy3 is selected from phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl, tetrahydrofuranyl, and piperinyl, wherein said phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl,
tetrahydrofuranyl, and piperidinyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
In some embodiments, Cy3 is selected from phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl, wherein said phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
In some embodiments, Cy3 is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13. In some embodiments, Cy3 is pyridinyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
In some embodiments, Cy3 is oxidopyridinyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
In some embodiments, Cy3 is thiazolyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
In some embodiments, Cy3 is cyclohexyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
In some embodiments, Cy3 is dihydrobenzofuranyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
In some embodiments, Cy3 is tetrahydrofuranyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
In some embodiments, Cy3 is piperidinyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
In some embodiments, R4 is H, -C(=0)NH2, -CH2NH2, -CH2N(H)C(=0)CH3,
-C(=0)N(H)CH3, -CH2CH3, or -CH3.
In some embodiments, R4 is H.
In some embodiments, R5 is =0 when C^^ N is a single bond.
In some embodiments, R5 is =S when C^^ N is a single bond.
In some embodiments, when C^^ N is a double bond then R5 is selected from H, C1-4 alkyl, -CH=CH2, NR15aR15b, -C(=0)NR15aR15b, phenyl, and a 4-10 membered
heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said alkyl, and 4-10 membered heterocycloalkyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
In some embodiments, when C=-^N is a double bond then R5 is selected from H, C1-4 alkyl, -CH=CH2, NR15aR15b, -C(=0)R15aR15b, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2,5-dihydro-lH-pyrrolyl, 1,4-diazepanyl, morpholinyl, and octahydropyrrolo[l,2-a]pyrazinyl, wherein said C1-4 alkyl, phenyl, azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2,5-dihydro-lH- pyrrolyl, 1,4-diazepanyl, morpholinyl, and octahydropyrrolo[l,2-a]pyrazinyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
In some embodiments, when C=-^N is a double bond then R5 is H, methyl, -CH=CH2, -N(H)CH3, -N(H)CH2CH3, -N(H)CH(CH3)2, -N(CH3)2, -N(H)CH2CH2OH,
-N(H)CH(CH3)CH2OH, -N(H)CH2CH(OH)CH3, -N(H)C(CH3)2CH2OH, - N(CH3)CH2CH2OH, morpholinyl, pyrrolidinyl, hydroxypyrrolidinyl, piperidinyl, hydroxypiperidinyl, azetidinyl, hydroxyazetidinyl, piperazinyl, butoxycarbonylpiperazinyl, or phenyl.
In some embodiments, when C is a double bond then R5 is selected from a 4-6 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said 4-6 membered heterocycloalkyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
In some embodiments, when C=^=N is a double bond then R5 is pyrrolidinyl, piperidinyl, azetidinyl, or piperazinyl, wherein said pyrrolidinyl, piperidinyl, azetidinyl, or piperazinyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
In some embodiments, when C^^N is a double bond then R5 is pyrrolidinyl, wherein said pyrrolidinyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
In some embodiments, when C=^=N is a double bond then R5 is piperidinyl, wherein said piperidinyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
In some embodiments, when C is a double bond then R5 is azetidinyl, wherein said azetidinyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
In some embodiments, when C is a double bond then R5 is piperazinyl, wherein said piperazinyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
In some embodiments, R15 is independently at each occurrence selected from Ci_6 alkyl, CN, ORa5, C(=0)Rb5, C(=0)NRc5Rd5, C(=0)ORa5, NRc5Rd5, NRc5C(=0)Rb5,
NRc5C(=0)NRc5Rd5, NRc5C(=0)ORa5, S(=0)2Rb5, NRc5S(=0)2Rb5, and S(=0)2NRc5Rd5, wherein said Ci_6 alkyl, is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa5, SRa5, C(=0)Rb5, C(=0)NRc5Rd5, C(=0)ORa5, OC(=0)Rb5, OC(=0)NRc5Rd5, NRc5Rd5, NRc5C(=0)Rb5, NRc5C(=0)NRc5Rd5, NRc5C(=0)ORa5, S(=0)Rb5, S(=0)NRc5Rd5, S(=0)2Rb5, NRc5S(=0)2Rb5, S(=0)2NRc5Rd5, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl, and C3-7 cycloalkyl.
In some embodiments, R6 is H, C1-4 alkyl, or C1-4 alkoxy.
In some embodiments, R6 is H, methyl, or methoxy.
In some embodiments, R6 is H. In some embodiments, R7 is selected from H, halo, CN, NRcRd, Ci_6 alkyl, C2-6 alkenyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 5-6 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, 5-6 membered heteroaryl group, and 5-6 membered heterocycloalkyl group of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17.
In some embodiments, R7 is selected from H, F, CI, Br, CN, NRcRd, Ci_4 alkyl, C2-4 alkenyl, pyrazolyl, pyridinyl, pyrimidinyl, and 1,2,3,6-tetrahydropyridinyl, wherein said Ci_6 alkyl, C2-6 alkenyl, pyrazolyl, pyridinyl, pyrmimidinyl, and 1,2,3,6-tetrahydropyridinyl of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17.
In some embodiments, R7 is selected from H, halo, Ci_4 alkyl, and CN.
In some embodiments, R7 is selected from H, Br, methyl, and CN.
In some embodiments, R7 is H.
In some embodiments, R7 is Br.
In some embodiments, R7 is methyl.
In some embodiments, R7 is CN.
In some embodiments, R8 is selected from H, halo, Ci_4 alkyl, and CN.
In some embodiments, R8 is H.
It is understood that when C^^N is a double bond then R6 is absent.
In some embodiments of the compounds of Formula (I), the compound is selected from the following compounds:
7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
(4R)-7-(3 ,5 -dimethylisoxazol-4-yl)-4-phenyl-4,5 -dihydroimidazo [1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-l-methyl-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-5-methyl-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
4-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-4-yl]benzonitrile; 7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(3-methoxyphenyl)-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(2-methoxyphenyl)-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(2,4-difluorophenyl)-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-2-methyl-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine;
7-(3,5-dimethylisoxazol-4-yl)-l-(2-morpholin-4-ylethyl)-4-phenyl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2(77i)-one;
7-(3,5-dimethyl-7H-pyrazol-4-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2(7H)-one;
7-(3-methyl-7H-pyrazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2(7H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
(4R)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
(4/S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2(7H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(l-oxidopyridin-2-yl)-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
4-cyclohexyl-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(tetrahydrofuran-2-yl)-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2(7H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(5-fluoropyridin-2-yl)-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2(7H)-one;
ethyl 7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l, 2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazine-5-carboxylate;
7-(3,5-dimethylisoxazol-4-yl)-4-(l,3-thiazol-2-yl)-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one; 2- {2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-4-yl]phenoxy } -N-ethylacetamide;
ethyl7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-phenyl-l,2,4,5-tetrahydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine-5-carboxylate;
7-(3,5-dimethylisoxazol-4-yl)-N-ethyl-2-oxo-4-phenyl- 1,2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazine-5-carboxamide;
7-(3,5-dimethylisoxazol-4-yl)-N-isopropyl-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2-amine;
7-(3,5-dimethylisoxazol-4-yl)-N-methyl-4-phenyl-4,5-dihydroimidazo[l,5,4- i/e][l,4]benzoxazin-2-amine ;
7-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-amine;
7-(3,5-dimethylisoxazol-4-yl)-N,N-dimethyl-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-amine;
2- {[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- i/e][l,4]benzoxazin-2-yl]amino}ethanol;
2- {[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]amino}propan- 1 -ol;
1- {[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- i/e][l,4]benzoxazin-2-yl]amino}propan-2-ol;
2- {[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]amino} -2-methylpropan- 1 -ol;
2- [ [7-(3 ,5 -dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo [1,5,4- i/e][l,4]benzoxazin-2-yl](methyl)amino]ethanol;
7-(l-methyl-7H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
9-bromo-7-(l -methyl- 7H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2(7H)-one;
9-methyl-7-(l -methyl- 7H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[l, 5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(4-chloro-l -methyl- 7H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazine; 7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-2-piperazin-l-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine;
7-(3,5-dimethylisoxazol-4-yl)-2,4-diphenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine;
7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-phenyl-l,2,4,5-tetrahydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine-9-carbonitrile;
7-(3,5-dimethylisoxazol-4-yl)-4,9-diphenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(l,4-dimethyl-7H-pyrazol-5-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
9-bromo-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-methyl-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-N,N-dimethyl-2-oxo-4-phenyl-l, 2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazine-5-carboxamide;
7-(3,5-dimethylisoxazol-4-yl)-N-(2-hydroxyethyl)-2-oxo-4-phenyl- 1,2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazine-5-carboxamide;
7-(3,5-dimethylisoxazol-4-yl)-4-(4-fluorophenyl)-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
2- {2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-4-yl]phenoxy } -N-(2-hydroxyethyl)acetamide;
2- {2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-4-yl]phenoxy } -N,N-dimethylacetamide;
7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-9-pyridin-3-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2(7H)-one;
7-(3,5-dimethylisoxazol-4-yl)-2-morpholin-4-yl-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine;
7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-2-pyrrolidin-l-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine;
l-[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3-ol;
7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-2-piperidin-l-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine; l-[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-ol;
l-[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperidin-3 -ol;
l-[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 -ol; and
4-[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperazine- 1 -carboxylate;
or a pharmaceutically acceptable salt thereof.
In some embodiments of the compounds of Formula (I), the compound is selected from the following compounds:
7-(3,5-Dimethylisoxazol-4-yl)-5,5-dimethyl-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( lH)-one;
7-(3,5-Dimethylisoxazol-4-yl)-5-(hydroxymethyl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2( lH)-one;
7-(3,5-Dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2( lH)-one;
4-(l-Acetylpiperidin-2-yl)-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( lH)-one;
[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-4-yl]methyl acetate;
7-(3,5-Dimethylisoxazol-4-yl)-4-(hydroxymethyl)-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( lH)-one;
7-(3,5-Dimethylisoxazol-4-yl)-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3 ,5 -Dimethylisoxazol-4-yl)-4-ethyl-4-pyridin-2-yl-4,5 -dihydroimidazo [1,5,4- de] [ 1 ,4]benzoxazin-2( lH)-one;
7-(3,5-Dimethylisoxazol-4-yl)-N-methyl-2-oxo-4-pyridin-2-yl- 1,2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazine-4-carboxamide;
N- { [7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl- 1 ,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-4-yl]methyl} acetamide;
4-(Aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2( lH)-one; 7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5-tetrahydroimidazo[l,5,4- de] [ 1 ,4]benzoxazine-4-carboxamide;
7-(3,5-dimethylisoxazol-4-yl)-5-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-dimethylisoxazol-4-yl)-N-methyl-2-oxo-4-pyridin-2-yl-l, 2,4,5- tetrahydroimidazo[l,5,4-de][l,4]benzoxazine-5-carboxamide;
7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5-tetrahydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine-5-carboxamide;
7-(3,5-dimethylisoxazol-4-yl)-4-(5-fluoropyridin-3-yl)-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-[l-(methylsulfonyl)piperidin-2-yl]-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-4-yl] -N-isopropylpiperidine- 1 -carboxamide;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(l-methyl-lH-pyrazol-4-yl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
5-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-9-yl]-N,N-dimethylpyridine-2 -carboxamide; tert-butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-9-yl]-3 ,6-dihydropyridine- 1 (2H)-carboxylate;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-9-pyrimidin-5-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(l-methyl-lH-pyrazol-5-yl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
ethyl (2E)-3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-9-yl]acrylate;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-9-(l,2,3,6-tetrahydropyridin-4-yl)- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2(l H)-one;
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-vinyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine;
(lR)-l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl] ethane- 1 ,2-diol;
l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2-yl] ethanol; (4S)-7-(3,5-Dimethylisoxazol-4-yl)-N,N-dimethyl-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine-2-carboxamide;
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine;
tert-Butyl (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazine-2-carboxylate;
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-(morpholin-4-ylcarbonyl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-N-methyl-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine-2-carboxamide;
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1 ,5,4- de] [ 1 ,4]benzoxazine-2-carboxamide;
tert-Butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]-3,6-dihydropyridine-l(2H)-carboxylate; tert-Butyl 3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]-2,5-dihydro-lH-pyrrole-l-carboxylate; tert-Butyl 5-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]-3,6-dihydropyridine-l(2H)-carboxylate; tert-Butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]piperidine-l-carboxylate;
tert-Butyl 3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidine- 1 -carboxylate;
tert-Butyl 3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]piperidine-l -carboxylate;
(4S)-2-(l-Acetylpiperidin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-(l,2,3,6-tetrahydropyridin-4-yl)- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-2-(2,5-dihydro-lH-pyrrol-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-pyrrolidin-3-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-(l,2,5,6-tetrahydropyridin-3-yl)- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine; (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-piperidin-3-yl-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-2-(l-Acetylpiperidin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-2-(l -acetyl- 1,2,3, 6-tetrahydropyridin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-2-[l-(cyclopropylcarbonyl)piperidin-4-yl]-7-(3,5-dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[l-(methylsulfonyl)piperidin-4-yl]-4-pyridin-2- y 1-4,5 -dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
(4S)-2-(l-acetylpyrrolidin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-2-[l-(cyclopropylcarbonyl)pyrrolidin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[l-(methylsulfonyl)pyrrolidin-3-yl]-4-pyridin-2- y 1-4,5 -dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
(4S)-2-(l -acetyl- 1,2,5, 6-tetrahydropyridin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-2-(l-acetylpiperidin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-2-[l-(cyclopropylcarbonyl)piperidin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[l-(methylsulfonyl)piperidin-3-yl]-4-pyridin-2- y 1-4,5 -dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-5,6-dihydro-4H-imidazo[4,5,l-ij]quinolin- 2(lH)-one;
7-(3,5-Dimethylisoxazol-4-yl)-l-methyl-4-phenyl-5,6-dihydro-4H-imidazo[4,5,l- ij ]quinolin-2( 1 H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-l-methoxy-4-pyridin-2-yl-5,6-dihydro-4H- imidazo[4,5,l-ij]quinolin-2(lH)-one;
7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,l- ij ]quinolin-2( 1 H)-one;
7-[5-(Hydroxymethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one; 7-[5-(Fluoromethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( 1 H)-one;
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de][l,4]benzoxazin-4-yl]pyridine-2-carbonitrile;
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-4-yl]pyridine-2-carboxamide;
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de][l,4]benzoxazin-4-yl]-N-methylpyridine-2-carboxamide;
3- [7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de][l,4]benzoxazin-4-yl]-N,N-dimethylpyridine-2-carboxamide;
4- [2-(Aminomethyl)pyridin-3 -yl]-7-(3 ,5 -dimethylisoxazol-4-yl)-4,5 - dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
N-( { 3 - [7-(3 ,5 -Dimethylisoxazol-4-yl)-2-oxo- 1 ,2,4,5 -tetrahydroimidazo [ 1 ,5 ,4- de] [ 1 ,4]benzoxazin-4-yl]pyridin-2-yl} methyl)acetamide;
Methyl 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de][l,4]benzoxazin-4-yl]pyridine-2-carboxylate;
3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de][l,4]benzoxazin-4-yl]-N-ethylpyridine-2-carboxamide;
N-Cyclopropyl-3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo- 1,2,4,5- tetrahydroimidazo[l,5,4-de][l,4]benzoxazin-4-yl]pyridine-2-carboxamide;
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo- l,2,4,5-tetrahydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-4-yl]-N-(2-hydroxyethyl)pyridine-2-carboxamide;
3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de][l,4]benzoxazin-4-yl]-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide;
(4S)-9-(Aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-9-yl]methyl} acetamide;
N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-9-yl]methyl} -2-phenylacetamide;
N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-9-yl]methyl} -2-methoxyacetamide;
N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-9-yl]methyl} methanesulfonamide; N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-9-yl]methyl} -N'-isopropylurea;
2-(Dimethylamino)-N- {[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl- l,2,4,5-tetrahydroimidazo[l,5,4-de][l,4]benzoxazin-9-yl]methyl}acetamide;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(l-hydroxyethyl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
(3R)-l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl] -N-isopropylpyrrolidine-3 -carboxamide;
1- [(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2-yl]-3 -methylpyrrolidin-3 -ol;
4-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2-yl]- 1 ,4-diazepane- 1 -sulfonamide;
(4S)-2-(4-Acetyl-l,4-diazepan-l-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-[4-(methylsulfonyl)-l,4-diazepan-l-yl]-4- pyridin-2-yl-4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-piperazin-l-yl-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
2- {4-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperazin- 1 -yl} -N,N-dimethylacetamide;
2-Cyano-N- {(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [1 ,4]benzoxazin-2-yl]pyrrolidin-3-yl} -N-methylacetamide;
N-{(3R)-l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -yl} morpholine-4-carboxamide;
7-(3,5-Dimethylisoxazol-4-yl)-2-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine;
Methyl {(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3-yl} carbamate;
7-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-N,N-dimethyl-4-pyridin-3-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-amine;
l-[7-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -ol;
7-(3,5-Dimethylisoxazol-4-yl)-N-ethyl-9-fluoro-4-pyridin-3-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-amine; (3R)-l-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -ol;
l-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2-yl]azetidin-3-ol;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-morpholin-4-yl-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-pyrrolidin-l-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-l-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-2-azetidin-l-yl-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2-yl]azetidin-3-ol;
4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2-yl]- 1 -methylpiperazin-2-one;
ethyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperazine- 1 -carboxylate;
(3R)-l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -ol;
(3S)-l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -ol;
l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-ol;
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperidin-3 -ol;
(3S)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperidin-3 -ol;
l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]-N,N-dimethylpiperidin-4-amine;
4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]piperazin-2-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(methylsulfonyl)piperazin-l-yl]-4-pyridin-2- yl-4,5 -dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazine; (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-isopropylpiperazin-l-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
1- [(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]piperidine-4-carbonitrile;
{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-yl} methanol;
2- {4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperazin- 1 -yl} ethanol;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-phenylpiperazin-l-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-2-(4-benzylpiperazin-l-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]-N,N-dimethylpyrrolidin-3 -amine;
(3S)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]-N,N-dimethylpyrrolidin-3 -amine;
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]-N-methylpyrrolidin-3 -amine;
(3S)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]-N-methylpyrrolidin-3 -amine;
tert-butyl {(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3-yl} carbamate;
tert-butyl {(3S)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -yl} carbamate;
(4S)-2-[4-(cyclopropylmethyl)piperazin-l-yl]-7-(3,5-dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(2-methoxyethyl)piperazin-l-yl]-4-pyridin-2- yl-4,5-dihydroimidazo[l ,5,4-de] [1 ,4]benzoxazine;
2-[[7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl](methyl)amino]ethanol;
7-(3,5-dimethylisoxazol-4-yl)-N-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-amine;
7-(3,5-dimethylisoxazol-4-yl)-N,N-dimethyl-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-amine; l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]piperidine-4-carboxamide;
1- [(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]-N-methylpiperidine-4-carboxamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-yl} acetamide;
2- {4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperazin- 1 -yl} acetamide;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-ethylpiperazin-l-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)- yl]-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[(8aR)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)- yl]-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
1- [(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]-4-methylpiperidin-4-ol;
4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]-3-methylpiperazin-2-one;
tert-butyl {l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]azetidin-3-yl}carbamate;
tert-butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]- 1 ,4-diazepane- 1 -carboxylate;
2- {[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]amino} ethanol;
tert-butyl (2-{[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1,5,4-de] [1 ,4]benzoxazin-2-yl] amino} ethyl)carbamate;
N-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1 ,5,4- de] [ 1 ,4]benzoxazin-2-yl]ethane- 1 ,2-diamine;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3-yl} acetamide;
N- { (3 S)- 1 - [(4S)-7-(3 ,5-dimethylisoxazol-4-yl)-4-pyridin-2-y 1-4,5 - dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3-yl} acetamide;
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]pyrrolidin-3-amine; (3S)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]pyrrolidin-3-amine;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2,2,2-trifluoroacetamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2-methoxyacetamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}cyclopropanecarboxamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}methanesulfonamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -yl}propanamide;
N- { (3 R) - 1 - [(4S)-7-(3 ,5 -dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5 - dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -yl} -2-methylpropanamide;
N- { (3 R) - 1 - [(4S)-7-(3 ,5 -dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5 - dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}cyclobutanecarboxamide;
2-cyano-N- {(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3-yl} acetamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}tetrahydro-2H-pyran-4- carboxamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}ethanesulfonamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -yl}propane- 1 -sulfonamide;
N'- {(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3-yl} -N,N-dimethylurea;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}propane-2-sulfonamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -yl} cyclopropanesulfonamide; methyl {(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}methylcarbamate; N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3-yl} -N- methylmethanesulfonamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2-methoxy-N- methylacetamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [1 ,4]benzoxazin-2-yl]pyrrolidin-3-yl} -N-methylacetamide;
(4S)-2-(4-acetylpiperazin-l-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-propionylpiperazin-l-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(ethylsulfonyl)piperazin-l-yl]-4-pyridin-2-yl- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3 ,5-dimethylisoxazol-4-yl)-2-[4-(2-oxo-2-pyrrolidin- 1 -ylethyl)piperazin- 1 - yl]-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperazine- 1 -sulfonamide;
l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de][l,4]benzoxazin-2-yl]azetidin-3-amine;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]azetidin-3 -yl} acetamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]azetidin-3-yl}propanamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]azetidin-3-yl} -2-methylpropanamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]azetidin-3 -yl} -2-methoxyacetamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]azetidin-3-yl}cyclopropanecarboxamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]azetidin-3 -yl} cyclobutanecarboxamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]azetidin-3-yl}methanesulfonamide; N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]azetidin-3 -yl} ethanesulfonamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]azetidin-3-yl}propane-2-sulfonamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-yl} methanesulfonamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]piperidin-4-yl}-2-methoxyacetamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-yl} -2,2,2-trifluoroacetamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]piperidin-4-yl}propanamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]piperidin-4-yl}propanamide;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-propionyl-l,4-diazepan-l-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(ethylsulfonyl)-l,4-diazepan-l-yl]-4- pyridin-2-yl-4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]-N-methylpyrrolidine-3 -carboxamide;
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl] -N-ethylpyrrolidine-3 -carboxamide;
(3R)-N-cyclopropyl-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidine-3-carboxamide;
(4S)-8,9-dichloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-9-[(isopropylamino)methyl]-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-9-(hydroxymethyl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1 ,5,4- de] [ 1 ,4]benzoxazine-2( 1 H)-thione;
7-(3,5-dimethylisoxazol-4-yl)-9-(lH-pyrazol-4-yl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one; 7-(3,5-dimethylisoxazol-4-yl)-9-(3-methyl-lH-pyrazol-4-yl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-(3,5-dimethyl- lH-pyrazol-4-yl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(6-hydroxypyridin-3-yl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(2-hydroxypyridin-4-yl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(2-hydroxypyridin-3-yl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
9-(anilinomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9- { [(4-methoxybenzyl)amino]methyl} -4-pyridin-2-yl- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2(l H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-(l-hydroxy-2-methylpropyl)-4-pyridin-2-yl-4,5- dihy droimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( 1 H)-one;
9-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( 1 H)-one;
9-bromo-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l ,5,4- de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( 1 H)-one; and
7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl- l,2,4,5-tetrahydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine-9-carbonitrile;
or a pharmaceutically acceptable salt thereof.
When the compounds listed above contain a chiral center, the compounds can be any of the possible stereoisomers. In compounds with a single chiral center, the stereochemistry of the chiral center can be (R) or (S). In compounds with two chiral centers, the
stereochemistry of the chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R) and (R), (R) and (5); (S) and (R), or (S) and (S). In compounds with three chiral centers, the stereochemistry each of the three chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R), (R) and (R); (R), R) and S); (R), (S) and (R); (R), (5) and (S); (S), (R) and (R); (5), (R) and S); (S), (S) and (R); or (S), (5) and (S).
It is appreciated that 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 subcombination.
The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The hydrogen atom is formally removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. The term "optionally substituted" means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. Throughout the definitions, the term "Cn-m" indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, Ci_6, and the like.
The term "n-membered" where n is an integer typically describes the number of ring- forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1 , 2, 3, 4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
As used herein, the term "Cn-m alkyl," employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms or from 1 to 4 carbon atoms, or from 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, w-propyl, isopropyl, n-butyl, s- butyl, and t-butyl.
As used herein, the term "Cn-m alkoxy," employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy). In some embodiments, the alkyl group has 1 to 3 carbon atoms.
As used herein, the term "alkylene," employed alone or in combination with other terms, refers to a divalent alkyl linking group. Examples of alkylene groups include, but are not limited to, ethan-1, 2-diyl, propan-1, 3-diyl, propan-1, 2-diyl, butan-1, 4-diyl, butan-1, 3- diyl, butan-1, 2-diyl, 2-methyl-propan-l, 3-diyl, and the like.
As used herein, "Cn-m alkenyl," employed alone or in combination with other terms, refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6 or to 2 to 4 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, w-propenyl, isopropenyl, n- butenyl, sec-butenyl, and the like.
As used herein, "Cn-m alkynyl," employed alone or in combination with other terms, refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.
As used herein, the term "Cn-m alkylamino," employed alone or in combination with other terms, refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "di-Cn-m-alkylamino," employed alone or in combination with other terms, refers to a group of formula -N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group
independently has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "thio," employed alone or in combination with other terms, refers to a group of formula -SH.
As used herein, the term "Cn-m alkylthio," employed alone or in combination with other terms, refers to a group of formula -S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "Cn-m alkylsulfinyl," employed alone or in combination with other terms, refers to a group of formula -S(=0)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "Cn-m alkylsulfonyl," employed alone or in combination with other terms, refers to a group of formula -S(=0)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "amino," employed alone or in combination with other terms, refers to a group of formula -NH2.
As used herein, the term "aryl," employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl is Ce-w aryl. In some embodiments, the aryl group is a naphthalene ring or phenyl ring. In some embodiments, the aryl group is phenyl.
As used herein, the term "arylalkyl," employed alone or in combination with other terms, refers to a group of formula -alkylene-aryl. In some embodiments, arylalkyl is Ce-w aryl-Ci-3 alkyl. In some embodiments, arylalkyl is Ce-w aryl-C1-4 alkyl. In some embodiments, arylalkyl is benzyl.
As used herein, the term "carbonyl," employed alone or in combination with other terms, refers to a -C(=0)- group.
As used herein, the term "carboxy," employed alone or in combination with other terms, refers to a group of formula -C(=0)OH.
As used herein, the term "cycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon moiety, which may optionally contain one or more alkenylene groups as part of the ring structure. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e.,, having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclopentene, cyclohexane, and the like. One or more ring- forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages. In some embodiments, cycloalkyl is C3-7 cycloalkyl, which is monocyclic or bicyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
As used herein, the term "cycloalkylalkyl," employed alone or in combination with other terms, refers to a group of formula -alkylene-cycloalkyl. In some embodiments, cycloalkylalkyl is C3-7 cycloalkyl-Ci-3 alkyl, wherein the cycloalkyl portion is monocyclic or bicyclic. In some embodiments, cycloalkylalkyl is C3-7 cycloalkyl-Ci-4 alkyl, wherein the cycloalkyl portion is monocyclic or bicyclic.
As used herein, "Cn-mhaloalkoxy," employed alone or in combination with other terms, refers to a group of formula -O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. An additional example haloalkoxy group is OCHF2. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. As used herein, the term "halo," employed alone or in combination with other terms, refers to a halogen atom selected from F, CI, I or Br. In some embodiments, "halo" refers to a halogen atom selected from F, CI, or Br. In some embodiments, exemplary halo groups are F.
As used herein, the term "Cn-m haloalkyl," employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the haloalkyl group is
trifluoromethyl. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "heteroaryl," employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen. In some embodiments, heteroaryl is 5- to 10-membered C1-9 heteroaryl, which is monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides.
Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[l,2- &]thiazole, purine, or the like.
A five-membered ring heteroaryl is a heteroaryl group having five ring atoms comprising carbon and one or more (e.g., 1, 2, or 3) ring atoms independently selected from N, O, and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,
1.2.3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl,
1.3.4- triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.
A six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from , O, and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl. As used herein, the term "heteroarylalkyl," employed alone or in combination with other terms, refers to a group of formula -alkylene-heteroaryl. In some embodiments, heteroarylalkyl is Ci_9 heteroaryl-Ci_3 alkyl, wherein the heteroaryl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, heteroarylalkyl is Ci_9 heteroaryl-Ci_4 alkyl, wherein the heteroaryl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
As used herein, the term "heterocycloalkyl," employed alone or in combination with other terms, refers to non-aromatic ring system, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and oxygen. When the heterocycloalkyl groups contains more than one heteroatom, the heteroatoms may be the same or different. Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spiro systems. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic ring, for example, 1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran and the like. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized. In some embodiments,
heterocycloalkyl is 5- to 10-membered C2-9 heterocycloalkyl, which is monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. Examples of heterocycloalkyl groups include 1, 2, 3, 4-tetrahydro- quinoline, dihydrobenzofuran, azetidine, azepane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, and pyran.
As used herein, the term "heterocycloalkylalkyl," employed alone or in combination with other terms, refers to a group of formula -alkylene-heterocycloalkyl. In some embodiments, heterocycloalkylalkyl is C2-9 heterocycloalkyl-Ci-3 alkyl, wherein the heterocycloalkyl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, heterocycloalkylalkyl is C2-9 heterocycloalkyl-Ci-4 alkyl, wherein the heterocycloalkyl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, 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 inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans 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.
Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt- forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.
Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4Η- 1, 2, 4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. 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.
The term, "compound," as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified (e.g., in the case of purine rings, unless otherwise indicated, when the compound name or structure has the 9H tautomer, it is understood that the 7H tautomer is also encompassed).
All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.
In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By "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 compounds 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 compounds of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
The phrase "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.
The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g. , a reaction 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.
The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used 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. Generally, 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, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington 's
Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Set, 1977, 66(1), 1-19, and in Stahl et ah, Handbook of
Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include the N-oxide forms.
The following abbreviations may be used herein: AcOH (acetic acid); AC2O (acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc (?-butoxycarbonyl); br (broad); Cbz (carboxybenzyl); calc. (calculated); d (doublet); dd (doublet of doublets); DCM
(dichloromethane); DEAD (diethyl azodicarboxylate); DIAD (N,N'-diisopropyl
azidodicarboxylate); DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU (N,N,N',N'-tetramethyl-0- (7-azabenzotriazol-l-yl)uronium hexafluorophosphate); HC1 (hydrochloric acid); HPLC (high performance liquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquid chromatography - mass spectrometry); m (multiplet); M (molar); mCPBA (3- chloroperoxybenzoic acid); MgS04 (magnesium sulfate); MS (Mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg (milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol (millimole(s)); N (normal); aHC03 (sodium bicarbonate); NaOH (sodium hydroxide); Na2S04 (sodium sulfate); NH4C1 (ammonium chloride); NH4OH (ammonium hydroxide); nM (nanomolar); NMR (nuclear magnetic resonance spectroscopy); OTf (trifluoromethanesulfonate); Pd (palladium); Ph (phenyl); pM (picomolar); POCI3 (phosphoryl chloride); RP-HPLC (reverse phase high performance liquid chromatography); s (singlet); t (triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets); ?-Bu (tert-butyl); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg
(microgram(s)); (microliter(s)); μΜ (micromolar); wt% (weight percent). II. SYNTHESIS
Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.
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 non-reactive 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. Depending on the particular reaction step, 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 is described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et ah, March 's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Peturssion et ah, "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ, 1997, 74(1 1), 1297; and Wuts et ah, Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).
Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., lH or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LCMS Purification: Improved Compound Specific Method Optimization " Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874- 883) and normal phase silica chromatography.
Compounds of Formula (I) can be formed as shown in Scheme I. The thiols (L = S) or phenols (L = O) (i) can be alkylated using standard alkylating conditions (Cy3COC(R1R2)- X (ii) , X = leaving group, such as halo (Br, CI, I or mesylate) or Mitsunobu conditions (e.g.,
Figure imgf000054_0001
where X = OH (ii), DEAD, Ph3P) to afford thioether or ether derivatives (iii), respectively. Cyclization in situ or upon heating can afford imine (iv) which upon treatment with a Grignard reagent of formula R4-MgXx (X1 = halo) and reduction of the nitro group (e.g., H2 Pd/C or Fe) to give an amine (v). Compounds (v) can either be reacted with carbonyldiamidazole or phosgene to form an urea and then halogenated with N- chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide to give tricyclic halide (vi) where X = CI, Br or I or halogenated first and then reacted with carbonyldiamidazole or phosgene to form an urea and give tricyclic halide (vi). Compound (vi) can be alkylated (e.g., R6-X, where X = halo (X = Br, CI, or I) and a base, such as triethylamine, NaH or a2C03; or under Mitsunobu conditions) to afford the tetrasubstituted urea (vii). Finally, the halo group of (vii) can be coupled to M-Cy1, where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., Cy^M is Cy1-B(OH)2, Cy1-Sn(Bu)4, or Zn- Cy1), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0), to give a derivative of Formula (I) (viii) wherein R5 is =0. Alternatively, M-Cy1 can be an amine containing heterocycle (where M is H and is attached to the amine nitrogen of the heterocycle Cy1) with coupling to compound (vii) being performed by heating with a base or under Buchwald conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxide base)) to give a derivative of Formula (I) (viii). Alternatively, urea (vi) can be coupled to M-Cy1, where M is a boronic acid, boronic ester or an
appropriately substituted metal (e.g., Cyx-M is Cy1-B(OH)2, Cy^S^Bu , or Zn- Cy1), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0), to give a derivative of Formula (I) (ix) which can be alkylated (e.g., R6-X, where X = halo (X = Br, CI, or I) and a base, such as triethylamine, NaH or Na2C03; or under Mitsunobu conditions) to afford the tetrasubstituted urea of Formula (I) (viii). Alternatively, urea (vi) can be converted to the 2- halo-imidazole, such as CI upon treatment with POCI3, and then treated with an amine (HNRR) to give benzoimidazole (x) where R5 = NRR. Benzoimidazole (x) can then be coupled to M-Cy1, where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., Cyl-M is Cy1-B(OH)2, Cy^Sn BuU, or Zn- Cy1), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0), to give a derivative of Formula (I) (xi). M-Cy1 can be an amine containing heterocycle (where M is H and is attached to the amine nitrogen of the heterocycle Cy1) with coupling to compound (x) being performed by heating with a base or under Buchwald conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxide base)) to give a derivative of Formula (I) (xi). Alternatively, urea (ix) can be converted to the 2-halo- imidazole, such as CI upon treatment with POCI3, and then treated with an amine (FTNRR) to give benzimidazole (xi) where R5 = NRR or the chloride derivative can be coupled to M-R5, where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., R5-M is R5-B(OH)2, R5-Sn(Bu)4, or Zn- R5), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as
tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0), to give a derivative of Formula (I) (xi). M-Cy1 can be an amine containing heterocycle (where M is H and is attached to the amine nitrogen of the heterocycle Cy1) with coupling to the halide of (ix) being performed by heating with a base or under Buchwald conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxide base)) to give a derivative of Formula (I) (xi). Amino compound (v) can either be treated with an ortho-ester, such as R5C(OEt)3, or an aldehyde R5CHO and aHS03 to give a benzimidazole which can be halogenated with N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide to give halo-benzimidazole (x), where X = CI, Br, or I, or these two steps can be run in the opposite order to give the same benzimidazole (x) which can be further converted to compounds of Formula (I) (xi) as previously described above. Scheme I
Figure imgf000056_0001
Compounds of Formula (I) can be formed as shown in Scheme II. The nitro-halide (i) can be reacted with an amine, such as HNR6, to give an amino derivative which can be alkylated with (Cj^COC^R^-X (ii) using standard alkylating conditions, X = leaving group, such as halo (Br, CI, I) or mesylate) or Mitsunobu conditions (e.g., Cy3COC(R1R2)-X, where X = OH (ii), DEAD, PI13P) to afford thioether or ether derivatives (iii), respectively. Reduction of the nitro group of (iii) under standard conditions (e.g., Fe or Zn) can give the amino compound which can cyclize in situ or upon heating to afford an imine which upon treatment with a Grignard reagent of formula R4-MgX1 (X1 = halo) to give an amine (iv) or (iii) can be reduced with H2 over Pd/C to give amine (iv) where R4 = H. Compounds (iv) can either be reacted with carbonyldiimidazole or phosgene to form an urea and then halogenated with N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide to give tricyclic halide (v) where X = CI, Br or I or halogenated first and then reacted with carbonyldiimidazole or phosgene to form an urea and give tricyclic halide (v). Finally, the halo group of (v) can be coupled to M-Cy1, where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., Cyl-M is Cy1-B(OH)2, Cy1-Sn(Bu)4, or Zn- Cy1), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0), to give a derivative of Formula (I) (vi). M-Cy1 can be an amine containing heterocycle (where M is H and is attached to the amine nitrogen of the heterocycle Cy1) with coupling to compound (v) being performed by heating with a base or under Buchwald conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxide base)) to give a derivative of Formula (I) (vi).
Scheme II
Figure imgf000057_0001
(vi)
Compounds of Formula (I) can be formed as shown in Scheme III. The nitro-halide (i) can be reacted with an amine of formula HOzCC^R^C CyV Hz, to give a carboxylic acid derivative (iii). Conversion of the carboxylic acid (iii) to an acyl-halide, such as acyl-chloride by treating with oxalyl-chloride, can affect a Friedel-Crafts intramolecular cyclization to give ketone (iv). Reduction of the ketone group and nitro group of (iv) under standard conditions (e.g., H2 over Pd/C or a Wolff-Kishner reaction (NH2NH2, KOH) followed by reduction of the nitro group with Fe) can give the diamine derivative (v). Diamine (v) can then be converted to compounds of Formula (I) (where L methods for diamine (v) shown in Scheme I.
Scheme III
Figure imgf000058_0001
Compounds of Formula (I) can be formed as shown in Scheme IV. Compounds (i) can be halogenated with N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide to give tricyclic halide (v) where X = CI, Br or I and the halo group of (ii) can be coupled to M- R7, where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., R7-M is R7-B(OH)2, R7-Sn(Bu)4, or Zn- R7), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as
tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0), to give a derivative of Formula (I) (vi). M-R7 can be an amine containing heterocycle (where M is H and is attached to the amine nitrogen of the heterocycle R7) with coupling to compound (ii) being performed by heating with a base or under Buchwald conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxide base)) to give a derivative of Formula (I) (iii).
Scheme IV
Figure imgf000059_0001
Compounds of Formula (I) can be formed as shown in Scheme V. The nitro-aniline (i) can be reacted with an aldehyde of formula OHCC(R1)=CHCy3 (ii), to give quinolone derivatives (iii). Reduction of the quinoline group and nitro group of (iii) under standard conditions (e.g., H2 over Pd/C can give the diamine derivative (iv). Diamine (iv) can then be converted to compounds of Formula (I) (where L = CH2) by similar methods for diamine (v) shown in Scheme I.
Scheme V
Figure imgf000059_0002
Compounds of Formula (I) can be formed as shown in Scheme VI. The sulfide (i) can be reacted with an oxidant, such as mCPBA or H2O2 or dioxirane, to give the sulfoxide (ii) which can be further oxidized with an oxidant, such as mCPBA or H2O2 or dioxirane, to give the sulfone (iii).
Scheme VI
Figure imgf000059_0003
Halo-ketones intermediate (ii) of Scheme I and Scheme II can be synthesized as shown in Scheme VII. The carboxylic acid (i) can be activated with a coupling agent (e.g., HBTU, HATU or EDC) and then reacted with N, O-dimethylhydroxylamine to give an N- methoxy-N-methylcarboxamide derivative (ii). Amide (ii) may then be reacted with a Grignard reagent of formula R1R2-CH-MgX1 (X1 = halo) to give a ketone (iii) which can be halogenated with Br2 or NXS (X = Br, CI or I) to give halo-ketone (iv). The halo-ketone (iv) can be transformed using similar methods as shown in Scheme I and Scheme II to afford compounds of Formula (I). Scheme VII
Figure imgf000060_0001
(ii) (iii) (iv)
Compounds of Formula (I) can be formed as shown in Scheme VIII. 2- Bromoquinoline (i) can be coupled to M-Cy3, where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., Cy^M is Cy1-B(OH)2, Cy1-Sn(Bu)4, or Zn- Cy1), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0), to give compound (ii). Compound (ii) can be reduced (eg. borane/pyridine or l,4-dihydro-3,5-dicarbethoxy-2,6- dimethylpyridine/diphenyl hydrogen phosphate) to give compound (iii). Compound (iii) can be converted to (iv) using triphosgene/ methoxylamine or 4-nitrophenyl methoxycarbamate. Cyclization of (iv) can be accomplished with [7J-bis(trifluoroacetoxy)iodo]benzene to give (v). The methoxy group of (v) can be removed by hydrogenation (Pd/C) to give (vi).
Compound (vi) can be halogenated with N-chlorosuccinimide, N-bromosuccinimide or N- iodosuccinimide to give tricyclic halide (vii) where X = CI, Br or I. Finally, the halo group of (vii) can be coupled to M-Cy1, where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., Cy^M is Cy1-B(OH)2, Cy1-Sn(Bu)4, or Zn- Cy1), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0), to give a derivative of Formula (I) (viii).
Scheme VIII
Figure imgf000061_0001
For the synthesis of particular compounds, the general schemes described above can be modified. For example, the products or intermediates can be modified to introduce particular functional groups. Alternatively, the substituents can be modified at any step of the overall synthesis by methods know to one skilled in the art, e.g., as described by Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations (Wiley, 1999); and Katritzky et al. (Ed.), Comprehensive Organic Functional Group Transformations (Pergamon Press 1996).
Starting materials, reagents and intermediates whose synthesis is not described herein are either commercially available, known in the literature, or may be prepared by methods known to one skilled in the art.
It will be appreciated by one skilled in the art that the processes described are not the exclusive means by which compounds of the invention may be synthesized and that a broad repertoire of synthetic organic reactions is available to be potentially employed in synthesizing compounds of the invention. The person skilled in the art knows how to select and implement appropriate synthetic routes. Suitable synthetic methods of starting materials, intermediates and products may be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963- 2012); Journal of Heterocyclic Chemistry Vols. 1-49 (Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.) Science of Synthesis, Vols. 1-48 (2001-2010) and
Knowledge Updates KU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky, et al. (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al. (Ed.); Comprehensive Organic Functional Group Transformations II (Elsevier, 2nd Edition, 2004); Katritzky et al. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).
III. USES OF THE COMPOUNDS
Compounds of the invention are BET protein inhibitors and, thus, are useful in treating diseases and disorders associated with activity of BET proteins. For the uses described herein, any of the compounds of the invention, including any of the embodiments thereof, may be used.
The compounds of Formula (I) can inhibit one or more of BET proteins BRD2, BRD3, BRD4, and BRD-t. In some embodiments, the compounds of the invention selectively inhibit one or more BET proteins over another. "Selective" means that the compound binds to or inhibits a BET protein with greater affinity or potency, respectively, compared to a reference, such as another BET protein. For example, the compounds can be selective for BRD2 over BRD3, BRD4 and BRD-t, selective for BRD3 over BRD2, BRD4 and BRD-t, selective for BRD4 over BRD2, BRD3 and BRD-t, or selective for BRD-t over BRD2, BRD3 and BRD4. In some embodiments, the compounds inhibit two or more of the BET proteins, or all of the BET proteins. In general, selectivity can be at least about 5 -fold, at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold or at least about 1000-fold.
The compounds of Formula (I) are therefore useful for treating BET protein mediated disorders. The term "BET-mediated" refers to any disease or condition in which one or more of the BET proteins, such as BRD2, BRD3, BRD4 and/or BRD-t, or a mutant thereof, plays a role, or where the disease or condition is associated with expression or activity of one or more of the BET proteins. The compounds of the invention can therefore be used to treat or lessen the severity of diseases and conditions where BET proteins, such as BRD2, BRD3, BRD4, and/or BRD-t, or a mutant thereof, are known to play a role.
Diseases and conditions treatable using the compounds of Formula (I) include cancer and other proliferative disorders, autoimmune disease, chronic inflammatory diseases, acute inflammatory diseases, sepsis, and viral infection. The diseases can be treated by
administering to an individual (e.g., a patient) in need of the treatment a therapeutically effective amount or dose of a compound of Formula (I), or any of the embodiments thereof, or a pharmaceutical composition thereof. The present disclosure also provides a compound of Formula (I), or any of the embodiments thereof, or a pharmaceutical composition thereof, for use in treating a BET-mediated disease or disorder. Also provided is the use of a compound of Formula (I), or any of the embodiments thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a BET-mediated disease or disorder.
Diseases that can be treated with the compounds of Formula (I) include cancers. The cancers can include adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma,
dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer,
medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T- lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary' s disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor. In some embodiments, the cancer can be adenocarcinoma, adult T-cell leukemia/lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, ocular cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer, spinal tumor, small intestine cancer, stomach cancer, T-cell lymphoma, testicular cancer, thyroid cancer, throat cancer, urogenital cancer, urothelial carcinoma, uterine cancer, vaginal cancer, or Wilms' tumor.
The diseases treatable using the compounds of Formula (I) also include MYC dependent cancers wherein the cancer is associated with at least one of myc RNA expression or MYC protein expression. A patient can be identified for such treatment by determining myc RNA expression or MYC protein expression in the cancerous tissue or cells.
Diseases that can be treated with compounds of Formula (I) also include noncancerous proliferative disorders. Examples of proliferative disorders that can be treated include, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.
The diseases and conditions that can be treated with the compounds of Formula (I) also include chronic autoimmune and inflammatory conditions. Examples of autoimmune and inflammatory conditions that can be treated include acute, hyperacute or chronic rejection of transplanted organs, acute gout, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia/reperfusion injury), Addison's disease, agammaglobulinemia, allergic rhinitis, allergy, alopecia, Alzheimer's disease, appendicitis, atherosclerosis, asthma, osteoarthritis, , juvenile arthritis, psoriatic arthritis, rheumatoid arthriti, satopic dermatitis, autoimmune alopecia, autoimmune hemolytic and thrombocytopenic states, autoimmune hypopituitarism, autoimmune polyglandular disease, Behcet's disease, bullous skin diseases, cholecystitis, chronic idiopathic thrombocytopenic purpura, chronic obstructive pulmonary disease (COPD), cirrhosis, degenerative joint disease, depression, dermatitis,
dermatomyositis, eczema, enteritis, encephalitis, gastritis glomerulonephritis, giant cell arteritis, Goodpasture's syndrome, Guillain-Barre syndrome, gingivitis, Graves' disease, Hashimoto's thyroiditis, hepatitis, hypophysitis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), inflammatory pelvic disease, irritable bowel syndrome, Kawasaki disease, LPS-induced endotoxic shock, meningitis, multiple sclerosis, myocarditis, myasthenia gravis, mycosis fungoides, myositis, nephritis, osteomyelitis, pancreatitis,
Parkinson's disease, pericarditis, pernicious anemia, pneumonitis, primary biliary sclerosing cholangitis, polyarteritis nodosa, psoriasis, retinitis, scleritis, scleracierma, scleroderma, sinusitis, Sjogren's disease, sepsis, septic shock, sunburn, systemic lupus erythematosus, tissue graft rejection, thyroiditis, type I diabetes, Takayasu's arteritis, urethritis, uveitis, vasculitis, vasculitis including giant cell arteritis, vasculitis with organ involvement such as glomerulonephritis, vitiligo, Waldenstrom macroglobulinemia and Wegener's
granulomatosis.
The diseases and conditions that can be treated with the compounds of Formula (I) also include diseases and conditions which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemic inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, postsurgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis, malaria, SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex and coronavirus.
The diseases for which the compounds of Formula (I) are indicated also include diseases associated with a systemic inflammatory response syndrome, such as sepsis, burns, pancreatitis, major trauma, hemorrhage and ischemia. The compound of Formula (I) can be administered to reduce the incidence of: SIRS, the onset of shock, multi-organ dysfunction syndrome, which includes the onset of acute lung injury, ARDS, acute renal, hepatic, cardiac and gastro-intestinal injury and mortality. For example, the compounds of the invention can be administered prior to surgical or other procedures associated with a high risk of sepsis, hemorrhage, extensive tissue damage, SIRS or MODS.
Other diseases that can be treated with the compounds of Formula (I) include viral infections. Examples of viral infections that can be treated include Epstein-Barr virus, hepatitis B virus, hepatitis C virus, herpes virus, human immunodeficiency virus, human papilloma virus, adenovirus, poxvirus and other episome-based DNA viruses. The compounds can therefore be used to treat disease and conditions such as herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including acute respiratory disease, and poxvirus infections such as cowpox and smallpox and African swine fever virus. In one particular embodiment the compounds of Formula (I) are indicated for the treatment of human papilloma virus infections of skin or cervical epithelia.
The diseases and conditions that can be treated with the compounds of Formula (I) also include conditions that are associated with ischemia-reperfusion injury. Examples of such conditions include, but are not limited to conditions such as myocardial infarction, cerebrovascular ischemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures and pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism.
The compounds of Formula (I) are also useful in the treatment of disorders of lipid metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease.
The compounds of Formula (I) can also be used for the treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma and cardiac fibrosis.
The compounds of Formula (I) can also be used to treat ophthalmological indications such as dry eye.
As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a BET protein with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having a BET protein, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the BET protein.
As used herein, the term "individual" or "patient, " used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician. As used herein, the term "treating" or "treatment" refers to one or more of (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
Combination Therapies
The compounds of Formula (I) can be used in combination treatments where the compound of the invention is administered in conjunction with other treatment such as the administration of one or more additional therapeutic agents. The additional therapeutic agents are typically those which are normally used to treat the particular condition to be treated. The additional therapeutic agents can include, e.g., chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, FAK, and JAK kinase inhibitors for treatment of BET protein-associated diseases, disorders or conditions. The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.
In some embodiments, the compounds of Formula (I) can be used in combination with a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulators include the histone lysine methyltransferases, histone arginine methyl transferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases. histone deacetylase inhibitors include, e.g., vorinostat.
For treating cancer and other proliferative diseases, the compounds of the invention can be used in combination with chemotherapeutic agents, or other anti-proliferative agents. The compounds of the invention can also be used in combination with medical therapy such as surgery or radiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes. Examples of suitable chemotherapeutic agents include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,
mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.
For treating cancer and other proliferative diseases, the compounds of formula (I) can be used in combination with ruxolitinib.
For treating autoimmune or inflammatory conditions, the compound of Formula (I) can be administered in combination with a corticosteroid such as triamcinolone,
dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone.
For treating autoimmune or inflammatory conditions, the compound of Formula (I) can be administered in combination with an immune suppressant such as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol, Alcon), or cyclosporine (Restasis®).
For treating autoimmune or inflammatory conditions, the compound of Formula (I) can be administered in combination with one or more additional agents selected from
Dehydrex™ (Holies Labs), Civamide (Opko), sodium hyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603, Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P) (Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen), 15-(s)- hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine, doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301, Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali), oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101 (2S,3S,4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl- oxolane-2-carbamyl, Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences), ARG103 (Agentis), RX- 10045 (synthetic resolvin analog, Resolvyx), DY 15 (Dyanmis Therapeutics), rivoglitazone (DEOl l, Daiichi Sanko), TB4 (RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REVl-31 (Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551 (Othera), PAI-2 (University of Pennsylvania and Temple University), pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednol etabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-061 1 (Kissei
Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab, mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267 (TorreyPines Therapeutics), or thalidomide.
In some embodiments, the compound of Formula (I) can be administered in combination with one or more agents selected from an antibiotic, antiviral, antifungal, anesthetic, anti-inflammatory agents including steroidal and non-steroidal anti- inflammatories, and anti-allergic agents. Examples of suitable medicaments include aminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin, netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naphthyridine; sulfonamides; polymyxin;
chloramphenicol; neomycin; paramomycin; colistimethate; bacitracin; vancomycin;
tetracyclines; rifampin and its derivatives ("rifampins"); cycloserine; beta-lactams;
cephalosporins; amphotericins; fluconazole; flucytosine; natamycin; miconazole;
ketoconazole; corticosteroids; diclofenac; flurbiprofen; ketorolac; suprofen; cromolyn;
lodoxamide; levocabastin; naphazoline; antazoline; pheniramine; or azalide antibiotic.
Other examples of agents, one or more of which a compound of Formula (I) may also be combined with include: a treatment for Alzheimer's Disease such as donepezil and rivastigmine; a treatment for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone; a treatment for asthma such as albuterol and montelukast; an agent for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; an anti-inflammatory agent such as a corticosteroid, such as dexamethasone or prednisone, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; an immunomodulatory agent, including immunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, an interferon, a corticosteroid, cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factor such as an acetylcholinesterase inhibitor, an MAO inhibitor, an interferon, an anti-convulsant, an ion channel blocker, riluzole, or an anti-Parkinson's agent; an agent for treating cardiovascular disease such as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, a calcium channel blocker, or a statin; an agent for treating liver disease such as a corticosteroid,
cholestyramine, an interferon, and an anti-viral agent; an agent for treating blood disorders such as a corticosteroid, an anti-leukemic agent, or a growth factor; or an agent for treating immunodeficiency disorders such as gamma globulin.
In some embodiments, the compounds of the invention can be used in combination with one or more therapeutic agents selected from: Janus kinase inhibitors (e.g., ruxolitinib, tofacitinib, baricitinib, CYT387, GLPG0634, lestaurtinib, pacritinib, TG101348), Pirn kinase inhibitors, PI3 kinase inhibitors (including PI3K-delta selective and broad spectrum PI3K inhibitors), MEK inhibitors, cyclin dependent kinase inhibitors, b-RAF inhibitors, mTOR inhibitors, proteasome inhibitors (e.g., bortezomib, carfilzomib), HDAC-inhibitors (e.g., panobinostat, vorinostat), DNA methyl transferase inhibitors, dexamethasone, melphalan, and immunomodulators such as lenolidomide and pomalidomide. In some embodiments, the Janus kinase inhibitor is selective for JAK1. In some embodiments, the Janus kinase inhibitor is selective for JAK1 and JAK2.
IV. Formulation, Dosage Forms and Administration
When employed as pharmaceuticals, the compounds of Formula (I) can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
This invention also includes pharmaceutical compositions which contain, as the active ingredient, the compound of the invention or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
The compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art, e.g., see International App. No. WO 2002/000196.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1, 000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
In some embodiments, the compositions of the invention contain from about 5 mg to about 50 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient.
In some embodiments, the compositions of the invention contain from about 50 mg to about 500 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient.
In some embodiments, the compositions of the invention contain from about 500 mg to about 1, 000 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1, 000 mg of the active ingredient.
The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid
preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.
The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
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. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
Topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline, and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g., glycerinemonostearate, PEG- glycerinemonostearate and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt % of the compound of the invention. The topical formulations can be suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.
The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
The therapeutic dosage of a compound of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a
pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
The compositions of the invention can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
V. Labeled Compounds and Assay Methods
In another aspect, the present disclosure provides labeled compounds of Formula (I)
(radio-labeled, fluorescent-labeled, etc.) that can be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating BET proteins in tissue samples, including human, and for identifying BET protein ligands by inhibition binding of a labeled compound. Accordingly, the disclosure provides BET protein assays that contain such labeled compounds.
An "isotopically" or "radio-labeled" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 3H (also written as T for tritium), nC, 13C, 14C, 13N, 15N, 150, 170, 180, 18F, 35S, 36C1, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I and 131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro BET protein
3 14 82 125 131 35 labeling and competition assays, compounds that incorporate H, C, Br, I , I, S or will generally be most useful. For radio-imaging applications nC, 18F, 125I, 1231, 124I, 1311, 75Br, 76Br or 77Br will generally be most useful.
It is to be understood that a "radio-labeled " or "labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is
3 14 125 35 82
selected from the group consisting of H, C, I, S and Br. In some embodiments, the compound incorporates 1, 2, or 3 deuterium atoms. Synthetic methods for incorporating radio-isotopes into organic compounds are known in the art.
The present invention can further include synthetic methods for incorporating radioisotopes into compounds of the invention. Synthetic methods for incorporating radio-isotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily recognize the methods applicable for the compounds of invention.
A labeled compound of the invention can be used in a screening assay to
identify/evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind a BET protein by monitoring its concentration variation when contacting with the BET protein, through tracking of the labeling. For example, a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to a BET protein (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the BET protein directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained. VI. Kits
The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of BET protein-associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or any of the embodiments thereof. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non- critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples were found to be inhibitors of one or more BET proteins as described below. EXAMPLES
Example 1
7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4-< ^] [l,4]benzoxazin- 2(/H)-one
Step 1. 5-Nitro-3-phenyl-2H- 1 ,4-be
Figure imgf000078_0001
The 2-bromoacetophenone (3.9 g, 19 mmol) [Aldrich, cat. # 115835] was added portion wise to a stirred suspension of 2-amino-3-nitrophenol (2.5 g, 16 mmol) [Aldrich, cat. # 297003] and K2C03 (3.4 g, 24 mmol) in MeCN (100 mL) at room temperature. The reaction was monitored by LC/MS. After stirring for 3 h the reaction was complete and then EtOAc added and solution filtered to remove the solids and the organic layer was washed with water, 1 N HQ, brine, dried over MgSC^, filtered and concentrated to give 5-nitro-3- phenyl-2H-l,4-benzoxazine as a dark oil (4.1 g, 100%). LCMS calc. for C14H11 2O3 (M+H)+: m/z = 255.3; found: 255.1.
Step 2. 3-Phenyl-3,4-dihydro-2H-l,4- e
Figure imgf000078_0002
The 5-nitro-3-phenyl-2H-l, 4-benzoxazine oil was taken up in MeOH (50 mL) in a Parr shaker bottle, deoxygenated with nitrogen, the catalyst 10% Pd on carbon (0.25 g) was added, the reaction vessel was charged to 55 psi with hydrogen and shaken. After 2 h the reaction was complete by LC/MS. The reaction was filtered to remove the catalyst and concentrated under reduced pressure to give 3-phenyl-3,4-dihydro-2H-l,4-benzoxazin-5- amine as a dark oil. (3.5 g, 97%). LCMS calc. for Ci4H15N20 (M+H) : m/z = 221.1 ; found: 227.1. 'H NMR (500 MHz, DMSO-i¾) δ 7.44 (d, J= 7.4 Hz, 2H), 7.37 (dd, J= 7.5 Hz, 2H), 7.31 (t, J= 7.2 Hz, 1H), 6.35 (dd, J= 7.9 Hz, 1H), 6.21 (dd, J= 7.8, 1.0 Hz, 1H), 6.07 (d, J= 7.9 Hz, 1H), 5.00 (s, 1H), 4.62 (s, 2H), 4.44 (dd, J= 4.9, 2.6 Hz, 1H), 4.21 - 4.13 (m, 1H), 3.87 (dd, J= 10.4, 7.7 Hz, 1H).
Step 3. 4-Phenyl-4, 5-dihydroimidazof 1, 5, 4-deJf l,4]benzoxazin-2( lH)-one
Figure imgf000079_0001
The 3-phenyl-3,4-dihydro-2H-l,4-benzoxazin-5-amine (0.95 g, 4.2 mmol) was dissolved in THF (30 mL) and DIPEA (1.5 mL, 8.4 mmol) at room temperature (room temperature). The N,N-carbonyldiimidazole (0.82 g, 5.0 mmol) was added portion wise over 10 min. The reaction was heated to 70 °C for 1 h and allowed to cool to room temperature and stirred overnight. To the reaction mixture was added EtOAc, and then the mixture was washed with water, sodium bicarbonate water and brine, then dried over magnesium sulfate and concentrated to give crude product as a dark oil. The oil was triturated with ethyl ether to give a precipitate. The solids were triturated twice with ethyl ether and then the solids were collected and air dried to give 4-phenyl-4,5-dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2(7H)- one as a brown solid (0.51 g, 48%). LCMS calc. for Ci5H13 202 (M+H)+: m/z = 253.1 ; found: 253.1. 'H NMR (300 MHz, DMSO-i¾) δ 10.88 (s, 1H), 7.39 - 7.22 (m, 3H), 7.15 - 7.04 (m, 2H), 6.88 (t, J= 8.0 Hz, 1H), 6.67 (d, J= 7.8 Hz, 1H), 6.57 (d, J= 8.2 Hz, 1H), 5.45 (s, 1H), 4.54 (dd, J= 11.6, 2.2 Hz, 1H), 4.37 (dd, J= 1 1.6, 3.0 Hz, 1H).
Step 4. 7-Bromo-4-phenyl-4, 5-dihydroi 1 , 5, 4-deJfl, 4]benzoxazin-2(lH)-one
Figure imgf000079_0002
A mixture of 4-phenyl-4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2(l H)-one (400 mg, 2 mmol) and N-bromosuccinimide (310 mg, 1.7 mmol) in AcOH (10 mL) was stirred at room temperature for 2 h. The reaction mixture was allowed to cool and was concentrated to remove AcOH. The residue was taken up in EtOAc and was washed with water saturated aHC03, brine, dried over magnesium sulfate, filtered and concentrated to give crude product. The product was purified by flash column chromatography on a Biotage system eluting with a hexane: EtOAc gradient (0-40%) to give 7-bromo-4-phenyl-4, 5- dihydroimidazo[l, 5, 4-de][l, 4]benzoxazin-2(lH)-one as an amber oil (0.30 g, 60%). LCMS calc. for Ci5H12BrN202 (M+H)+: m z = 331.1, 333.1 ; found: 331.0, 333.0. 'H NMR (300 MHz, CD3OD) δ 7.42 - 7.23 (m, 3H), 7.23 - 7.09 (m, 3H), 6.70 (d, J= 8.4 Hz, 1H), 5.46 (dd, J= 2.6 Hz, 1H), 4.66 (dd, J= 1 1.6, 2.4 Hz, 1H), 4.47 (dd, J= 1 1.6, 3.1 Hz, 1H). Step 5. 7-(3, 5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- dejf 1 ,4] benzoxazin-2( lH)-one
7-Bromo-4-phenyl-4, 5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(7H)-one
(200 mg, 0.6 mmol) and 3, 5-dimethyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)isoxazole (160 mg, 0.72 mmol) [Aldrich, cat. # 643882] were dissolved in 1, 4-dioxane (20 mL) and potassium carbonate (200 mg, 1 mmol) in water (8 mL). The reaction was deoxygenated with nitrogen and the catalyst [1, 1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (1 : 1) (20 mg, 0.03 mmol) was added. The reaction mixture was deoxygenated with nitrogen and was heated at 100 °C. After heating for 2 h the reaction was complete by LCMS. The reaction mixture was allowed to cool to room temperature, EtOAc was added and the mixture was washed with water, brine, then dried over magnesium sulfate and concentrated to give the crude product. The product was purified on preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 2 with TFA to give 7-(3,5-dimethylisoxazol-4-yl)-4- phenyl-4,5-dihydroimidazo[l, 5, 4-de][l, 4]benzoxazin-2(7H)-one as white solid (0.10 g, 50%). LCMS calc. for C2oH18 303 (M+H)+: m/z = 348.1 ; found: 348.1. XH NMR (500 MHz, DMSO-i/6) δ 10.96 (s, 1H), 7.38 - 7.24 (m, 3H), 7.16 (d, J= 7.2 Hz, 2H), 6.84 (d, J= 8.0 Hz, 1H), 6.76 (d, J= 8.0 Hz, 1H), 5.47 (s, 1H), 4.57 (dd, J= 11.6, 2.2 Hz, 1H), 4.40 (dd, J= 11.6, 3.1 Hz, 1H), 2.25 (s, 3H), 2.08 (s, 3H). Example 1A
7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4-de] [l,4]benzoxazin- 2(lH)-one (Enantiomer 1)
Example IB
7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4-de] [l,4]benzoxazin- 2(lH)-one (Enantiomer 2)
The enantiomers were separated from racemic 7-(3,5-dimethylisoxazol-4-yl)-4- phenyl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one from Example 1, Step 5 by chiral column HPLC using a Phenomenex Lux Cellulose-4 column, 5 micron, 21.2 x 250 mm, eluting 30% ethanol in hexanes with a flow rate of 18 mL/min., loading approx. 36 mg per injection with UV, 220 nm detection to give peak 1 at: 14.32 min. and peak 2 at: 18.89 min.
Enantiomer 1 : Peak 1 : Example 1A (more active enantiomer), LCMS calc. for
C2oH18N303 (M+H)+: m/z = 348.1; found: 348.1. 'H NMR (500 MHz, DMSO-i¾) δ 10.96 (s, 1H), 7.38 - 7.24 (m, 3H), 7.16 (d, J= 7.2 Hz, 2H), 6.84 (d, J= 8.0 Hz, 1H), 6.76 (d,
J= 8.0 Hz, 1H), 5.47 (s, 1H), 4.57 (dd, J= 11.6, 2.2 Hz, 1H), 4.40 (dd, J= 1 1.6, 3.1 Hz, 1H),
2.25 (s, 3H), 2.08 (s, 3H).
Enantiomer 1 : Peak 2: Example IB (less active enantiomer), LCMS calc. for
C2oH18N303 (M+H)+: m/z = 348.1; found: 348.1. 'H NMR (500 MHz, DMSO- d6) δ 10.96 (s, 1H), 7.38 - 7.24 (m, 3H), 7.16 (d, J= 7.2 Hz, 2H), 6.84 (d, J= 8.0 Hz, 1H), 6.76 (d,
J= 8.0 Hz, 1H), 5.47 (s, 1H), 4.57 (dd, J= 11.6, 2.2 Hz, 1H), 4.40 (dd, J= 1 1.6, 3.1 Hz, 1H),
2.25 (s, 3H), 2.08 (s, 3H).
Example 2
7-(3,5-Dimethylisoxazol-4-yl)-l-methyl-4-phenyl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2(/H)-one
Figure imgf000081_0001
Sodium hydride in mineral oil 60% (3.2 mg, 0.13 mmol) was added to a solution of 7- (3 ,5 -dimethylisoxazol-4-yl)-4-phenyl-4,5 -dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2(7H)- one (0.040 g, 0.10 mmol) from Example 1 , Step 5 in DMF (3 mL) cooled in an ice bath. The reaction mixture was stirred for 15 min. and methyl iodide (8 \L, 0.1 mmol) was added. The reaction mixture was stirred for 30 min. and was complete by LCMS. The reaction mixture was partitioned between water and EtOAc. The organic layer was concentrated and purified on preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 2 with TFA to give the title compound as a solid product solid (0.015 g, 37%). LCMS calc. for C2iH2o 303 (M+H)+: m/z = 362.1 ; found: 362.1. XH NMR (300 MHz, DMSO-i¾) δ 7.39 - 7.24 (m, 5H), 7.19 - 7.12 (m, 2H), 5.52 (s, 1H), 4.59 (dd, J= 9.2 Hz, 1H), 4.41 (dd,
J= 8.4 Hz, 1H), 3.38 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H).
Example 3
7-(3,5-Dimethylisoxazol-4-yl)-5-methyl-4-phenyl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2(/H)-one
Figure imgf000082_0001
The title compound was prepared by methods analogous to Example 1 but using 2- bromo- l-phenylpropan-l -one [Alfa Aesar, cat. # A 10661] in Step 1. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 2 with TFA to give the title compound as a white amorphous solid (0.015 g, 37%). LCMS calc. for C2iH2oN303 (M+H)+: m/z = 362.1 ; found: 362.1. ¾ NMR (500 MHz, DMSO-i/6) δ 10.89 (s, 1H), 7.36 - 7.26 (m, 3H), 7.06 - 7.01 (m, 2H), 6.87 (d, J= 8.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.30 (d, J = 2.8 Hz, 1H), 4.62 - 4.54 (m, 1H), 2.30 (s, 3H), 2.14 (s, 3H), 1.12 (d, J = 6.4 Hz, 3H). Example 4
4-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- <fe] [l,4]benzoxazin-4-yl]benzonitril
Figure imgf000083_0001
The title compound was prepared by methods analogous to Example 1 but using 4-(2- bromoacetyl)benzonitrile [Aldrich, cat. # 539392] in Step 1. The product was purified by preparative HPLC on a C- 18 column eluting with water : MeCN gradient buffered pH 2 with TFA to give the title compound as a white amorphous solid (0.021 g, 52%). LCMS calc. for C2iH17N403 (M+H)+: m/z = 373.1; found: 373.2. 'H NMR (500 MHz, DMSO-i¾) δ 1 1.03 (s, 1H), 7.83 (d, J= 8.3 Hz, 2H), 7.37 (d, J= 8.3 Hz, 2H), 6.86 (d, J= 8.0 Hz, 1H), 6.78 (d,
J= 8.0 Hz, 1H), 5.60 (s, 1H), 4.60 (dd, J= 11.7, 2.4 Hz, 1H), 4.43 (dd, J= 1 1.7, 3.1 Hz, 1H), 2.25 (s, 3H), 2.08 (s, 3H).
Example 5
7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2(/H)-one
Figure imgf000083_0002
The title compound was prepared by methods analogous to Example 1 but using 2- bromo-l-(pyridin-3-yl)ethanone [Oakwood, cat. # 005885] in Step 1. The product was purified by preparative HPLC on a C- 18 column eluting with water : MeCN gradient buffered pH 2 with TFA to give the TFA salt of the title compound as a white amorphous solid
(0.010 g, 25%). LCMS calc. for Ci9H17N403 (M+H)+: m/z = 349.1 ; found: 349.1. XH NMR (500 MHz, DMSO-i + TFA) δ 1 1.09 (s, 1H), 8.94 (bs, 2H), 8.37 (d, J= 8.1 Hz, 1H), 8.04 (s, 1H), 6.89 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 8.0 Hz, 1H), 5.76 (s, 1H), 4.65 (dd, J= 11.7, 3.5 Hz, 1H), 4.53 (dd, J= 1 1.7, 3.1 Hz, 1H), 2.28 (s, 3H), 2.1 1 (s, 3H).
Example 6
7-(3,5-Dimethylisoxazol-4-yl)-4-(3-methoxyphenyl)-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2(/H)-one
Figure imgf000084_0001
The title compound was prepared by methods analogous to Example 1 but using 2- bromo-l-(3-methoxyphenyl)ethanone [Aldrich, cat. # 1 15673] in Step 1 and using dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2- yl)(chloro)palladium as catalyst in Step 5. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 2 with TFA to give the title compound as a white amorphous solid (0.015 g, 37%). LCMS calc. for C21H20 3O4 (M+H)+: m/z = 378.1 ; found: 378.1. ¾ NMR (300 MHz, DMSO-i/6) δ 10.97 (s, 1H), 7.21 (t,
J= 7.9 Hz, 1H), 6.88 - 6.79 (m, 2H), 6.77 - 6.71 (m, 2H), 6.63 (d, J= 7.8 Hz, 1H), 5.42 (s, 1H), 4.57 (dd, J= 11.5 Hz, 1H), 4.36 (dd, J= 1 1.6, 2.9 Hz, 1H), 3.67 (s, 3H), 2.23 (s, 3H), 2.06 (s, 3H).
Example 7
7-(3,5-Dimethylisoxazol-4-yl)-4-(2-methoxyphenyl)-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2(/H)-one
Figure imgf000084_0002
The title compound was prepared by methods analogous to Example 1 but using 2- bromo-l-(2-methoxyphenyl)ethanone [Aldrich, cat. # 100854] in Step 1 and using dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2- yl)(chloro)palladium as catalyst in Step 5. The product was purified by preparative HPLC on a C- 18 column eluting with water : MeCN gradient buffered pH 2 with TFA to give the title compound as a white amorphous solid (0.010 g, 25%). LCMS calc. for C21H20N3O4 (M+H)+: m/z = 378.1 ; found: 378.1. ¾ NMR (300 MHz, DMSO-i/6) δ 1 1.03 (s, 1H), 7.37 - 7.21 (m, 1H), 7.09 (d, J= 7.6 Hz, 1H), 6.91 - 6.74 (m, 3H), 6.38 (d, J= 7.5 Hz, 1H), 5.61 (s, 1H), 4.49 (dd, J= 11.5 Hz, 1H), 4.37 (dd, J= 1 1.3, 3.0 Hz, 1H), 3.88 (s, 3H), 2.22 (s, 3H), 2.05 (s, 3H).
Example 8
7-(3,5-Dimethylisoxazol-4-yl)-4-(2,4-difluorophenyl)-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2(/H)-one
Figure imgf000085_0001
The title compound was prepared by methods analogous to Example 1 but using 2- bromo-l-(2,4-difluorophenyl)ethanone [Aldrich, cat. # 595152] in Step 1 and using dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2- yl)(chloro)palladium as catalyst in Step 5. The product was purified by preparative HPLC on a C- 18 column eluting with water : MeCN gradient buffered pH 2 with TFA to give the title compound as a white amorphous solid (0.018 g, 45%). LCMS calc. for C20H16F2N3O3
(M+H)+: m/z = 384.1; found: 384.1. ¾ NMR (300 MHz, DMSO-i¾) δ 11.05 (s, 1H), 7.44 - 7.27 (m, 1H), 7.09 - 6.97 (m, 1H), 6.95 - 6.82 (m, 2H), 6.78 (d, J= 8.0 Hz, 1H), 5.62 (s, 1H), 4.54 - 4.36 (m, 2H), 2.26 (s, 3H), 2.09 (s, 3H). Example 9
7-(3,5-Dimethylisoxazol-4-yl)-2-methyl-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [l,4]benzoxazine
Figure imgf000086_0001
The title compound was prepared by methods analogous to Example 1 but using
1,1,1-trimethoxy ethane [Aldrich, cat. # 237876] in Step 3. The product was purified by preparative HPLC on a C- 18 column eluting with water : MeCN gradient buffered pH 2 with TFA to give the TFA salt of the title compound as a white amorphous solid (0.003 g, 7%). LCMS calc. for C21H20N3O2 (M+H)+: m/z = 346.1; found: 346.2. ¾ NMR (500 MHz, DMSO-i/6) δ 7.44 - 7.36 (m, 4H), 7.26 (d, J= 8.4 Hz, 1H), 7.19 (d, J= 5.8 Hz, 2H), 6.03 (s, 1H), 4.72 (dd, J= 11.8, 3.9 Hz, 1H), 4.64 (dd, J= 11.7, 3.3 Hz, 1H), 2.37 (s, 3H), 2.30 (s, 3H), 2.13 (s, 3H).
Example 10
7-(3,5-Dimethylisoxazol-4-yl)-l-(2-morpholin-4-ylethyl)-4-phi
dihydroimidazo[l,5,4-<fe] [l,4]b
Figure imgf000086_0002
Step 1. 7-Bromo-l-(2-morphoUn-4-ylethyl)-4-phenyl-4, 5-dihydroimidazofl, 5, 4-deJfl, 4 ] benzoxazin-2 (lH)-one
Figure imgf000086_0003
To a O °C mixture of 7-bromo-4-phenyl-4, 5-dihydroimidazo[l, 5, 4- ife][l,4]benzoxazin-2(7H)-one (0.065 g, 0.20 mmol) from Example 1, step 4 and 4-(2- chloroethyl)morpholine hydrochloride (0.12 g, 0.63 mmol) in DMF (1 mL) was added NaH in mineral oil (0.048 g, 1.2 mmol). The reaction mixture was stirred over a weekend. EtOAc and water were added. The organic layer was washed with water and brine, dried over Na2S04 and evaporated to dryness to give an orange oil. The crude was purified by LCMS (CI 8 column eluting with a gradient MeCN/H20 containing 0.15% NH4OH at 5 mL/min.) and gave a white solid (7.7 mg, 9% yield). ¾ NMR (400 MHz, CD30D/CDC13): d 7.31 (3H, m); 7.18 (3H, m); 6.65 (1H, d); 5.19 (1H, m); 4.61 (1H, m); 4.43 (1H, m); 3.99 (2H, m); 3.6 (4H, m); 2.65 (2H, m); 2.51 (4H, m). LCMS calc. for C26H29N404 (M+H)+: m/z = ; found: 444.1, 446.1.
Step 2. 7-(3, 5-Dimethylisoxazol-4-yl)-l-(2-morpholin-4-ylethyl)-4-phenyl-4, 5- dihydroimidazof 1, 5, 4-de][ 1 4]benzoxazin-2( lH)-one
A deoxygenated solution of 7-(3,5-dimethylisoxazol-4-yl)-l-(2-morpholin-4-ylethyl)- 4-phenyl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one(7.0 mg, 0.015 mmol), 3,5- dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (4.6 mg, 0.021 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2- yl)(chloro)palladium (1: 1) (0.0017 g, 0.0022 mmol) and potassium phosphate (0.013 g, 0.061 mmol) in 1, 4-dioxane (0.2 mL) and water (0.08 mL) was refluxed for 2 h. The reaction mixture was cooled to room temperature and then additional reagents (3,5-dimethyl-4-
(4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)isoxazole (4.6 mg), potassium phosphate (12 mg) and catalyst (2.7 mg)) were added. The solution mixture was deoxygenated and then refluxed for 2.3 h. EtOAc and water were added. The organic layer was washed with brine and then concentrated to give a pale orange glass/oil (22 mg). The crude product was purified by LCMS (C 18 column eluting with a gradient MeCN/H20 containing 0.15% NH4OH at
5 mL/min.) and gave the title compound as a white solid (7.6 mg, 95% yield). XH NMR (500 MHz, DMSO-i/6): d 7.35 (3H, m); 7.18 (2H, m); 7.0 (1H, m); 6.95 (1H, m); 5.55 (1H, m); 4.61 (1H, m); 4.42 (1H, m); 3.99 (2H, m); 3.5 (4H, m); 2.63 (2H, m); 2.42 (4H, m); 2.23 (3H, s); 2.08 (3H, s). LCMS calc. for C2iH23BrN303 (M+H)+: m/z = 460.2; found: 460.2. Example 11
7-(3,5-Dimethyl-7H-pyrazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2(/H)-one
Figure imgf000088_0001
The title compound was prepared by methods analogous to Example 1 but using added 3, 5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7H-pyrazole[Aldrich, cat. # 636010] in Step 5. The product was purified by preparative HPLC on a C- 18 column eluting with water : MeCN gradient buffered pH 2 with TFA to give the title compound as a white amorphous solid (0.018 g, 45%). LCMS calc. for C2oH19 402 (M+H)+: m/z = 347.1; found: 347.2.
Example 12
7-(3-Methyl-lH-pyrazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4-de] [l,4]benzoxazin- 2(lH)-one
Figure imgf000088_0002
The title compound was prepared by methods analogous to Example 1 but using added 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole [Aldrich, cat. # 706078] in Step 5. The product was purified by preparative HPLC on a C- 18 column eluting with water : MeCN gradient buffered pH 2 with TFA to give the title compound as a white amorphous solid (0.018 g, 45%). LCMS calc. for Ci9H17N402 (M+H)+: m/z = 333.1; found: 333.2. Example 13
7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2(/H)-one
Figure imgf000089_0001
The title compound was prepared by methods analogous to Example 1 but using 2- bromo-l-(pyridin-2-yl)ethanone HBr [Maybridge CC04005DA] in Step 1. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 2 with TFA to give the TFA salt of the title compound as a white amorphous solid (0.015 g, 30%). LCMS calc. for CigHnWs (M+H)+: m/z = 349.1; found: 349.1. XH NMR (300 MHz, DMSO-i¾) δ 11.01 (s, 1H), 8.52 (d, J= 4.8 Hz, 1H), 7.79 (td, 1H), 7.32 (dd, J= 7.5, 4.9 Hz, 1H), 7.12 (d, J= 7.8 Hz, 1H), 6.83 (d, J= 8.0 Hz, 1H), 6.76 (d, J= 8.0 Hz, 1H), 5.52 (s, 1H), 4.76 (dd, 1H), 4.44 (dd, J= 11.4, 3.1 Hz, 1H), 2.22 (s, 3H), 2.05 (s, 3H).
Example 14
7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2(/H)-one (Enantiomer 1)
Example 15
7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2(/H)-one (Ena
Figure imgf000089_0002
The enantiomers were prepared from racemic 7-(3,5-dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2(7H)-one from Example 13, by chiral column HPLC using a Phenomenex Lux Cellulose-C4 column, 5 micron, 21.2 x 250 mm, eluting with 60% ethanol in hexanes with a flow rate of 18 mL/min., loading approx. 36 mg per injection with UV (220 nm) detection to give peak 1 at: 7.51 min. and peak 2 at: 12.92 min.
Enantiomer 2. Peak 1 : Example 15. LCMS calc. for C 9H17N4O3 (M+H)+:
m/z = 349.1 ; found: 349.1. ¾ NMR (300 MHz, DMSO-i/6) δ 1 1.01 (s, 1H), 8.52 (d,
J= 4.8 Hz, 1H), 7.79 (td, 1H), 7.32 (dd, J = 7.5, 4.9 Hz, 1H), 7.12 (d, J= 7.8 Hz, 1H), 6.83 (d, J= 8.0 Hz, 1H), 6.76 (d, J= 8.0 Hz, 1H), 5.52 (s, 1H), 4.76 (dd, 1H), 4.44 (dd, J= 11.4, 3.1 Hz, 1H), 2.22 (s, 3H), 2.05 (s, 3H). This enantiomer is believed to have the S configuration based on X-ray crystallography data.
Enantiomer 1. Peak 2: Example 14. LCMS calc. for C19H17N4O3 (M+H)+:
m/z = 349.1 ; found: 349.1. ¾ NMR (300 MHz, DMSO-i/6) δ 1 1.01 (s, 1H), 8.52 (d,
J= 4.8 Hz, 1H), 7.79 (td, 1H), 7.32 (dd, J = 7.5, 4.9 Hz, 1H), 7.12 (d, J= 7.8 Hz, 1H), 6.83 (d, J= 8.0 Hz, 1H), 6.76 (d, J= 8.0 Hz, 1H), 5.52 (s, 1H), 4.76 (dd, 1H), 4.44 (dd, J= 11.4, 3.1 Hz, 1H), 2.22 (s, 3H), 2.05 (s, 3H).
Example 16
7-(3,5-Dimethylisoxazol-4-yl)-4-(l-oxidopyridin-2-yl)-4,5-dihydroimidazo[l,5,4- de] [l,4]benzoxazin-2(/H)-one
Figure imgf000090_0001
Methyltrioxorhenium(VII) (2 mg, 0.008 mmol) was added to a solution of 7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)- one (20 mg, 0.06 mmol) from Example 15, in tetrahydrofuran (2 mL) at room temperature and then 3.0 M hydrogen peroxide in water (0.04 mL) was added. The reaction mixture was heated to 80 °C for 20 min. allowed to cool and was diluted with water and EtOAc. The combined organic layers were washed with brine, dried over MgS04, filtered and
concentrated to give the crude product. The product was purified by preparative HPLC on a C-18 column eluting with a water : MeCN gradient buffered pH 10 to give the title compound as a white amorphous solid (0.007 g, 30%). LCMS calc. for Ci9H17 404 (M+H)+: m/z = 365.1; found: 365.1. 1H NMR (400 MHz, DMSO-i/6) δ 11.12 (s, 1H), 8.37 (d, J = 5.8 Hz, 1H), 7.39 (td, J = 7.2, 6.5, 2.0 Hz, 1H), 7.25 (td, J = 7.7, 0.9 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.63 (dd, J = 7.9, 2.0 Hz, 1H), 5.84 (d, J = 2.2 Hz, 1H), 4.78 (dd, J = 11.6, 1.3 Hz, 1H), 4.36 (dd, J = 11.6, 3.4 Hz, 1H), 2.17 (s, 3H), 2.00 (s, 3H).
Example 17
4-Cyclohexyl-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2(/H)-one
Figure imgf000091_0001
Step 1. 2-Bromo-l-cyclohexylethanone
Figure imgf000091_0002
Cyclohexyl methyl ketone (0.30 mL, 2.4 mmol) [Alfa Aesar cat# L05501] was dissolved in methanol (3.0 mL, 74 mmol) cooled in an ice bath and bromine (0.38 g, 2.4 mmol) was added drop wise. The mixture was stirred for 2 h and then water (3.0 mL) was added and the reaction mixture was allowed to stir for 4 h. The reaction mixture was extracted with EtOAc: hexane (3: 1). The combined organic layer was washed with water saturated potassium carbonate, brine, dried over magnesium sulfate and concentrated to give as 2-bromo-l-cyclohexylethanone as a clear oil (0.49 g, 100%). ¾ NMR (300 MHz, CDC13) δ 3.96 (s, 2H), 2.86 - 2.55 (m, 1H), 2.24 - 1.08 (m, 10H). Step 2.
The title compound was prepared by methods analogous to Example 1 but using 2- bromo-l-cyclohexylethanone from Step 1 above. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 2 with TFA to give the title compound as a white amorphous solid (0.010 g, 30%). LCMS calc. for
C2oH24 303 (M+H)+: m/z = 354.1; found: 354.2. XH NMR (400 MHz, DMSO-i¾) δ 10.86 (s, 1H), 6.78 (d, J= 8.0 Hz, 1H), 6.68 (d, J= 8.0 Hz, 1H), 4.65 (d, J= 11.1 Hz, 1H), 4.04 (d, J= 6.4 Hz, 1H), 3.97 (dd, J= 1 1.8, 2.9 Hz, 1H), 2.28 (s, 3H), 2.12 (s, 3H), 1.82 - 1.51 (m, 6H), 1.13 (d, J= 18.1 Hz, 5H).
Example 18A
7-(3,5-Dimethylisoxazol-4-yl)-4-(tetrahydrofuran-2-yl)-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2(/H)-one (Diastereoisomer 1)
Example 18B
7-(3,5-Dimethylisoxazol-4-yl)-4-(tetrahydrofuran-2-yl)-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2(/H)-one (Diast
Figure imgf000092_0001
The title compound was prepared by methods analogous to Example 1, but using 2- bromo-l-(furan-2-yl)ethanone in Step 1 and the furan was reduced to the tetrahydrofuran in Step 2. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH2 to give the title compound as two separated diastereoisomers Diastereoisomer 1. Peak 1. Example 18A. Solid residue. LCMS calc. for C18H20 3O4
(M+H)+: m/z = 342.1; found: 342.1.
Diastereoisomer 2. Peak 2. Example 18B. Solid residue. LCMS calc. for C18H20 3O4 (M+H)+: m/z = 342.1; found: 342.1.
Example 19
7-(3,5-Dimethylisoxazol-4-yl)-4-(5-fluoropyridin-2-yl)-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2(7H)-one
Figure imgf000092_0002
Step 1. 2-(l-Ethoxyvinyl)-5-fluoropyridine
Figure imgf000093_0001
A mixture of 2-bromo-5-fluoropyridine (200 mg, 1 mmol), tributyl(l-ethoxyvinyl)tin (500 mg, 1 mmol), copper(I) iodide (20 mg, 0.1 mmol) and
bis(triphenylphosphine)palladium(II) chloride (50 mg, 0.07 mmol) in MeCN (5 mL) was heated to 80 °C for 30 h. The reaction mixture was allowed to cool to room temperature and was diluted with EtOAc, washed with 5% NH4OH, brine, dried over MgS04, filtered and concentrated to give a crude oil. The product was purified by flash column chromatography on silica gel eluting with a hexane ; EtOAc gradient (0-30%) to give 2-(l-ethoxyvinyl)-5- fluoropyridine as a clear oil (0.2 g, 90%). LCMS calc. for C9HnFNO (M+H)+: m/z = 168.1 ; found: 168.2.
Step 2. 2-Bromo-l-(5-fluoropyridin-2-yl)ethanone
Figure imgf000093_0002
N-Bromosuccinimide (200 mg, 1 mmol) was added to a mixture of 2-(l-ethoxyvinyl)- 5-fluoropyridine (200 mg, 1 mmol) in THF (6 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 15 min., diluted with EtOAc and washed with brine. The combined organic layer was dried with MgS04, filtered and concentrated to give 2-bromo-l- (5-fluoropyridin-2-yl)ethanone as a clear oil, which was used in the next step.
Step3.7-(3, 5-Dimethylisoxazol-4-yl)-4-(5-fluoropyridin-2-yl)-4, 5-dihydroimidazo[ 1, 5, 4- dejf 1 ,4] benzoxazin-2( lH)-one
The title compound was prepared by methods analogous to Example 1, but using 2- bromo-l-(5-fluoropyridin-2-yl)ethanone from above, in Step 1. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH2 to give the title compound as a solid residue. LCMS calc. for C19H16F 4O3 (M+H)+:
m/z = 367.1 ; found: 367.1. Example 20
Ethyl 7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[l,5,4-< ^][l,4]benzoxazine-5-carboxylate
Figure imgf000094_0001
Step 1. Ethyl 2-bromo-3-oxo-3-pyridin-2-ylpropanoate hydrobromide
Figure imgf000094_0002
Bromine (0.83 g, 5.2 mmol) in chloroform (2 mL) was added slowly to a solution of ethyl 3-oxo-3-pyridin-2-ylpropanoate (1.0 g, 5.2 mmol) and chloroform (25.0 mL) at room temperature. The reaction mixture was stirred for 1 h and was concentrated under reduced pressure to give 1 ethyl 2-bromo-3-oxo-3-pyridin-2-ylpropanoate hydrobromide salt as an amber oil (1.8 g, 100%). LCMS calc. for Ci0HnBrNO3 (M+H)+: m/z = 272.0, 274.0; found: 272.0, 274.0.
Step 2. Ethyl 7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazof 1, 5, 4-de][ 1, 4 ]benzoxazine-5-carboxylate
The title compound was prepared by methods analogous to Example 1, but using 2- bromo-3 -oxo-3 -pyridin-2-ylpropanoate from above, in Step 1. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 10 to give a mixture of the two diastereoisomers of the title compound as a solid residue. LCMS calc. for C22H21N4O5 (M+H)+: m/z = 421.1 ; found: 421.1.
Example 21
7-(3,5-Dimethylisoxazol-4-yl)-4-(l,3-thiazol-2-yl)-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2(/H)-one
Figure imgf000095_0001
Step 1. 2-Bromo-l-(l,3-thiazol-2-yl)ethanone
Figure imgf000095_0002
Bromine (70 \L, 1 mmol) was added to a mixture of l-(l,3-thiazol-2-yl)ethanone (200 mg, 2 mmol) in AcOH (5 mL). The reaction mixture was stirred at 100 °C for 30 min. and was concentrated under reduced pressure to give 2-bromo-l-(l,3-thiazol-2-yl)ethanone as an oil (100%) used as crude.
Step 2. 7-(3, 5-dimethylisoxazol-4-yl)-4-( 1, 3-thiazol-2-yl)-4, 5-dihydroimidazo[ 1, 5, 4- dejf 1 ,4] benzoxazin-2( lH)-one
The title compound was prepared by a method analogous to Example 1, but using 2- bromo-l-(l,3-thiazol-2-yl)ethanone from above, in Step 1. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 2 to give the title compound as a solid residue. LCMS calc. for C17H15N4O3S (M+H)+:
m/z = 355.1; found: 355.1. ¾ NMR (500 MHz, DMSO-i/6) δ 11.05 (s, 1H), 7.78 (d, J= 3.2 Hz, 1H), 7.69 (d, J= 3.2 Hz, 1H), 6.85 (d, J= 8.0 Hz, 1H), 6.77 (d, J= 8.0 Hz, 1H), 5.90 (s, 1H), 4.83 (d, J= 10.4 Hz, 1H), 4.44 (dd, J= 11.6, 2.9 Hz, 1H), 2.24 (s, 3H), 2.07 (s, 3H). Example 22
2-{2-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- < ^][l,4]benzoxazin-4-yl]phenox -iV-ethylacetamide
Figure imgf000096_0001
Step 1. Methyl ( 2 -acetylphenoxy) acetate
Figure imgf000096_0002
l-(2-Hydroxyphenyl)ethanone (1.0 g, 7.3 mmol) and methyl bromoacetate (0.70 mL, 7.3 mmol) were combined in acetone (20.0 mL) with potassium carbonate (2.0 g, 15 mmol) and was stirred at room temperature. The reaction mixture was stirred for 18 h, diluted with EtOAc and filtered to remove the solids. The organic layer was concentrated to give the subtitle compound as a clear oil (1.5 g, 100%). LCMS calc. for CnH1304 (M+H)+: m/z = 209.1 ; found: 209.1.
Step 2. Methyl [2-(bromoacetyl)phenoxy] acetate
Figure imgf000096_0003
Bromine (1.2 g, 7.2 mmol) in chloroform (5 mL) was added drop wise to a solution of methyl (2-acetylphenoxy)acetate (1.5 g, 7.2 mmol) in chloroform (45 mL) at room temperature. The reaction mixture was stirred for 1 h at room temperature, diluted with EtOAc and washed with sodium bicarbonate water, brine, dried over magnesium sulfate and concentrated to give the sub-title compound as an oil which solidified (2.1 g, 100%). LCMS calc. for CnH12Br04 (M+H)+: m/z = 287.0, 289.0; found: 287.0, 289.0. Step 3. {2-[7-(3, 5-dimethylisoxazol-4-yl)-2-oxo-l,2, 4, 5-tetrahydroimidazof 1, 5, 4- de] [l,4]benzoxazin-4-yl]phenoxy}acetic acid
Figure imgf000097_0001
The intermediate compound was prepared by methods analogous to Example 1, but using methyl [2-(bromoacetyl)phenoxy]acetate from above, in Step 1 and the ester was found to saponify in Step 5 to give the sub-title compound as a solid residue. LCMS calc. for C22H2o 306 (M+H)+: m/z = 422.1; found: 422.1.
Step 4. 2-{2-[7-(3, 5-Dimethylisoxazol-4-yl)-2-oxo-l, 2, 4, 5-tetrahydroimidazofl, 5, 4-deJfl,
4]benzoxazin-4-yl]phenoxy}-N-ethylacetamide
A mixture of {2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5- tetrahydroimidazo[l,5,4-de][l,4]benzoxazin-4-yl]phenoxy}acetic acid (0.03 g, 0.07 mmol) in
DMF (2.0 mL) with DIPEA (0.025 mL, 0.14 mmol) and HATU (0.027 g, 0.071 mmol) was stirred at room temperature for 10 min. and ethylamine (0.0064 g, 0.14 mmol) was added.
The reaction mixture was stirred for 1 h and the product was purified without workup by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 2 buffered with TFA to give the title compound as an off-white amorphous solid. LCMS calc. for C24H25 405 (M+H)+: m/z = 449.1 ; found: 449.2.
Example 23
Ethyl 7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-phenyl-l,2,4,5-tetrahydroimidazo[l,5,4- de] [l,4]benzoxazine-5-carboxylat
Figure imgf000097_0002
Step 1. Ethyl 2-bromo-3-oxo-3-phenylpropanoate
Figure imgf000098_0001
Ethyl benzoylacetate (0.27 mL, 1.6 mmol) [Fluka cat# 12990] was dissolved in dimethyl sulfoxide (5.0 mL) at room temperature and the N-bromosuccinimide (0.30 g, 1.7 mmol) was added portion wise. The reaction mixture was stirred for 3 h and EtOAc was added and washed with water, water saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give Ethyl 2-bromo-3-oxo-3-phenylpropanoate (0.40 g, 95%) as an oil %). LCMS calc. for CnH12Br03 (M+H)+: m/z = 271.0, 273.0; found: 271.0, 273.0. Step 2. Ethyl 7-( 3, 5-dimethylisoxazol-4-yl)-2-oxo-4-phenyl-l, 2, 4, 5-tetrahydroimidazo[ 1,5,4- dejf 1, 4 ] benzoxazine-5-carboxylate
The title compound was prepared by a method analogous to Example 1, but using ethyl 2-bromo-3-oxo-3-phenylpropanoate Step 1 above. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 2 with TFA to give a mixture of diastereoisomers of the title compound as a white amorphous solid (0.012 g, 25%). LCMS calc. for C23H22 305 (M+H)+: m/z = 320.1; found: 320.2. XH NMR (300 MHz, DMSO-i¾) δ 1 1.01 (d, J= 5.1 Hz, 1H), 7.38 - 7.19 (m, 3H), 7.14 - 6.94 (m, 2H), 6.94 - 6.65 (m, 2H), 5.70 (s, 0.4H), 5.54 (t, J= 2.4 Hz, 1H), 5.36 (d, J= 3.3 Hz, 0.6H), 3.99 (dq, J= 14.2, 7.1 Hz, 2H), 2.29 (s, 1.8H), 2.19 (s, 1.2H), 2.14 (s, 1.8H), 2.02 (s, 1.2H), 0.99 (dt, J= 9.8, 7.1 Hz, 3H).
Example 24A
7-(3,5-Dimethylisoxazol-4-yl)-7V-ethyl-2-oxo-4-phenyl-l,2,4,5-tetrahydroimidazo[l,5,4- <fe] [l,4]benzoxazine-5-carboxamide (Diastereoisomer 1).
Example 24B
7-(3,5-Dimethylisoxazol-4-yl)-7V-ethyl-2-oxo-4-phenyl-l,2,4,5-tetrahydroimidazo[l,5,4- <fe] [l,4]benzoxazine-5-carboxamid 2).
Figure imgf000099_0001
Step 1. 7-(3, 5-Dimethylisoxazol-4-yl)-2-oxo-4-phenyl- 1 , 2, 4, 5-tetrahydroimidazof 1, 5, 4- dejf 1, 4 ] benzoxazine-5-carboxyUc acid
Figure imgf000099_0002
Ethyl 7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-phenyl-l,2,4,5-tetrahydroimidazo[l,5,4- de][l,4]benzoxazine-5-carboxylate(0.150 g, 0.358 mmol) from Example 23 was dissolved in MeOH (3.0 mL) and lithium hydroxide, monohydrate (0.030 g, 0.72 mmol) dissolved in water (1.0 mL) was added. The reaction mixture was stirred at room temperature for 2 h, diluted with EtOAc and washed with saturated water ammonium chloride, brine, dried over magnesium sulfate and concentrated to give a mixture of the diastereoisomers of the title compound as a solid residue (0.145 g, 100%). LCMS calc. for C2iH18 305 (M+H)+:
m/z = 392.1; found: 392.1.
Step 2. 7-(3, 5-Dimethylisoxazol-4-yl)-N-ethyl-2-oxo-4-phenyl-l, 2, 4, 5- tetrahydroimidazof 1, 5, 4-de][ 1, 4 ] benzoxazine-5-carboxamide
7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-phenyl-l,2,4,5-tetrahydroimidazo[l,5,4- de][l,4]benzoxazine-5-carboxylic acid (0.04 g, 0.1 mmol) was dissolved in DMF (2.0 mL) with DIPEA (0.036 mL, 0.20 mmol) at room temperature. HATU (0.054 g, 0.14 mmol) was added and then the 2.0 M ethylamine in THF (0.20 mL, 0.41 mmol) was added. The reaction mixture was stirred at room temperature for an hour and was diluted with EtOAc. The organic layer was washed with 1 N HC1, brine, dried over magnesium sulfate and concentrated to give a solid. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 2 to give the title compound as two separated diastereoisomers.
Diastereoisomer 1. Peak 1. Example 24A. Solid residue (0.010 g, 25%). LCMS calc. for C23H23 404 (M+H)+: m/z = 419.1 ; found: 419.1.
Diastereoisomer 2. Peak 2. Example 24B. Solid residue (0.008 g, 20%). LCMS calc. for C23H23 404 (M+H)+: m/z = 419.1 ; found: 419.1.
Example 25
7-(3,5-Dimethylisoxazol-4-yl)-7V-isopropyl-4-phenyl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2-amine
Figure imgf000100_0001
Step 1. 2-Chloro-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazofl,5,4- dejf 1, 4 Jbenzoxazine
Figure imgf000100_0002
To 7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- ife][l,4]benzoxazin-2(7H)-one(40.0 mg, 0.1 15 mmol) in a vial, phosphoryl chloride (1.5 mL, 16 mmol) was added and the mixture was heated at 95 °C overnight. The mixture was evaporated and extracted with EtOAc. The extracts were washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. Filtration and evaporation gave the desired compound (42 mg, 100%). LCMS calc. for C2oH17Cl 302 (M+H)+: m/z = 366.1; found: 366.1.
Step 2. 7-(3, 5-Dimethylisoxazol-4-yl)-N-isopropyl-4-phenyl-4, 5-dihydroimidazo[ 1, 5, 4- de] [l,4]benzoxazin-2-amine
To 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazine(9.1 mg, 0.025 mmol) in N-methylpyrrolidinone (0.40 mL), triethylamine (10 xL, 0.075 mmol) and 2-propanamine (21.2 \L, 0.25 mmol) were added and the mixture was heated at 120 °C overnight. The mixture was diluted with MeOH and purified by preparative LCMS (pH 10) to give the desired compound (2.8 mg, 29%). *H NMR (500 MHz, DMSO-i/6): δ 7.29 (3H, m); 6.92 (3H, m); 6.78 (1H, m); 6.55 (1H, m); 5.80 (1H, s); 4.68 (1H, m); 4.45 (1H, m); 4.00 (1H, m); 2.20 (3H, s); 2.02 (3H, s); 1.20 (3H, m); 1.09 (3H, m). LCMS calc. for C23H25 402 (M+H)+: m/z = 389.2 ; found: 389.2.
Example 26
7-(3,5-Dimethylisoxazol-4-yl)-7V-methyl-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [l,4]benzoxazin-2-amine
Figure imgf000101_0001
The title compound was prepared by a method analogous to Example 25, but using methylamine in Step 2. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 10 with ammonium hydroxide to give the title compound (2.1 mg, 13%). 'H NMR (500 MHz, DMSO-i¾): d 7.29 (3H, m); 6.93 (3H, m); 6.83 (1H, m); 6.79 (1H, m); 5.70 (1H, s); 4.61 (1H, m); 4.43 (1H, m); 2.87 (3H, m); 2.11 (3H, s); 2.03 (3H, s); 1.49 (1H, m). LCMS calc. for C2iH21 402 (M+H)+: m/z = 361.2; found: 361.2. Example 27
7-(3,5-Dimethylisoxazol-4-yl)-7V-ethyl-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [l,4]benzoxazin-2-amine
Figure imgf000102_0001
The title compound was prepared by methods analogous to Example 25, but using ethyl amine in Step 2. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 10 with ammonium hydroxide to give the title compound (6.0 mg, 42%). XH NMR (500 MHz, DMSO-i¾): d 7.29 (3H, m); 6.93 (3H, m); 6.87 (1H, m); 6.78 (1H, m); 5.78 (1H, s); 4.63 (1H, m); 4.43 (1H, m); 3.32 (2H, m); 2.20 (3H, s); 2.02 (3H, s); 1.12 (3H, m). LCMS calc. for C22H23N402 (M+H)+: m/z = 375.2; found: 375.2.
Example 28
7-(3,5-Dimethylisoxazol-4-yl)-7V,iV-dimethyl-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [l,4]benzoxazin-2-amine
Figure imgf000102_0002
The title compound was prepared by methods analogous to Example 25, but using dimethylamine in Step 2. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 10 with ammonium hydroxide to give the title compound ( 6.7 mg, 72%). XH NMR (500 MHz, DMSO-i¾): δ 7.29 (3H, m); 7.00 (1H, m); 6.85 (3H, m); 6.11 (1H, s); 4.52 (2H, m); 2.99 (6H, s); 2.20 (3H, s); 2.02 (3H, s). LCMS calc. for C22H23N402 (M+H)+: m/z = 375.2; found: 375.2 Example 29
2-{[7-(3, 5-Dimethylisoxazol-4-yl)-4-phenyl-4, 5-dihydroimidazo[l, 5, 4-de] [l,
4] benzoxazin-2-yl] amino} ethan
Figure imgf000103_0001
The title compound was prepared by a method analogous to Example 25, but using ethanolamine [Aldrich #41 1000] in Step 2. The product was purified by preparative HPLC on a C-18 column eluting with a water : MeCN gradient buffered pH 10 with ammonium hydroxide to give the title compound (5.5 mg, 40%). LCMS calc. for C22H23 4O3 (M+H)+: m/z = 391.2; found: 391.2. Example 30
2-{[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [l,4]benzoxazin-2-yl]amino}propan-l-ol (Diastereoisomer 1)
Example 31
2-{[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [l,4]benzoxazin-2-yl]amino} mer 2)
Figure imgf000103_0002
The title compound was prepared by a method analogous to Example 25, but using DL-alaninol [Aldrich #192171] in Step 2. The product was purified by preparative HPLC on a C-18 column eluting with a water : MeCN gradient buffered pH 10 with ammonium hydroxide to give the two racemic diastereoisomers of the title compound.
Diastereoisomer 1. Peak I. Example 30 (3.9 mg, 27%). XH NMR (500 MHz, DMSO- d6): d 7.30 (4H, m); 6.92 (3H, m); 6.79 (1H, m); 6.53 (1H, m); 5.82 (1H, s); 4.76 (1H, m); 4.68 (1H, m); 4.43 (1H, m); 3.92 (1H, m); 3.45 (1H, m); 3.20 (1H, m); 2.20 (3H, s); 2.03 (3H, s); 1.19 (3H, m). LCMS calc. for C23H25N4O3 (M+H)+: m/z = 405.2; found: 405.2.
Diastereoisomer 2. Peak 2. Example 31. LCMS calc. for C23H25 4O3 (M+H)+:
m/z = 405.2; found: 405.2. Example 32
l-{[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]amino}
Figure imgf000104_0001
The title compound was prepared by a method analogous to Example 25, but using 1- amino-2-propanol [Aldrich #110248] in Step 2. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 10 with ammonium hydroxide to give the title compound (5.3 mg, 37%) as a mixture of
diastereoisomers. LCMS calc. for C23H25N4O3 (M+H)+: m/z = 405.2; found: 405.2.
Example 33
2-{[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]amino}- -methylpropan-l-ol
Figure imgf000104_0002
The title compound was prepared by a method analogous to Example 25, but using 2- amino-2-methyl-l-propanol [Aldrich #A65182] in Step 2. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 10 with ammonium hydroxide to give the title compound (1.5 mg, 10%). LCMS calc. for C24H27N4O3 (M+H)+: m/z = 419.2; found: 419.2. Example 34
2-[[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [1,4] benzoxazin-2-yl] (methy
Figure imgf000105_0001
The title compound was prepared by a method analogous to Example 25, but using 2-
(methylamino)ethanol [Aldrich #471445] in Step 2. The product was purified by preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 10 with ammonium hydroxide to give the title compound (2.6 mg, 18%). LCMS calc. for C23H25 4O3 (M+H)+: m/z = 405.2; found: 405.2. Example 35
7-(l-Methyl-lH-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4-< ^] [l,4]benzoxazin- 2(lH)-one
Figure imgf000105_0002
7-Bromo-4-phenyl-4, 5-dihydroimidazo[l, 5, 4-<ie][l, 4]benzoxazin-2(lH)-one (100 mg, 0.3mmol) was dissolved in 1, 4-dioxane (2.4 mL). A solution of l-methyl-5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (94 mg, 0.45 mmol) and potassium phosphate (100 mg, 0.6 mmol) in water (0.60 mL) was added. Reaction was deoxygenated with nitrogen. Dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'- aminobiphenyl-2-yl)(chloro)palladium (1 : 1) (7 mg, 0.009 mmol) was added and
deoxygenated with nitrogen. The reaction mixture was stirred at 100 °C for 4 h. Water and EtOAc were added and the layers were separated. The organic layer was concentrated under reduced pressure. Purification on silica using EtOAc/hexanes gave the title compound (61 mg). LCMS calc. for Οι9Η17Ν402 (M+H)+: m/z = 333.1; found: 333.2. XH NMR (300 MHz, OMSO-d6): d 7.40 (s, 1H); 7.31 (m, 3H); 7.13 (m, 2H); 6.92 (m, 1H); 6.79 (m, 1H); 6.22 (s, 1H); 5.49 (s, 1H); 4.59 (m, 1H); 4.41 (m, 1H); 3.60 (s, 3H).
Example 36
9-Bromo-7-(l-methyl-lH-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2(lH)-one
Figure imgf000106_0001
To a solution of 7-(l-methyl-lH-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- ife][l,4]benzoxazin-2(lH)-one (32 mg, 0.096 mmol) in THF (0.7 mL) was added N- bromosuccinimide (19 mg, 0.10 mmol). The solution was stirred at room temperature for 1 h and then concentrated under reduced pressure. Purification on silica gel using EtOAc/hexane gave the title compound, 24 mg. LCMS calc. for Ci9Hi6Br 402 (M+H)+: m/z = 411.0, 413.0; found: 41 1.1, 413.1. XH NMR (300 MHz, DMSO-i¾): d 7.40 (s, 1H); 7.31 (m, 3H); 7.13 (m, 2H); 7.08 (s, 1H); 6.30 (s, 1H); 5.50 (s, 1H); 4.59 (m, 1H); 4.41 (m, 1H); 3.60 (s, 3H). Example 37
9-Methyl-7-(l-methyl-lH-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2(lH)-one
Figure imgf000106_0002
A reaction mixture of 9-bromo-7-(l -methyl- lH-pyrazol-5-yl)-4-phenyl-4,5- dihydroimidazo[l,5,4-<ie][l,4]benzoxazin-2(lH)-one (17 mg, 0.04 mmol), a solution of 2.0 M methylzinc chloride in THF (0.10 mL) and tetrakis(triphenylphosphine)palladium(0) (2 mg, 0.002 mmol) in THF (0.5 mL) under nitrogen was heated in a microwave at 130 °C for 5 min. The title compound was purified by preparative LCMS using a pHIO buffer. LCMS calc. for C2oH19 402 (M+H)+: m/z = 347.1; found: 347.2.
Example 38
7-(4-Chloro-l-methyl-lH-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2(lH)-one
Step 1. 4-Chloro-l-methyl-5-(4, 4, 5, 5- borolan-2-yl)-lH-pyrazole
Figure imgf000107_0001
A mixture of l-methyl-5-(4,4,5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl)-lH-pyrazole (1.3 g, 6.3 mmol), N-chlorosuccinimide (0.93 g, 7.0 mmol) and THF (6.6 mL) was stirred at 70 °C for 3 h. The mixture was extracted with EtOAc, dried and concentrated under reduced pressure. The sub-title compound was purified by chromatography on silica gel using 40% EtOAc in hexanes gave the desired compound, 1.456 g, 95%.
Step 2. 7-(4-Chloro-l-methyl-lH-pyrazol-5-yl)-4-phenyl-4, 5-dihydroimidazofl, 5, 4-deJfl, 4]benzoxazin-2(lH)-one
The title compound was prepared by a method analogous to Example 35, but using 4- chloro-l-methyl-5-(4,4,5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl)-lH-pyrazole. The product was purified by preparative HPLC on a C- 18 column eluting with water : MeCN gradient buffered at pH2 to give the title compound. LCMS calc. for Ci9Hi6ClN402 (M+H)+:
m/z = 367.1; found: 367.1. Example 39
7-(3,5-Dimethylisoxazol-4-yl)-4-pheny -4,5-dihydroimidazo[l,5,4-< ^][l,4]benzoxazine
Figure imgf000108_0001
A reaction mixture of 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5- dihydroimidazo[l,5,4-ife][l,4]benzoxazine (15 mg, 0.041 mmol), 0.5 M bromo(propyl)zinc in THF (0.5 mL) and tetrakis(triphenylphosphine)palladium(0) (2 mg, 0.002 mmol) in THF (0.4 mL) under nitrogen was heated in a microwave at 150 °C for 5 min. Purification of the product by preparative LCMS using pH 10 buffer gave the title compound. LCMS calc. for C2oH17N302 (M+H)+: m/z = 332.1; found: 332.2. Example 40
7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-2-piperazin-l-yl-4,5-dihydroimidazo[l,5,4- de] [l,4]benzoxazine
Figure imgf000108_0002
4-[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]piperazine-l-carboxylate (Example 60) was stirred in 4 N HCl for 15 min. at room temperature and evaporated. Purification by preparative LCMS at pH 10 gave the desired compound which was isolated as the dihydrochloride salt. LCMS calc. for C24H26 502 (M+H)+: m/z = 416.2; found: 416.2. Example 41
7-(3, 5-Dimethylisoxazol-4-yl)-2,4-diphenyl-4, 5-dihydroimidazo[l, 5, 4-de] [l,
4]benzoxazine
Figure imgf000109_0001
A mixture of 2-chloro-7-(3, 5-dimethylisoxazol-4-yl)-4-phenyl-4, 5- dihydroimidazo[l, 5, 4-<ie][l, 4]benzoxazine (14 mg, 0.039 mmol), phenylboronic acid (5.6 mg, 0.046 mmol), [1, r-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (1 : 1) (2 mg, 0.002 mmol) and potassium carbonate (16 mg, 0.12 mmol) in 1, 4-dioxane (0.2 mL), and water (0.1 mL). The resulting mixture was heated at 80 °C for 3 h. The reaction mixture was diluted with MeOH and purified on Preparative LCMS using pH 10 buffer to give the desired compound.
LCMS calc. for C26H22 3O2 (M+H)+: m/z = 408.2; found: 408.2. Example 42
7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-phenyl-l,2,4,5-tetrahydroimidazo[l,5,4- de\ [l,4]benzoxazine-9-carbonitrile
Figure imgf000109_0002
9-Bromo-7-(3, 5-dimethylisoxazol-4-yl)-4-phenyl-4, 5-dihydroimidazo[l, 5, 4-<ie][l, 4]benzoxazin-2(lH)-one (6.9 mg, 0.016 mmol), zinc cyanide (19 mg, 0.16 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.8 mg, 0.0024 mmol) were dissolved in DMF (1.6 mL) and the solution was deoxygenated. The stirred reaction mixture was heated at 150 °C in a microwave for 5 min. The mixture was diluted with MeOH and purified by preparative LCMS using pH 10 buffer to give the title compound. LCMS calc. for
C2iH17 403 (M+H)+: m/z = 373.1; found: 373.2.
Example 43
7-(3,5-Dimethylisoxazol-4-yl)-4,9-diphenyl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2(lH)-one
Figure imgf000110_0001
A mixture of 9-bromo-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one (9.0 mg, 0.021 mmol), phenylboronic acid (3.1 mg, 0.025 mmol), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (1 :1) (0.9 mg, 0.001 mmol) and potassium carbonate (8.8 mg,
0.063 mmol) in 1,4-dioxane (0.1 mL), and water (0.07 mL) was heated at 80 °C for 3 h. The reaction mixture was diluted with MeOH and purified on by preparative LCMS using a pH 10 buffer to give the title compound. LCMS calc. for C26H22 3O3 (M+H)+: m/z = 424.2; found: 424.0. Example 44
7-(l,4-Dimethyl-lH-pyrazol-5-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [l,4]benzoxazin-2(lH)-one
Figure imgf000110_0002
Step 1. 1, 4-Dimethyl-5-( 4, 4, 5, 5-tetrame orolan-2-yl)-lH-pyrazole
Figure imgf000111_0001
l,4-Dimethyl-7H-pyrazole (50 mg, 0.5 mmol) was stirred in THF (2 mL) and cooled to 0 °C. A solution of 1.6 M w-butyllithium in hexanes (390 mL) was added dropwise by syringe and the mixture was allowed to warm to room temperature for 2 h. The mixture was cooled to -78 °C and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane(110 mL, 0.52 mmol) was added dropwise by syringe. The mixture was stirred at -78 °C for 15 min. and at 0 °C for 3 h. The mixture was diluted with EtOAc and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel using EtOAc in hexanes gave the sub-title compound. LCMS calc. for CnH2oB 202 (M+H)+: m/z = 223.2; found: 223.0.
Step 2. 7-(l, 4-dimethyl-lH-pyrazol-5-yl)-4-pyridin-2-yl-4, 5-dihydroimidazo[ 1, 5, 4- dejf 1 ,4] benzoxazin-2( lH)-one
7-Bromo-4-pyridin-2-y 1-4,5 -dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one (28 mg, 0.084 mmol) was dissolved in 1, 4-dioxane (0.67 mL). l,4-Dimethyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (28 mg, 0.13 mmol) and potassium phosphate (40 mg, 0.2 mmol) in water (0.17 mL) was added. The reaction mixture was deoxygenated with nitrogen. Dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'- aminobiphenyl-2-yl)(chloro)palladium (1 : 1) (2 mg, 0.002 mmol) was added and the mixture was again deoxygenated with nitrogen. The reaction mixture was then stirred at 90 °C under nitrogen for 2 h. Product was purified using preparative LCMS (pH 10) to give the title compound. LCMS calc. for CigHn jOz (M+H)+: m/z = 348.1 ; found: 348.0.
Example 45
9-Bromo-7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2(lH)-one
Figure imgf000112_0001
The title compound was prepared by methods analogous to Example 36, but using 7-
(3 ,5 -dimethylisoxazol-4-yl)-4-phenyl-4,5 -dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 Η)- one. LCMS calc. for C2oH17Br 303 (M+H)+: m/z = 426.0; found: 426.0.
Example 46
7-(3,5-Dimethylisoxazol-4-yl)-9-methyl-4-phenyl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2(lH)-one
Figure imgf000112_0002
The title compound was prepared by methods analogous to Example 37, but using 9- bromo-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- i/e][l,4]benzoxazin-2(lH)-one. LCMS calc. for C2iH2o 303 (M+H)+: m/z = 362.1; found: 362.2.
Examples 47A-52
The experimental procedures used to prepare the compounds of Examples 47A to 52 are summarized in Table 1 below. Examples 47A and 47B and Examples 48A and 48B are pairs of diastereoisomers which were chromatographically separated by methods analogous to the separations described above.
I l l Table 1
Figure imgf000113_0001
Figure imgf000113_0002
Figure imgf000114_0001
Synthesized according to an experimental procedure analogous to that used for the synthesis of the Example compound indicated.
Examples 53-60
The experimental procedures used to prepare the compounds of Examples 53 to 61 are summarized in Table 2 below.
Table 2
Figure imgf000114_0002
Figure imgf000114_0003
Example
Name R5 Cy3 Procedure1 No.
l-[7-(3,5-Dimethylisoxazol-4-yl)-4-
57 phenyl-4,5-dihydroimidazo[l,5,4- Cr0H Ph 25 de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-ol
OH
l-[7-(3,5-Dimethylisoxazol-4-yl)-4-
58 phenyl-4,5-dihydroimidazo[l,5,4- Ph 25 de] [ 1 ,4]benzoxazin-2-yl]piperidin-3 -ol
l-[7-(3,5-Dimethylisoxazol-4-yl)-4-
59 phenyl-4,5-dihydroimidazo[l,5,4- r °H Ph 25 de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 -ol
4-[7-(3,5-Dimethylisoxazol-4-yl)-4-
60 phenyl-4,5-dihydroimidazo[l,5,4- Ph 25 de] [ 1 ,4]benzoxazin-2-yl]piperazine- 1 - carboxylate
Synthesized according to the experimental procedure of compound listed;
Example 61A
7-(3,5-Dimethylisoxazol-4-yl)-5,5-dimethyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2(lH)-one (Diastereoisomer 1)
Example 61B
7-(3,5-Dimethylisoxazol-4-yl)-5,5-dimethyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2(lH)-one (Dias
Figure imgf000115_0001
Step 1. 2-Bromo-2-methyl-l-(pyridin-2-yl)propan-l-
Figure imgf000115_0002
Bromine (2.1 g, 13.4 mmol) dissolved in acetic acid (1 mL) was added slowly to a mixture of 2-methyl-(l-pyridin-2-yl)propan-l-one (2.0 g, 13 mmol) in acetic acid (20 mL) at room temperature. The reaction was heated to 105 °C for 3 h, allowed to cool to room temperature, and concentrated in vacuo to give a dark semisolid. The crude product was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 2-bromo-2-methyl-l-(pyridin-2-yl)propan-l-one as a very dark oil (3.0 g, 98%). LCMS calculated for C9HuBrNO (M+H)+: m/z = 227.9, 229.9; found: 228.1, 230.1.
Step 2. 7-(3, 5-Dimethylisoxazol-4-yl)-5, 5-dimethyl-4-pyridin-2-yl-4, 5-dihydroimidazo[ 1, 5, 4- dejf l,4]benzoxazin-2(lH)-one
The title compound was prepared by methods analogous to Example 13, but using 2- bromo-2-methyl-l-(pyridin-2-yl)propan-l-one in Step 1. The product was purified by prep HPLC on a C- 18 column eluting a water: acetonitrile gradient buffered at pH 10 to give the title compound as a mixture of diastereomers. The isomers were separated by prep chiral column chromatography using the following conditions: Column: phenomenex Lux Cellulose C-2 5 μιη, 21, 2x250 mm, Mobile phase: 45% EtOH/Hexanes, gradient condition: isocratic at 18 mL/min, Loading: 13.0 mg in 900 μΕ, ηαη ίήηε: 18 min, peak time: 9.0, and 12.0 min.
Diastereoisomer 1, Peak 1 as a solid residue. LCMS calculated for C21H21 4O3
(M+H)+: m/z = 377.1; found: 377.1. 1H NMR (400 MHz, DMSO-i/6) δ 10.87 (s, 1H), 8.41 (dt, J = 4.0, 0.9 Hz, 1H), 7.74 (td, J = 7.7, 1.8 Hz, 1H), 7.27 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 5.24 (s, 1H), 2.27 (s, 3H), 2.1 1 (s, 3H), 1.36 (s, 3H), 1.1 1 (s, 3H).
Diastereoisomer, Peak 2 as a solid residue. LCMS calculated for C21H21 4O3
(M+H)+: m/z = 377.1; found: 377.1. 1H NMR (400 MHz, DMSO-i/6) δ 10.87 (s, 1H), 8.41 (dt, J = 4.0, 0.9 Hz, 1H), 7.74 (td, J = 7.7, 1.8 Hz, 1H), 7.27 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 5.24 (s, 1H), 2.27 (s, 3H), 2.1 1 (s, 3H), 1.36 (s, 3H), 1.1 1 (s, 3H).
Example 62A
7-(3,5-Dimethylisoxazol-4-yl)-5-(hydroxymethyl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-<fe] [l,4]benzoxazin-2(lH)-one (Diastereoisomer 1)
Example 62B
7-(3,5-Dimethylisoxazol-4-yl)-5-(hydroxymethyl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-<fe] [l,4]benzoxazin-2(lH)-one (Diastereoisomer 2)
Example 62C
7-(3,5-Dimethylisoxazol-4-yl)-5-(hydroxymethyl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-<fe] [l,4]benzoxazin-2(lH)-one (Diastereoisomer 3) Example 62D
7-(3,5-Dimethylisoxazol-4-yl)-5-(hydroxymethyl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-<fe] [l,4]benzoxa tereoisomer 4)
Figure imgf000117_0001
Lithium tetrahydroborate (1.6 mg, 0.071 mmol) was added to ethyl 7-(3,5- dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5-tetrahydroimidazo[l,5,4- ife][l,4]benzoxazine-5-carboxylate (20 mg, 0.05 mmol), from Example 20, in tetrahydrofuran (3 mL). The reaction was stirred at 70 °C for 3 h, then partitioned between water and ethyl acetate. The organic layer was concentrated and the crude product was purified by FCC on silica gel eluting a hexane:ethyl acetate gradient to obtain the product as a mixture of diastereomers. The isomers were separated by prep chiral column chromatography using the following conditions: Column: phenomenex Lux Cellulose C-2 5 μιη, 21, 2x250 mm, Mobile phase: 45% EtOH/Hexanes, Gradient condition: isocratic at 18 mL/min, Loading: 13.5 mg in 900 μί, run time: 18 min, peak time: 9.0, 12.1, 24.2 and 15.0 min.
Diastereoisomer 1, Peak 1 as a solid residue. LCMS calculated for C20H19 4O4 (M+H)+: m/z = 379.1; found: 379.1.
Diastereoisomer 2, Peak 2 as a solid residue. LCMS calculated for C20H19 4O4 (M+H)+: m/z = 379.1; found: 379.1. 'H NMR (400 MHz, DMSO-i/6) δ 10.93 (s, 1H), 8.47 (d, J = 4.1 Hz, 1H), 7.79 - 7.65 (m, 1H), 7.26 (dd, J = 7.0, 5.2 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.37 (d, J = 3.2 Hz, 1H), 5.22 (t, J = 5.4 Hz, 1H), 4.71 - 4.57 (m, 1H), 3.45 (q, J = 5.5 Hz, 2H), 2.17 (s, 3H), 2.01 (s, 3H).
Diastereoisomer 3, Peak 3 as a solid residue. LCMS calculated for C20H19N4O4 (M+H)+: m/z = 379.1; found: 379.1.
Diastereoisomer 4, Peak 4 as a solid residue. LCMS calculated for C20H19 4O4
(M+H)+: m/z = 379.1; found: 379.1. Example 63A
7-(3,5-Dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2(lH)-one 2,2,2-trifluoroacetate (Diastereoisomer 1)
Example 63B
7-(3,5-Dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2(lH)-one 2,2,2-t (Diastereoisomer 2)
Figure imgf000118_0001
Step 1. 4-Piperidin-2-yl-4, 5-dihydroimida -deJf 1 ,4]benzoxazin-2(lH)-one
Figure imgf000118_0002
The tricycle intermediate, 4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2(lH)-one (0.25 g, 0.98 mmol) from Example 13, was partially dissolved in methanol (50.0 mL) and 12.0 M hydrogen chloride in water (1.0 mL, 12 mmol) in a Parr bottle. The reaction was degassed with nitrogen, followed by addition of palladium (10% on carbon), and the reaction was charged to 55 PSI hydrogen and shaken for 6 days. The reaction was filtered to remove the catalyst and concentrated in vacuo to give 4-piperidin-2- yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one as a dark oil (0.21 g, 82%). LCMS calculated for Ci4H18 302 (M+H)+: m/z = 260.1; found: 260.1.
Step 2. 7-Bromo-4-piperidin-2-yl- -dihydroimidazo[ 1, 5, 4-deJf l,4]benzoxazin-2(lH)-one
Figure imgf000118_0003
The 4-piperidin-2-yl-4,5-dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2(17i)-one (0.20 g, 0.77 mmol) of Step 1 was dissolved in acetic acid (10.0 mL, 176 mmol) at room temperature and N-bromosuccinimide (0.14 g, 0.77 mmol) was slowly added. The reaction was stirred for 2 h and was concentrated in vacuo to give a residue. The residue was dissolved in ethyl acetate, washed with aqueous potassium carbonate, washed with brine, dried over magnesium sulfate, and concentrated to give 7-bromo-4-piperidin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one as a dark oil (0.22 g, 85%). LCMS calculated for Ci4H17Br 302 (M+H)+: m/z = 338.0, 340.0; found: 338.0, 340.0.
Step 3. 7-(3, 5-Dimethylisoxazol-4-yl)-4-piperidin-2-yl-4, 5-dihydroimidazo[ 1, 5, 4- dejf l,4]benzoxazin-2( lH)-one 2, 2, 2-trifluoroacetate
The 7-bromo-4-piperidin-2-yl-4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2(lH)- one (0.025 g, 0.074 mmol) of Step 2 was combined with (3,5-dimethylisoxazol-4-yl)boronic acid (0.016 g, 0.1 1 mmol) in 1,4-dioxane (3.0 mL) with potassium carbonate (0.02 g, 0.15 mmol) in water (0.38 mL) and was degassed with nitrogen. The cataylst [Ι, - bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1 : 1) (0.006 g, 0.007 mmol) was added and the reaction was heated in a sealed tube to 100
°C. After stirring for 2 h the reaction was allowed to cool to room temperature and was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give the crude product as a dark oil. The product was purified by prep HPLC on a C- 18 column eluting a water: acetonitrile gradient buffered at pH 2 with TFA to give 7-(3,5-dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5- dihydroimidazo[l,5,4-<ie][l,4]benzoxazin-2(lH)-one as two fractions.
Diastereoisomer 1, Peak 1 as a solid residue (0.008 g, 30%). LCMS calculated for Ci9H23 403 (M+H)+: m/z = 355.1; found: 355.1. 'H NMR (400 MHz, DMSO-i¾) δ 11.13 (d, J = 12.8 Hz, 1H), 8.78 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.79 (d, J = 12.3 Hz, 1H), 4.42 (dd, J = 8.7, 2.1 Hz, 1H), 4.02 (dd, J = 12.3, 2.8 Hz, 1H), 3.37 (s, 2H), 3.26 (d, J = 10.5 Hz, 2H), 2.84 (s, 1H), 2.28 (s, 3H), 2.12 (s, 3H), 2.01 (d, J = 13.3 Hz, 1H), 1.75 (d, J = 13.2 Hz, 1H), 1.64 - 1.52 (m, 1H), 1.47 (s, 1H).
Diastereoisomer 2, Peak 2 as a solid residue (0.007 g, 27%). LCMS calculated for Ci9H23N403 (M+H)+: m/z = 355.1; found: 355.1.
Example 69A
7-(3,5-Dimethylisoxazol-4-yl)-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2(lH)-one (Diastereoisomer 1)
Example 69B
7-(3,5-Dimethylisoxazol-4-yl)-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2(lH)-one (Dias
Figure imgf000120_0001
Step 1. 2-(2-Amino-3-nitrophenoxy)- -pyridin-3-ylethanone
Figure imgf000120_0002
2-Bromo-l-(pyridin-3-yl)ethanone hydrobromide (600 mg, 2 mmol) (HBr salt) was added to a mixture of 2-amino-3-nitrophenol (300 mg, 2 mmol) and potassium carbonate (400 mg, 3 mmol) in acetone (30 mL, 400 mmol) at room temperature. The reaction was stirred at room temperature for 18 h, was diluted with water, and was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 2-(2-amino-3-nitrophenoxy)-l-pyridin-3- ylethanone (0.35 g, 60%). LCMS calculated for Ci3H12 304 (M+H)+: m/z = 274.1; found:
274.1.
Step 2. 2-Nitro-6-[(2-pyridin-2-ylprop-2- -l-yl)oxy] aniline
Figure imgf000120_0003
Potassium tert-butoxide (1.10 g, 9.9 mmol) was added to a suspension of methyl triphenylphosphonium bromide (3.0 g, 8 mmol) in tetrahydrofuran (30 mL) under nitrogen. The reaction was stirred at room temperature for 1 h, followed by addition of 2-(2- amino-3-nitrophenoxy)-l-pyridin-2-ylethanone (2 g, 8 mmol). The mixture was stirred for 3 h, and was then partitioned between water and ethyl ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. The product was purified by FCC on silica gel eluting with a hexane:ethyl acetate gradient to give 2-nitro-6-[(2-pyridin-2-ylprop-2-en-l-yl)oxy]aniline as light brown solid (0.5 g, 20%). LCMS calculated for Ci4H14N303 (M+H)+: m/z = 272.1 ; found: 272.1.
Step 3. 2-{l-[(2-Azido-3-nitrophenoxy)methyl]vinyl}pyridine
Figure imgf000121_0001
Sodium nitrite (100 mg, 2 mmol) in water (4 mL, 60 mmol) was added to a solution of 2-nitro-6-[(2-pyridin-2-ylprop-2-en-l-yl)oxy]aniline (350 mg, 1.3 mmol) in 4.0 M hydrogen chloride in water (4 mL, 10 mmol) at 0°C. The reaction was stirred for 5 min and was then neutralized to pH 6-7 with solid sodium bicarbonate. Sodium azide (80 mg, 1 mmol) in water (2 mL) was added drop-wise to the mixture, followed by stirring for 30 min, over which time the reaction mixture became a thick slurry. The resulting mixture was filtered and dried to give 2-{ l-[(2-azido-3-nitrophenoxy)methyl]vinyl}pyridine as a dark yellow solid (0.25 g. 83%). LCMS calculated for Ci4H12N503 (M+H)+: m/z = 298.1; found: 298.1
Step 4. 7-Nitro-la-pyridin-2-yl-la,2- ireno[2,l-c] [l,4]benzoxazine
Figure imgf000121_0002
A mixture of 2- { l-[(2-azido-3-nitrophenoxy)methyl]vinyl}pyridine (250 mg, 0.84 mmol) in benzene (15 mL) was refluxed at 80 °C for 15 h. The reaction was concentrated to give the crude product. The product was purified by FCC on silica gel eluting with a hexane:ethyl acetate gradient to give 7-nitro-la-pyridin-2-yl-la,2-dihydro-lH-azireno[2,l- c][l,4]benzoxazine as a solid (0.225 g, 90%). LCMS calculated for Ci4H12N303 (M+H)+: m/z = 270.1 ; found: 270.1. Step 5. 3-Methyl-3-pyridin-2-yl-3, 4- -benzoxazin-5-amine
Figure imgf000122_0001
A mixture of 7-nitro- 1 a-pyridin-2-yl- 1 a,2-dihydro- 1 H-azireno[2, 1 -c] [ 1 ,4]benzoxazine (100 mg, 0.4 mmol) in methanol (6 mL) and tetrahydrofuran (2 mL) was degassed with nitrogen in a Parr bottle followed by addition of palladium (10% on carbon) (30 mg, 0.28 mmol). The reaction was charged with hydrogen to 40 psi and shaken for 6 hrs. The reaction was filtered and concentrated to give crude 3-methyl-3-pyridin-2-yl-3,4-dihydro-2H-l,4- benzoxazin-5 -amine (0.030 g. 30%). LCMS calculated for Ci4Hi6N30 (M+H)+: m/z = 242.1; found: 242.1.
Step 6. 4-Methyl-4-pyridin-2-yl-4, 5- , 5, 4-deJf 1 ,4] benzoxazin-2( lH)-one
Figure imgf000122_0002
Triphosgene (40 mg, 0.1 mmol) was added to the solution of 3-methyl-3-pyridin-2-yl- 3,4-dihydro-2H-l,4-benzoxazin-5-amine (90 mg, 0.4 mmol) in tetrahydrofuran (10 mL) and N,N-diisopropylethylamine (100 \L) at room temperature. The reaction was stirred for 1 h and was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 4-methyl- 4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2(lH)-one as a semisolid (0.10 g. 90%). LCMS calculated for Ci5H14N302 (M+H)+: m/z = 268.1; found: 268.0.
Step 7. 7-Bromo-4-methyl-4-pyridin-2-yl-4, 5-dihydroimidazo[ 1, 5, 4-deJ '[ 1, 4 Jbenzoxazin- 2(lH)-one
Figure imgf000122_0003
N-Bromosuccinimide (60 mg, 0.3 mmol) was added to a solution of 4-methyl-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-(ie][l,4]benzoxazin-2(lH)-one (90 mg, 0.3 mmol), acetic acid (6 mL) and acetonitrile (6 mL) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C, quenched with water, and was concentrated to give the crude product. The crude product was dissolved in ethyl acetate and washed with saturated aqueous sodium
bicarbonate. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give a dark oil. The product was purified by FCC on silica gel eluting a hexane: ethyl acetate gradient containing 20% ethanol to give 7-bromo-4- methyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2(lH)-one as an off white solid (0.090 g. 80%). LCMS calculated for Ci5H13Br 302 (M+H)+: m/z = 346.1, 348.1; found: 345.9,347.9.
Step 8. 7-(3, 5-Dimethylisoxazol-4-yl)-4-methyl-4-pyridin-2-yl-4, 5-dihydroimidazo[ 1, 5, 4- dejf l,4]benzoxazin-2(lH)-one
7-Bromo-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-(ie][l,4]benzoxazin- 2(lH)-one (80 mg, 0.2 mmol) was combined in 1,4-dioxane (10 mL) with potassium (3,5- dimethylisoxazol-4-yl)(trifluoro)borate (0.070 g, 0.35 mmol) and potassium carbonate (60 mg, 0.5 mmol) in water (5 mL), and was degassed with nitrogen. The catalyst [Ι, Γ- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1 : 1) (30 mg, 0.04 mmol) was added and the reaction was stirred at 80 °C for 4 h, at which time reaction mixture was allowed to cool to room temperature and was partitioned between water and ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to give the crude product. The product was purified by FCC on silica gel eluting a hexane:ethyl acetate gradient containing 20% ethanol to give 7- (3,5-dimethylisoxazol-4-yl)-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- ife][l,4]benzoxazin-2(lH)-one as a clear oil. The enantiomers were separated on chiral column using the following conditions: Phenomenex Lux Cellulose C-4, 5 μιη, 21x2x250 mm; mobile phase: 45% ethanol in Hexanes gradient: 18 mL/min isocratic; Run time: 11 min; Loading: 4 mg in 900 μί; Peak time: 7.1 & 8.8 min.
Diastereoisomer 1, Peak 1, as a white amorphous solid (0.010 g. 10%). LCMS calculated for C20H19N4O3 (M+H)+: m/z = 363.1; found: 363.1. ¾ NMR (500 MHz, DMSO- d6) δ 1 1.02 (s, 1H), 8.55 (d, J = 4.5 Hz, 1H), 7.83 - 7.69 (m, 1H), 7.29 (dd, J = 7.3, 4.9 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 4.79 (d, J = 11.1 Hz, 1H), 4.19 (d, J = 11.1 Hz, 1H), 2.17 (s, 3H), 1.99 (s, 3H), 1.95 (s, 3H).
Diastereoisomer 2, Peak 2, as a white amorphous solid (0.010 g. 10%). LCMS calculated for C2oH19 403 (M+H)+: m/z = 363.1; found: 363.1.
Example 70
7-(3,5-Dimethylisoxazol-4-yl)-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2(lH)-one 2,2,2-t
Figure imgf000124_0001
Figure imgf000124_0002
The mixture of 5-nitro-3-pyridin-2-yl-2H-l,4-benzoxazine and 5-nitro-3-pyridin-2- yl-3,4-dihydro-2H-l,4-benzoxazin-3-ol (intermediate, Example 13) (200 mg, 0.7 mmol) was dissolved in acetonitrile (0.2 mL) and acetic acid (0.8 mL) at room temperature and stirred for 10 min. The reaction was diluted with acetonitrile (15 mL) and concentrated at room temperature to remove residual acetic acid to give 5-nitro-3-pyridin-2-yl-2H-l,4-benzoxazine as a light green solid (0.20 g. 100%). LCMS calculated for Ci3H10 3O3 (M+H)+: m/z = 256.1; found: 255.9.
Step 2. 3-Ethyl-5-nitro-3-pyridin-2-yl- -dihydro-2H-l, 4-benzoxazine
Figure imgf000124_0003
0.5 M Ethyl lithium in benzene-cyclohexane (1.8 mL, 0.88 mmol) was added drop- wise to a solution of 5-nitro-3-pyridin-2-yl-2H-l, 4-benzoxazine (0.025 g, 0.88 mmol) in tetrahydrofuran (4 mL), cooled to -78 °C. The reaction was stirred for 1 h at -78 °C and was then quenched with methanol. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude product. The product was purified by FCC on silica gel eluting a hexane:ethyl acetate gradient to give 3-ethyl-5-nitro-3-pyridin-2-yl-3,4-dihydro- 2H-l,4-benzoxazine as a solid (0.021 g. 84%). LCMS calculated for Ci5Hi6 303 (M+H)+: m/z = 286.1; found: 286.0.
Step 3. 3-EthyI-3-pyridin-2-yI-3, 4- -5 -amine
Figure imgf000125_0001
3-Ethyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-l,4-benzoxazine (10 mg, 0.3 mmol) was dissolved in methanol (10 mL) in a Parr bottle, degassed with nitrogen, and
palladium (10% on carbon) (10 mg) was added. The reaction vessel was pressurized to 50 PSI with hydrogen and shaken for 2 h. The reaction mixture was filtered and concentrated to give crude 3-ethyl-3-pyridin-2-yl-3,4-dihydro-2H-l,4-benzoxazin-5-amine (0.005 g, 40%). LCMS calculated for Ci5Hi8N30 (M+H)+: m/z = 256.1; found: 256.0. Step 4. 4-Ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[l ,5,4-de] ' [1 ,4]benzoxazin-2(lH)-one
Figure imgf000125_0002
Triphosgene (40 mg, 0.1 mmol) was added to a solution of 3-ethyl-3-pyridin-2-yl-3,4- dihydro-2H- 1 ,4-benzoxazin-5 -amine (80 mg, 0.3 mmol) in tetrahydrofuran (5 mL) and N,N- diisopropylethylamine (0.1 mL). The reaction was stirred at room temperature for 1 h and was then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 4-ethyl-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2(lH)-one (0.060 g. 60%).
LCMS calculated for Ci6H16N302 (M+H)+: m/z = 282.1; found: 282.0. Step 5. 7-Bromo-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de] [l,4]benzoxazin- 2(lH)-one
Figure imgf000126_0001
N-Bromosuccinimide (70 mg, 0.4 mmol) was added to a solution of 4-ethyl-4-pyridin- 2-yl-4,5-dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2(lH)-one (80 mg, 0.4 mmol) in acetonitrile (5 mL) and acetic acid (10 mL) cooled to 0 °C. The reaction was stirred for 30 min, was concentrated to remove residual acetic acid, and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 7- bromo-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2(17i)-one (0.07 g. 80%). LCMS calculated for Ci6H15Br 302 (M+H)+: m/z = 360.1, 362.1; found: 359.8, 361.8.
Step 6. 7-(3, 5-Dimethylisoxazol-4-yl)-4-ethyl-4-pyridin-2-yl-4, 5-dihydroimidazof 1, 5, 4- dejf l,4]benzoxazin-2( lH)-one 2, 2, 2-trifluoroacetate
7-Bromo-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2(lH)- one (50 mg, 0.1 mmol) was combined in 1,4-dioxane (6 mL) with potassium (3,5- dimethylisoxazol-4-yl)(trifluoro)borate (42 mg, 0.21 mmol) and potassium carbonate (40 mg, 0.3 mmol) in water (3 mL) and was degassed with nitrogen. The catalyst [Ι,Γ- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1 : 1) (20 mg, 0.02 mmol) was added and the mixture was stirred at 100 °C for 18 h. The reaction mixture was allowed to cool to room temperature and was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give the crude product. The product was purified on prep HPLC using a C-18 column eluting a water: acetonitrile gradient buffered to pH 2 with TFA to give 7-(3,5- dimethylisoxazol-4-yl)-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-(ie][l,4]benzoxazin- 2(lH)-one as a white solid (0.005 g, 10%). LCMS calculated for C2iH21 403 (M+H)+: m/z = 377.1; found: 377.0. 'H NMR (400 MHz, DMSO-i/6) δ 11.01 (s, 1H), 8.58 - 8.47 (m, 1H), 7.75 (td, J = 7.7, 1.8 Hz, 1H), 7.28 (dd, J = 6.6, 4.8 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 4.84 (d, J = 11.2 Hz, 1H), 4.29 (d, J = 11.2 Hz, 1H), 2.71 - 2.51 (m, 1H), 2.37 - 2.21 (m, 1H), 2.16 (s, 3H), 1.98 (s, 3H), 0.98 (t, J = 7.4 Hz, 3H). Example 71
7-(3,5-Dimethylisoxazol-4-yl)-N-methyl-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[l,5,4-rfe] [l,4 e 2,2,2-trifluoroacetate
Step 1. 5-Nitro-3-pyridin-2-yl-3, 4 e-3-carbonitrile
Figure imgf000127_0001
Potassium cyanide (500 mg, 7 mmol) was added to a solution of 5-nitro-3-pyridin-2- yl-2H- 1 ,4-benzoxazine (1 g, 4 mmol) (Example 70, Step 1), in acetonitrile (20 mL), and was stirred overnight at room temperature. The reaction was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. The product was crystallized from methylene chloride to give 5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-l,4-benzoxazine-3- carbonitrile as a dark yellow powder (0.60 g. 60%). LCMS calculated for C 4H11 4O3 (M+H)+: m/z = 283.1; found: 282.9
Step 2. 5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-l,4-benzoxazine-3-carboxylic acid
Figure imgf000127_0002
5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-l,4-benzoxazine-3-carbonitrile (80 mg, 0.3 mmol) was dissolved in concentrated hydrochloric acid (3 mL, 100 mmol) and heated to 100 °C for 2 h. The reaction was allowed to cool to room temperature, diluted with water, and the pH was adjusted to pH 7 with sodium bicarbonate. The neutralized solution was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to give crude 5-nitro-3-pyridin-2-yl-3,4-dihydro- 2H-l,4-benzoxazine-3-carboxylic acid as a solid (0.025 g. 30%). LCMS calculated for Ci4H12N305(M+H)+: m/z = 302.1 ; found: 301.9. Step 3. N-Methyl-5-nitro-3-pyridin-2- -3,4-dihydro-2H-l,4-benzoxazine-3-carboxamide
Figure imgf000128_0001
5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-l,4-benzoxazine-3-carboxylic acid (0.044 g. 0.15 mmol) in N,N-dimethylformamide (3 mL) was combined with N,N,N',N'-tetramethyl-0- (7-azabenzotriazol-l-yl)uronium hexafluorophosphate [Oakwood #: 023926] (160 mg, 0.42 mmol) and N,N-diisopropylethylamine (100 \L, 0.6 mmol) at room temperature. 3.0 M methylamine in ethanol (0.2 mL, 0.6 mmol) was added, and the resulting mixture was stirred for 1 h, at which time the mixture was partitioned between water and ethyl acetate. The organic layer was washed with 1 Ν HC1, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude N-methyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-l,4- benzoxazine-3-carboxamide solid (0.020 g. 30%). LCMS calculated for Ci5Hi5N404 (M+H)+: m/z = 315.1; found: 315.0 .
Step 4. 5-Amino-N-methyl-3-pyridin-2- -3, 4-dihydro-2H-l, 4-benzoxazine-3-carboxamide
Figure imgf000128_0002
N-Methyl-5-nitro-3 -pyridin-2-yl-3 ,4-dihydro-2H- 1 ,4-benzoxazine-3 -carboxamide (25 mg, 0.080 mmol) was dissolved in methanol (5 mL) in a Parr bottle and degassed with nitrogen, followed by addition of palladium (10% on carbon) (5 mg, 0.05 mmol). The reaction vessel was charged to 50 PSI hydrogen and shaken for 2 h. The reaction mixture was filtered and concentrated in vacuo to give crude 5-amino-N-methyl-3-pyridin-2-yl-3,4- dihydro-2H-l,4-benzoxazine-3 -carboxamide (0.005 g. 100%). LCMS calculated for Ci5H17N402 (M+H)+: m/z = 285.1; found: 285.0 .
Step 5. N-Methyl-2-oxo-4-pyridin-2-yl-l, 2, 4, 5-tetrahydroimidazo[ 1, 5, 4- dejf 1, 4 ] benzoxazine-4-carboxamide
Figure imgf000129_0001
Triphosgene (10 mg, 0.04 mmol) was added to a solution of 5-amino-N-methyl-3- pyridin-2-yl-3,4-dihydro-2H-l,4-benzoxazine-3-carboxamide (30 mg, 0.1 mmol) in tetrahydrofuran (3 mL) and N,N-diisopropylethylamine (40 \L, 0.2 mmol) at room temperature and was stirred for 1 h. The reaction mixture was then partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give crude N-methyl-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[l,5,4-de][l,4]benzoxazine-4-carboxamide as a semisolid (0.031 g, 100%). LCMS calculated for Ci6H15N403 (M+H)+: m/z = 311.1 ; found: 311.1.
Step 6. 7-Bromo-N-methyl-2-oxo-4-pyridin-2-yl- 1 , 2, 4, 5-tetrahydroimidazof 1, 5, 4- dejf 1, 4 ] benzoxazine-4-carboxamide
Figure imgf000129_0002
N-Methyl-2-oxo-4-pyridin-2-yl- 1 ,2,4,5-tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine-
4-carboxamide (20 mg, 0.1 mmol) was dissolved in acetonitrile (3 mL) and acetic acid (2 mL), and cooled to 0 °C, followed by addition of N-bromosuccinimide (20 mg, 0.1 mmol). The reaction mixture was stirred for 1 h and was then concentrated to give a crude residue. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 7-bromo-N-methyl-2-oxo-4-pyridin-2-yl-l,2,4,5-tetrahydroimidazo[l,5,4- ife][l,4]benzoxazine-4-carboxamide (0.020 g, 50%). LCMS calculated for Ci6Hi4BrN403 (M+H)+: m/z = 389.1, 391.1 ; found: 388.9, 390.9. Step 7. 7-(3,5-Dimethylisoxazol-4-yl)-N-methyl-2-oxo-4-pyridin-2-yl-l, 2,4,5- tetrahydroimidazof 1, 5, 4-de][ 1, 4 ] benzoxazine-4-carboxamide 2, 2, 2-trifluoroacetate
7-Bromo-N-methyl-2-oxo-4-pyridin-2-yl- l,2,4,5-tetrahydroimidazo[ 1 ,5,4- i/e][l,4]benzoxazine-4-carboxamide (20 mg, 0.05 mmol) was combined with 1,4-dioxane (2 mL), potassium (3,5-dimethylisoxazol-4-yl)(trifluoro)borate (16 mg, 0.077 mmol) and potassium carbonate (10 mg, 0.1 mmol) in water (1 mL, 60 mmol) and was degassed with nitrogen. The catalyst [l, l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1 : 1) (7 mg, 0.008 mmol) was added, and the reaction mixture was stirred at 110 °C for 5 h. The reaction mixture was allowed to cool to room temperature and was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and was concentrated to give crude product. The product was purified on prep HPLC on a C- 18 column eluting a water: acetonitrile gradient buffered at pH 2 with TFA to give 7-(3,5-dimethylisoxazol-4-yl)-N-methyl-2-oxo-4-pyridin- 2-yl-l,2,4,5-tetrahydroimidazo[l,5,4-de][l,4]benzoxazine-4-carboxamide as an off white solid (0.007 g, 30%). LCMS calculated for C21H20N5O4 (M+H)+: m/z = 406.1; found: 405.9. 1H NMR (400 MHz, DMSO-i¾) δ 11.03 (s, 1H), 8.57 - 8.45 (m, 1H), 8.19 (d, J = 4.7 Hz, 1H), 7.82 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.36 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 4.73 (s, 2H), 2.72 - 2.60 (m, 3H), 2.22 (s, 3H), 2.04 (s, 3H).
Example 72
N-{[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5-tetrahydroimidazo[l,5,4- de\ [l,4]benzoxazin-4-yl]methyl}acetamide 2,2,2-trifluoroacetate
Step 1. l-(5-Nitro-3-pyridin-2-yl-3, 4- -3-yl)methanamine
Figure imgf000130_0001
1.0 M Diisobutylaluminum hydride in toluene (200 \L, 0.2 mmol) was added drop- wise to a solution of 5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-l,4-benzoxazine-3-carbonitrile (50 mg, 0.2 mmol) (Example 71, Step 1), in toluene (5 mL) at room temperature. The reaction mixture was stirred for 10 min, then quenched with methanol. The resulting mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and
concentrated to give crude l-(5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-l,4-benzoxazin-3- yl)methanamine solid (0.05 g. 100%). LCMS calculated for C 4H15 4O3 (M+H)+: m/z = 287.1; found: 287.1.
Step 2. N-f ( 5-Nitro-3-pyridin-2-yl-3, 4-dihydro-2H-l, 4-benzoxazin-3-yl)methyl]acetamide
Figure imgf000131_0001
Acetyl chloride (15 \L, 0.21 mmol) was added to a mixture of l-(5-nitro-3-pyridin-2- yl-3,4-dihydro-2H-l,4-benzoxazin-3-yl)methanamine (50 mg, 0.2 mmol) in methylene chloride (3 mL), N,N-diisopropylethylamine (60 μΚ) and was stirred at room temperature for 1 h. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude N-[(5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-l,4-benzoxazin-3-yl)methyl]acetamide (0.040 g. 70%). LCMS calculated for Ci6H17 404 (M+H)+: m/z = 329.1 ; found: 329.0
N-[(5-Amino-3-pyridin-2-yl-3, 4-dihydro-2H-l, 4-benzoxazin-3-yl)methyl]acetamide
Figure imgf000131_0002
N-[(5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-l,4-benzoxazin-3-yl)methyl]acetamide (0.040 g. 0.122mmol) was dissolved in ethanol (5 mL) in a Parr bottle and degassed with nitrogen, followed by addition of palladium (10% on carbon) (10 mg, 0.09
mmol) catalyst. The reaction vessel was charged to 50 PSI with hydrogen, and shaken for 2 h. The mixture was then filtered and concentrated to give crude N-[(5-amino-3-pyridin-2-yl- 3,4-dihydro-2H-l,4-benzoxazin-3-yl)methyl]acetamide (0.040 g, 80%). LCMS calculated for Ci6H19N402 (M+H)+: m/z = 299.1; found: 299.0. Step 4. N-[ ( 2-Oxo-4-pyridin-2-yl-l , 2, 4, 5-tetrahydroimidazof 1, 5, 4-deJf 1, 4 ] benzoxazin-4- yl)methyl] acetamide
Figure imgf000132_0001
Triphosgene (20 mg, 0.07 mmol) was added to a mixture of N-[(5-amino-3-pyridin-2- yl-3,4-dihydro-2H-l,4-benzoxazin-3-yl)methyl]acetamide (50 mg, 0.2 mmol),
tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (60 \L) at room temperature. The reaction was stirred for 1 h then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude N- [(2-oxo-4-pyridin-2-yl- 1 ,2,4,5 -tetrahydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-4- yl)methyl] acetamide (0.040 g. 70%). LCMS calculated for Οι7Η17Ν403 (M+H)+: m/z = 325.1; found: 325.1.
Step 5. N-f (7-Bromo-2-oxo-4-pyridin-2-yl-l, 2, 4, 5-tetrahydroimidazo[ 1,5,4- de] [1,4] benzoxazin-4-yl)methyl] acetamide
Figure imgf000132_0002
N-Bromosuccinimide (40 mg, 0.2 mmol) was added to a mixture of N-[(2-oxo-4- pyridin-2-yl-l,2,4,5-tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazin-4-yl)methyl]acetamide in acetonitrile (5 mL) and acetic acid (3 mL), and cooled to 0 °C. The reaction was stirred for 1 h, concentrated to remove residual acetic acid, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude N-[(7-bromo-2-oxo-4-pyridin-2- yl- 1 ,2,4,5-tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-4-yl)methyl]acetamide (0.040 g. 60%). LCMS calculated for Ci7H16BrN403 (M+H)+: m/z = 403.1, 405.1 ; found: 402.9, 405.0. Step 6. N-{[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyndin-2-yl-l, 2,4,5- tetrahydroimidazof 1, 5, 4-de][ 1, 4] benzoxazin-4-yl] methyl jacetamide 2,2, 2-trifluoroacetate
N-[(7-Bromo-2-oxo-4-pyridin-2-yl-l,2,4,5-tetrahydroimidazo[ 1,5,4- i/e][l,4]benzoxazin-4-yl)methyl]acetamide (20 mg, 0.05 mmol) was combined in 1,4-dioxane (2 mL) with potassium (3,5-dimethylisoxazol-4-yl)(trifluoro)borate (16 mg, 0.077 mmol) and potassium carbonate (10 mg, 0.1 mmol) in water (1 mL) and was degassed with
nitrogen. The catalyst [l, l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1 : 1) (7 mg, 0.008 mmol) was added and the reaction was stirred at 110 °C for 5 h. The reaction mixture was allowed to cool to room temperature, at which time it was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and was concentrated to give crude product. The product was purified by prep HPLC on a C- 18 column eluting a water: acetonitrile gradient buffered at pH 2 with TFA to give N-{[7-(3, 5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l, 2,4,5- tetrahydroimidazo[l,5,4-de][l,4]benzoxazin-4-yl]methyl}acetamide as an off white solid (0.010 g, 50%). LCMS calculated for C22H22N504 (M+H)+: m/z = 420.1 ; found: 420.1.
Example 73
4-(Aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2(lH)-one bis(2,2 -trifluoroacetate)
Figure imgf000133_0001
N- {[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazin-4-yl]methyl}acetamide (10 mg, 0.02 mmol) was dissolved in tetrahydrofuran (1 mL) and concentrated hydrochloric acid (200 \L, 6 mmol) in water (800 \L). The reaction was heated to 100 °C for 4 h and was then purified without workup by prep HPLC on a C- 18 column eluting a water: acetonitrile gradient buffered at pH 2 with TFA to give 4-(aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one as off white solid (0.0045 g, 40%). LCMS calculated for C2oH2o 503 (M+H)+: m/z = 378.1; found: 378.1. XH NMR (400 MHz, DMSO-i¾) δ 11.40 (s, 1H), 8.68 - 8.58 (m, 1H), 8.20 (bs, 2H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.48 - 7.37 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.73 (d, 1H), 4.41 (d, 1H), 4.12 - 3.97 (m, 1H), 3.75 - 3.58 (m, 1H), 2.18 (s, 3H), 2.00 (s, 3H).
Example 74
7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5-tetrahydroimidazo[l,5,4- de\ [l,4]benzoxazine-4-carboxamide -trifluoroacetate
Step 1. 5-Nitro-3-pyridin-2-yl-3, 4 e-3-carboxamide
Figure imgf000134_0001
5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-l,4-benzoxazine-3-carbonitrile (100 mg, 0.4 mmol) was added to a vigorously stirring mixture of aluminum oxide (100 mg, 1 mmol) and methanesulfonic acid (2 mL, 30 mmol) at room temperature. The reaction mixture was then heated to 120 °C for 20 min, allowed to cool to room temperature, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude product. The product was purified by FCC on silica gel eluting a hexane:ethyl acetate gradient to give 5-nitro-3-pyridin-2-yl-3,4-dihydro- 2H-l,4-benzoxazine-3-carboxamide as clear oil (0.040 g. 40%). LCMS calculated for
Ci4H13 404 (M+H)+: m/z = 301.1; found: 301.1. Step 2. 5-Amino-3-pyridin-2-yl-3,4-dihydro-2H-l,4-benzoxazine-3-carboxamide
Figure imgf000134_0002
5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-l,4-benzoxazine-3-carboxamide (0.040 g, 0.13 mmol) was dissolved in methanol (5 mL) in a Parr bottle and degassed with nitrogen, followed by addition of palladium (10% on carbon) (20 mg, 0.2 mmol). The reaction vessel was charged to 50 PSI with hydrogen and shaken for 2 h. The reaction mixture was then filtered and concentrated to give crude 5-amino-3-pyridin-2-yl-3,4-dihydro-2H-l,4- benzoxazine-3-carboxamide as a glass (0.040 g. 100%). LCMS calculated for C14H15 4O2 (M+H)+: m/z = 271.1 ; found: 271.1.
Step 3. 2-Oxo-4-pyridin-2-yl-l , 2, 4, 5-tetrahydroimidazo[ 1, 5, 4-de][ 1, 4 ] benzoxazine-4- carboxamide
Figure imgf000135_0001
Triphosgene (20 mg, 0.07 mmol) was added to a solution of 5-amino-3-pyridin-2-yl- 3,4-dihydro-2H-l,4-benzoxazine-3-carboxamide (40 mg, 0.2 mmol) in tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (60 \L, 0.3 mmol) at room temperature. The reaction was stirred for 1 h and then partitioned between ethyl acetate and water. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and
concentrated to give crude 2-oxo-4-pyridin-2-yl-l,2,4,5-tetrahydroimidazo[l,5,4- ife][l,4]benzoxazine-4-carboxamide (0.040 g. 80%). LCMS calculated for C15H13 4O3 (M+H)+: m/z = 297.1; found: 297.1.
Step 4. 7-Bromo-2-oxo-4-pyridin-2-yl-l , 2, 4, 5-tetrahydroimidazof 1, 5, 4-deJf 1, 4 ]benzoxazine- 4-carboxamide
Figure imgf000135_0002
N-Bromosuccinimide (40 mg, 0.2 mmol) was added to a solution of 2-oxo-4-pyridin- 2-yl- 1 ,2,4,5-tetrahydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazine-4-carboxamide, acetonitrile (5 mL) and acetic acid (3 mL) and cooled to 0 °C. The reaction mixture was stirred for 1 h and then concentrated to remove residual acetic acid. The resulting residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 7- bromo-2-oxo-4-pyridin-2-yl-l,2,4,5-tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazine-4- carboxamide (0.040 g. 60%). LCMS calculated for Ci5H12BrN403 (M+H) : m/z = 375.1, 377.1 ; found: 375.0, 376.9.
Step 5. 7-(3, 5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l, 2, 4, 5-tetrahydroimidazof 1, 5, 4- dejf 1, 4 ] benzoxazine-4-carboxamide 2, 2, 2-trifluoroacetate
7-Bromo-2-oxo-4-pyridin-2-yl- 1 ,2,4,5 -tetrahydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazine- 4-carboxamide (20 mg, 0.05 mmol) was combined in 1,4-dioxane (2 mL) with potassium (3,5-dimethylisoxazol-4-yl)(trifluoro)borate (16 mg, 0.077 mmol) and potassium carbonate (10 mg, 0.1 mmol) in water (1 mL) was degassed with nitrogen. The catalyst [Ι, - bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1 : 1) (7 mg, 0.008 mmol) was added and degassed with nitrogen. The reaction was stirred at 110 °C for 5 h, allowed to cool to room temperature, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give crude product. The product was purified by prep HPLC on a C- 18 column eluting a water: acetonitrile gradient buffered to pH 2 to give 7-(3,5-dimethylisoxazol- 4-yl)-2-oxo-4-pyridin-2-yl- 1 ,2,4,5 -tetrahydroimidazo [ l,5,4-de] [ 1 ,4]benzoxazine-4- carboxamide as an off white solid (0.010 g. 50%). LCMS calculated for C2oHi8N504 (M+H)+: m/z = 392.1; found: 392.1. 'H NMR (400 MHz, DMSO-i¾) δ 1 1.04 (s, 1H), 8.56 - 8.48 (m, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.78 - 7.70 (m, 2H), 7.52 (d, J = 8.1 Hz, 1H), 7.42 - 7.32 (m, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 4.76 (d, J = 1 1.2 Hz, 1H), 4.71 (d, 1H), 2.23 (s, 3H), 2.05 (s, 3H).
Example 79
7-(3,5-dimethylisoxazol-4-yl)-4-[l-(methylsulfonyl)piperidin-2-yl]-4,5- dihydroimidazo[l,5,4-de] [l,4]benzo
Figure imgf000136_0001
The amine 7-(3,5-dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5-dihydroimidazo[l,5,4- ife][l,4]benzoxazin-2(lH)-one (0.05 g, 0.14 mmol) (Example 63) was dissolved in methylene chloride (2.0 mL) and N,N-diisopropylethylamine (0.049 mL, 0.28 mmol) at rt under nitrogen. Methanesulfonyl chloride (0.010 mL, 0.14 mmol) was added and the reaction was stirred at rt. After stirring for 1 h, the reaction was dissolved in ethyl acetate and washed with water, brine, dried over magnesium sulfate and concentrated to give crude product as a dark oil. The product was purified by prep HPLC on a C- 18 column eluting water : acetonitrile gradient buffered pH 2 with TFA to give 7-(3,5-dimethylisoxazol-4-yl)-4-[l-
(methylsulfonyl)piperidin-2-yl]-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one as two fractions:
Example 79, Peak 1 as a solid residue (0.015 g, 26%). LCMS calculated for C20H25 4O5S (M+H)+: m/z = 433.1; found: 433.2. 'H NMR (400 MHz, DMSO-i¾) δ 10.69 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 4.89 - 4.65 (m, 3H), 4.4-3.9 (m, 2H), 3.62 (m, 1H), 2.28 (s, 3H), 2.11 (s, 3H), 1.96 (m, 1H), 1.82 (s, 3H), 1.73 - 1.51 (m, 3H), 1.41 (m, 1H), 1.1 (m, lH).
Example 79, Peak 2 as a solid residue (0.010 g, 18%). LCMS calculated for C2oH25 404S (M+H)+: m/z = 433.1; found: 433.2.
Examples 75-87
The experimental procedures used to prepare the compounds of Examples 75 to 87 are summarized in Table 3 below.
Table 3
Figure imgf000137_0001
Figure imgf000137_0002
Figure imgf000138_0001
Ex.
Name R1 R7 Cy' Salt Proc* No.
(4S)-7-(3,5-dimethylisoxazol-
4-yl)-4-pyridin-2-yl-9-
84 pyrimidin-5-yl-4,5- H TFA 43 dihydroimidazo [1,5,4- ^ N
de] [ 1 ,4]benzoxazin-2( 1 H)-one
2,2,2-trifluoroacetate
(4S)-7-(3,5-dimethylisoxazol-
4- yl)-9-( 1 -methyl- 1 H-pyrazol-
85 5- yl)-4-pyridin-2-yl-4,5- H TFA 43 dihydroimidazo [1,5,4- ^ N
de] [ 1 ,4]benzoxazin-2( 1 H)-one
2,2,2-trifluoroacetate
ethyl (2E)-3-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-2-oxo- 4-pyridin-2-yl-l,2,4,5- o
86 tetrahy droimidazo [1,5,4- H TFA 43 de] [ 1 ,4]benzoxazin-9- ^ N
yljacrylate 2,2,2- trifluoroacetate
(4S)-7-(3,5-dimethylisoxazol-
4-yl)-4-pyridin-2-yl-9-
87 ( 1 ,2,3 ,6-tetrahydropyridin-4- H TFA 43 yl)-4,5 -dihydroimidazo [1,5,4- ^
de] [ 1 ,4]benzoxazin-2( 1 H)-one 0 2
N
bis(2,2,2-trifluoroacetate)
Synthesized according to the experimental procedure of Example number isted.
Example 88
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-vinyl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazine
Figure imgf000139_0001
(45")-2-Chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-i/e][l,4]benzoxazine (277 mg, 0.755 mmol), 4,4,5, 5-tetramethyl-2- vinyl-l,3,2-dioxaborolane (0.19 mL, 1.1 mmol) [Aldrich, cat. # 633348], and potassium phosphate (0.3 g, 2 mmol) [Aldrich, cat. # P5629], were dissolved in water (2.4 mL) and 1,4- dioxane (10 mL). The reaction mixture was deoxygenated with nitrogen and
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2- yl)(chloro)palladium (1 : 1) (0.03 g, 0.04 mmol) [Aldrich, cat. # 741825] was added. The resulting mixture was deoxygenated with nitrogen and heated at 80 °C for 3 h. The reaction mixture was then allowed to cool to room temperature. Ethyl acetate was added, and the mixture was washed with water and brine, then dried over sodium sulfate and concentrated. The resulting residue was purified by flash chromatography eluting ethyl acetate in hexanes (75-100%, ethyl acetate containing 20% MeOH) to afford the desired product (0.21 g, 78%). LCMS for C2iH1902 4 (M+H)+: calculated m/z = 359.2; found 359.3; XH NMR (400 MHz, CD3OD) δ 8.61 - 8.53 (m, 1H), 7.74 (m, 1H), 7.39 (d, J= 8.4 Hz, 1H), 7.34 (dd, J= 7.7, 4.8 Hz, 1H), 7.14 (d, J= 8.4 Hz, 1H), 6.75 (d, J= 4.1 Hz, 1H), 6.69 (d, J= 11.4 Hz, 1H), 6.34 (dd, J= 17.5, 1.0 Hz, 1H), 6.09 (dd, J= 2.5 Hz, 2H), 5.68 (dd, J= 1 1.4, 1.0 Hz, 1H), 4.96 (dd, J= 11.6, 2.1 Hz, 1H), 4.64 (dd, J= 11.6, 3.1 Hz, 1H), 2.29 (s, 3H), 2.15 (s, 3H).
Example 89
(l ?)-l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2-yl]ethane-l,2-diol
Figure imgf000140_0001
(45)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-vinyl-4,5-dihydroimidazo[l,5,4- ife][l,4]benzoxazine (40 mg, 0.1 mmol) was dissolved in tert-butyl alcohol (4 mL) and water (4 mL). To the resulting solution, the mixture of A-D ιηίχβ (300 mg, 0.7 mmol) [Aldrich, cat. # 392766] was added at room temperature. The resulting mixture was stirred overnight. Saturated aqueous sodium sulfite (2 mL) was added and the suspension was stirred for 15 min at room temperature. The mixture was then extracted with dichloromethane. The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the desired product (0.021 g, 50%). LCMS for C2iH2104 4 (M+H)+: calculated m/z = 393.2; found 393.2. Example 90
l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2-yl]ethanol
Figure imgf000141_0001
Step 1. (4S)-7-(3, 5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- dejf 1, 4 Jbenzoxazine-2-carbaidehyd
Figure imgf000141_0002
(45)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-vinyl-4,5-dihydroimidazo[l,5,4- ife][l,4]benzoxazine (0.05 g, 0.1 mmol) was dissolved in tetrahydrofuran (1.7 niL). The resulting solution was cooled to 0 °C, then a solution of 0.16 M osmium tetraoxide in water (0.3 mL, 0.04 mmol) [Aldrich, cat. # 251755] and sodium metaperiodate (140 mg, 0.66 mmol) [Aldrich, cat. # SI 878] in water (0.1 mL) were added. The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with saturated aqueous sodium sulfite (10 mL) for 10 min at room temperature. The mixture was filtered through a Celite plug and the plug was rinsed with dichloromethane. The organic layer was concentrated under vacuum. The resulting residue was purified by flash chromatography elucting ethyl acetate in hexanes (75-100%, ethyl acetate containing 20% MeOH) to afford the desired product (0.053 g, 100%). LCMS for C2oH1703 4 (M+H)+: calculated m/z = 361.1; found 361.2. Step 2. 1-[(4S)- 7-(3, 5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4, 5-dihydroimidazof 1, 5, 4- de] [1 ,4] benzoxazin-2-yl] ethanol
To the solution of (45')-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-i/e][l,4]benzoxazine-2-carbaldehyde (8 mg, 0.02 mmol) in tetrahydrofuran (1 mL) at 0 °C, 3.0 M methylmagnesium chloride in THF (0.01 mL, 0.04 mmol) [Aldrich, cat. # 189901] was added dropwise. After continued stirring for 30 min at 0 °C, the reaction was quenched by adding saturated aqueous ammonium chloride (0.5 mL) dropwise. The resulting mixture was diluted with ethyl acetate/brine (3 : 1), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the desired product as a mixture of diastereomers (4 mg, 50%). LCMS for
C2iH2103N4 (M+H)+: calculated m/z = 377.2, found 377.1.
Example 91
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-7V,7V-dimethyl-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-rfe] [l,4]be mide
Figure imgf000142_0001
Example 92
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [l,4]benzoxazine
Figure imgf000143_0001
Example 93
teri-Butyl (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de\ [ 1 ,4] b enzoxazine-2-carb oxylat
Figure imgf000143_0002
(45)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- ife][l,4]benzoxazine-2-carbaldehyde (15 mg, 0.042 mmol) and dimethylamine hydrochloride (0.0041 g, 0.050 mmol) [Aldrich, cat. # 126365] were dissolved in acetonitrile (1.5 mL) at room temperature. To the resulting mixture, copper(II) sulfate pentahydrate (0.0005 g, 0.002 mmol) [Aldrich, cat. # 209198], calcium carbonate (0.0046 g, 0.046 mmol) [Aldrich, cat. # C6763] and 6.0 M tert-butyl hydroperoxide in decane (0.0076 mL, 0.046 mmol) [Aldrich, cat. # 416665] were added. The reaction vessel was capped, degassed, and allowed to stir at 40 °C for 10 hours. After filtration through Celite, the solution was concentrated and the resulting residue was purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the following three compounds:
Example 91 (7.2 mg, 43%) LCMS for C22H2203 5 (M+H)+: calculated m/z = 404.2; found 404.2. ¾ NMR (400 MHz, CD3OD) δ 8.49 (d, J= 4.6 Hz, 1H), 7.81 - 7.71 (m, 1H), 7.46 (d, J= 8.4 Hz, 1H), 7.37 - 7.28 (m, 1H), 7.18 (d, J= 8.4 Hz, 1H), 7.03 (d, J= 7.9 Hz, 2H), 6.15 (d, J= 3.6 Hz, 1H), 5.48 (s, 1H), 4.79 (dd, J= 1 1.8, 3.9 Hz, 2H), 4.70 (dd, J= 11.7, 3.2 Hz, 1H), 3.38 (s, 3H), 2.94 (s, 3H), 2.30 (s, 3H), 2.15 (s, 3H). Example 92 (2.4 mg, 17%) LCMS for Ci9H1702N4 (M+H)+: calculated m/z = 333.1; found 333.2 'H NMR (400 MHz, CD3OD) δ 8.61 (d, J= 3.9 Hz, 1H), 8.23 (s, 1H), 7.83 (dd, J= 7.8 Hz, 1H), 7.48 - 7.36 (m, 2H), 7.14 (d, J= 7.8 Hz, 2H), 7.06 (d, J= 7.9 Hz, 2H), 5.94 (s, 1H), 4.82 - 4.74 (m, 2H), 4.74 - 4.67 (m, 2H), 2.32 (s, 3H), 2.18 (s, 3H).
Example 93 (3.2 mg, 18%) LCMS for C24H2504 4 (M+H)+: calculated m/z = 433.2, found 433.2; XH NMR (400 MHz, CD3OD) δ 8.52 (d, J= 4.8 Hz, 1H), 7.77 - 7.67 (m, 1H), 7.53 (d, J= 8.5 Hz, 1H), 7.38 - 7.29 (m, 1H), 7.24 (d, J= 8.5 Hz, 1H), 6.71 (d, J= 7.9 Hz, 1H), 6.40 (s, 1H), 5.00 (dd, J= 11.7, 3.1 Hz, 1H), 4.69 (dd, J= 1 1.8, 3.1 Hz, 1H), 2.28 (s, 3H), 2.14 (s, 3H), 1.47 (s, 9H).
Example 94
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-(morpholin-4-ylcarbonyl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-<fe] [l,4]benzoxazine
Figure imgf000144_0001
The title compound was prepared by methods analogous to Example 91, using morpholine [Aldrich, cat. # 252360] as the nucleophile. Purification by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the title compound. LCMS for C24H2404N5 (M+H)+: calculated m/z = 446.2, found 446.1; XH NMR (400 MHz, CD3OD) δ 8.51 (d, J= 4.2 Hz, 1H), 7.78 (m, 1H), 7.47 (d, J= 8.4 Hz, 1H), 7.34 (dd, J= 7.1, 5.4 Hz, 1H), 7.20 (d, J= 8.4 Hz, 1H), 7.06 (d, J= 7.9 Hz, 1H), 6.20 (m, 1H), 4.81 (dd, J= 11.8, 3.7 Hz, 1H), 4.72 (dd, J= 11.7, 3.3 Hz, 1H), 4.12 (s, 2H), 3.83 - 3.69 (m, 2H), 3.59 (t, J= 8.1 Hz, 4H), 2.16 (s, 3H), 2.04 (s, 3H).
Example 95
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-7V-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazine-2-carboxamide
Figure imgf000145_0001
The title compound was prepared by methods analogous to Example 91, using 2.0 M methylamine in tetrahydrofuran [Aldrich, cat. # 395056] as the nucleophile. Purification by preparative LCMS (XBridge C 18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the title compound. LCMS for C2iH2o03 5 (M+H)+: calculated m/z = 390.2, found 390.2; XH NMR (400 MHz, CD3OD) δ 8.49 (d, J= 4.8 Hz, 1H), 7.69 (m, 1H), 7.49 (d, J= 8.5 Hz, 1H), 7.28 (dd, J= 6.9, 4.9 Hz, 1H), 7.19 (d, J= 8.5 Hz, 1H), 6.64 (d, J= 7.9 Hz, 1H), 6.56 - 6.50 (m, 1H), 4.96 (dd, J= 11.7, 3.1 Hz, 1H), 4.65 (dd, J= 1 1.7, 3.0 Hz, 1H), 2.88 (s, 1H), 2.27 (s, 3H), 2.13 (s, 3H).
Example 96
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazine-2-carboxami
Figure imgf000145_0002
The title compound was prepared by methods analogous to Example 91, using hydroxylamine hydrochloride [Aldrich, cat. # 159417] as the nucleophile. Purification by preparative LCMS (XBridge C 18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the title compound. LCMS for C20H18O3 5 (M+H)+: calculated m/z = 376.1, found 376.2; XH NMR (400 MHz, CD3OD) δ 8.49 (d, J= 4.8 Hz, 1H), 8.20(s, 1H), 7.69 (m, 1H), 7.43 (d, J= 8.5 Hz, 1H), 7.28 (dd, J= 6.9, 4.9 Hz, 1H), 7.19 (d, J= 8.5 Hz, 1H), 6.54 (d, J= 7.9 Hz, 1H), 6.33 (m, 1H), 4.96 (dd, J= 11.7, 3.1 Hz, 1H), 4.65 (dd, J= 1 1.7, 3.0 Hz, 1H), 2.27 (s, 3H), 2.13 (s, 3H).
Example 97
tert-Butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- < ^] [l,4]benzoxazin-2-yl]-3,6-dihydropyridine-l(2H)-carboxylate
Figure imgf000146_0001
(45")-2-Chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-ife][l,4]benzoxazine (80 mg, 0.2 mmol), tert-butyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (100 mg, 0.4 mmol) [Aldrich, cat. # CDS015890], and potassium phosphate (0.09 g, 0.4 mmol) [Aldrich, cat. # P5629] were suspended in 1,4-dioxane (3 mL) and water (0.70 mL). The resulting mixture was degassed with nitrogen for 10 min and dicyclohexyl(2',4',6'- triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1 : 1) (0.008 g, 0.01 mmol) [Aldrich, cat. # 741825] was added, followed by an additional 10 min of degassing. The reaction mixture was sealed and heated at 50 °C for 16 h. After cooling to room temperature, the reaction mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting ethyl acetate in hexanes (75-100%) to afford the desired product (98 mg, 90%). LCMS for C29H32O4N5 (M+H)+: calculated m/z = 514.2, found 514.2; XH NMR (300 MHz, CD3OD) δ 8.54 (d, J= 4.7 Hz, 1H), 7.72 (m, 2H), 7.44 - 7.27 (m, 2H), 7.10 (d, J= 8.4 Hz, 1H), 6.75 (d, J= 8.1 Hz, 1H), 6.14 (s, 1H), 6.07 (d, J= 2.8 Hz, 1H), 4.78 (dd, J= 1 1.6, 2.9 Hz, 1H), 4.59 (dd, J= 11.6, 3.1 Hz, 1H), 4.1 1 - 3.72 (m, 2H), 3.51 (d, J= 16.0 Hz, 2H), 2.60 (s, 2H), 2.25 (s, 3H), 2.10 (s, 3H), 1.42 (s, 9H).
Example 98
tert-Butyl 3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- < ^] [l,4]benzoxazin-2-yl]-2,5-dihydro-lH-pyrrole-l-carboxylate
Figure imgf000147_0001
The title compound was prepared by methods analogous to Example 97, using tert- butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate [Combi-Blocks, cat. # FM2879] as the Suzuki-coupling reagent. The crude product was purified by flash chromatography with ethyl acetate in hexanes (75-100%) to afford the title compound. LCMS for C28H30O4 5 (M+H)+: calculated m/z = 500.2, found 500.4; XH NMR (400 MHz, CD3OD) δ 8.64 - 8.52 (m, 1H), 7.78 - 7.67 (m, 1H), 7.43 (d, J= 8.4 Hz, 1H), 7.39 - 7.29 (m, 1H), 7.16 (d, J= 8.4 Hz, 1H), 6.70 (m, 1H), 6.30 (d, J= 8.5 Hz, 1H), 6.18 (s, 1H), 4.95 (d, J= 1 1.6 Hz, 1H), 4.69 (s, 1H), 4.63 (dd, J= 11.6, 3.1 Hz, 1H), 4.57 (s, 1H), 4.32 (d, J= 17.3 Hz, 1H), 4.21 (d, J= 17.6 Hz, 1H), 2.29 (s, 3H), 2.15 (s, 3H), 1.51 (s, 6H), 1.48 (s, 3H).
Example 99
teri-Butyl 5-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- < ^] [l,4]benzoxazin-2-yl]-3,6-dihydropyridine-l(2H)-carboxylate
Figure imgf000147_0002
The title compound was prepared by methods analogous to Example 97, using tert- butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate [Anisyn, cat. # CT603191] as the Suzuki-coupling reagent. The crude product was purified by flash chromatography eluting ethyl acetate in hexanes (75-100%) to afford the title compound. LCMS for C29H32O4N5 (M+H)+: calculated m/z = 514.2, found 514.2; XH NMR (400 MHz, CD3OD) δ 8.56 (m, 1H), 7.74 (dd, J= 7.8, 1.7 Hz, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.33 (dd, J= 6.9, 5.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.79 (d, J= 7.8 Hz, 1H), 6.30 (s, 1H), 6.08 (t, J= 2.8 Hz, 1H), 4.81 (dd, J= 11.6, 2.9 Hz, 1H), 4.61 (dd, J= 1 1.6, 3.1 Hz, 1H), 4.39 (s, 2H), 4.14 - 4.02 (m, 2H), 3.50 (m, 1H), 3.31 (m, 1H), 2.27 (s, 3H), 2.13 (s, 3H), 1.47 (s, 9H).
Example 100
teri-Butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2-yl]piper
Figure imgf000148_0001
(tert-Butyl 4-[(45)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl] -3 ,6-dihydropyridine- 1 (2H)-carboxylate (80 mg, 0.2 mmol) was dissolved in methanol (6 mL), and the mixture was degassed with nitrogen for 15 min, followed by addition of palladium on carbon (30 mg, 0.02
mmol) [Aldrich, cat. # 130108]. After three vacuum/nitrogen gas refilling cycles, 1 atm hydrogen gas was charged to the mixture with a balloon. After stirring for 2 h at room temperature, the reaction mixture was filtered through Celite and the filter was subsequently washed with methanol (30 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography eluting ethyl acetate in hexanes (75-100%) to afford the desired product (48 mg, 60%). LCMS for C29H34O4N5 (M+H)+: calculated m/z = 516.3, found 516.2; 'H NMR (400 MHz, CD3OD) δ 8.59 - 8.49 (m, 1H), 7.73 (m, 1H), 7.36 - 7.28 (m, 2H), 7.06 (d, J= 8.3 Hz, 1H), 6.78 (d, J= 7.9 Hz, 1H), 6.00 (m, 1H), 4.89 (dd, J= 1 1.7, 3.1 Hz, 1H), 4.60 (dd, J= 11.6, 3.1 Hz, 1H), 4.16 (d, J = 13.4 Hz, 1H), 4.04 (d, J= 13.5 Hz, 1H), 2.95 (ddd, J= 11.8, 8.3, 3.6 Hz, 1H), 2.88 - 2.51 (m, 2H), 2.25 (s, 3H), 2.1 1 (s, 3H), 2.06 - 1.94 (m, 1H), 1.92 - 1.66 (m, 2H), 1.44 (s, 9H). Example 101A
tert-Butyl 3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2-yl]pyrrolidine-l-carboxylate (Diastereoisomer 1)
Example 101B
tert-Butyl 3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2-yl]pyrrolidine-l-carboxylate (Diastereoisomer 2)
Figure imgf000149_0001
The title compounds were prepared by methods analogous to Example 99, using tert- butyl 3-[(45,)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- i/e][l,4]benzoxazin-2-yl]-2,5-dihydro-lH-pyrrole-l-carboxylate as the starting material. Purification by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the title compound as two diastereoisomers.
Diastereoisomer 1. Preparative LCMS Peak I. LCMS for C28H32O4 5 (M+H)+:
calculated m/z = 502.2; found 502.1 ; XH NMR (400 MHz, CD3OD) 5 8.57 (s, 1H), 7.78 (s, 1H), 7.37 (d, J= 7.9 Hz, 2H), 7.1 1 (d, J= 8.3 Hz, 1H), 6.93 - 6.77 (m, 1H), 6.04 (s, 1H), 4.96 (d, J= 12.8 Hz, 1H), 4.64 (dd, J= 11.7, 2.9 Hz, 1H), 3.63 (d, J= 5.0 Hz, 2H), 3.38 (m, 1H), 2.40 (m, 1H), 2.29 (s, 3H), 2.15 (s, 3H), 1.45 (s, 3H), 1.39 (s, 6H).
Diastereoisomer 2. Preparative LCMS Peak II. LCMS for C28H32O4 5 (M+H)+: calculated m/z = 502.2; found 502.1 ; XH NMR (400 MHz, CD3OD) δ 8.57 (d, J= 4.5 Hz,
1H), 7.76 (m, 1H), 7.42 - 7.29 (m, 2H), 7.1 1 (d, J= 8.3 Hz, 1H), 6.91 - 6.73 (m, 1H), 6.04 (s, 1H), 4.93 (dd, J= 11.7, 2.0 Hz, 2H), 4.64 (d, J= 10.5 Hz, 1H), 3.96 - 3.82 (m, 1H), 3.80 - 3.49 (m, 1H), 2.29 (s, 3H), 2.14 (s, 3H), 2.11 - 1.82 (m, 2H), 1.47 (s, 9H). Example 102
tert-Butyl 3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2-yl]piperidine-l-carboxylate
Figure imgf000150_0001
The title compound was prepared by methods analogous to Example 100, using tert- butyl 5-[(45,)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- i/e][l,4]benzoxazin-2-yl]-3,6-dihydropyridine-l(2H)-carboxylate as starting material.
Purification by preparative LCMS (XB ridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the title compound. LCMS for C29H34O4N5 (M+H)+: calculated m/z = 516.3, found 516.2.
Example 103
(4S)-2-(l-Acetylpiperidin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-<fe] [l,4]benzoxazine
Figure imgf000150_0002
tert-Butyl 4-[(45)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl] -3 ,6-dihydropyridine- 1 (2H)-carboxylate (3 mg, 0.006 mmol) was dissolved in methanol (0.5 mL) at room temperature, followed by addition of 4.0 M hydrogen chloride in dioxane (0.5 mL, 2 mmol) [Aldrich, cat. # 345547]. The resulting mixture was stirred at room temperature for 10 min. The solvents were removed under a flow of nitrogen gas. Purification by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the title compound (1.8 mg, 70%). LCMS for
C24H26O2 5 (M+H)+: calculated m/z = 416.2, found 416.2.
Examples 104-108
The experimental procedures used to prepare the compounds of Examples 104 to 108 in Table 4 were analogous to those used for the synthesis of the Example compound 103.
Table 4
Figure imgf000151_0001
Figure imgf000151_0002
Example 109
(4S)-2-(l-Acetylpiperidin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-<fe] [l,4]benzoxazine
Figure imgf000152_0001
To the solution of tert-butyl 4-[(45')-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2-yl]piperidine-l-carboxylate (8.8 mg, 0.017 mmol) in methanol (1 mL) was added 4.0 M hydrogen chloride in dioxane (1 ml) at room temperature. The resulting mixture was stirred at room temperature for 10 min. The solvents were then evaporated under a steam of nitrogen. Triethylamine (0.23 mL, 1.7 mmol) was added to the resulting residue, followed by acetyl chloride (0.029 mL, 0.41 mmol). The mixture was then stirred under a stream of nitrogen for 5 min at room temperature, followed by removal of solvents and residual reagents. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the title compound (6.3 mg, 81%). LCMS for C26H2803 5 (M+H)+: calculated m/z = 458.2, found 458.2.
Examples 110-121
The experimental procedures used to prepare the compounds of Examples 1 10 to 121 in Table 5 were analogous to those used for the synthesis of the Examplel09.
Table 5
Figure imgf000153_0001
Figure imgf000153_0002
Example Reaction
Name R
No. Temperature
(4iS)-2-(l-acetyl-l,2,5,6-tetrahydropyridin-
1 16 3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4- 23 °C
pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazine 0
(45)-2-(l-acetylpiperidin-3-yl)-7-(3,5-
1 17 dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- 23 °C
dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazine
(mixture of diastereomers) 0
(4iS)-2-[ 1 -(cyclopropylcarbonyl)piperidin- 3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4-
1 18 pyridin-2-yl-4,5-dihydroimidazo[l,5,4- 23 °C
de] [ 1 ,4]benzoxazine
(mixture of diastereomers) 0
(41S)-7-(3,5-dimethylisoxazol-4-yl)-2-[l- (methylsulfonyl)piperidin-3 -yl] -4-pyridin-
1 19 2-yl-4,5-dihydroimidazo[l,5,4- o °c
de] [ 1 ,4]benzoxazine
Figure imgf000154_0001
(mixture of diastereomers)
Example 120
7-(3,5-Dimethylisoxazol-4-yl)-4^henyl-5,6-dihydro-4H-imidazo[4,5 -^]quinolin-2(lH)- one
Figure imgf000154_0002
Step 1. 2-Phenyl-l,2,3,4-tetrahydroquinoline
Figure imgf000154_0003
A solution of 2-phenylquinoline, (0.248 g, 1.21 mmol) [Aldrich, cat. # 299650] in acetic acid (6.0 mL) was treated with borane-pyridine complex (0.605 mL, 5.99 mmol) and stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 3 M sodium hydroxide solution (70 mL), water (20 mL), and brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give a crude oil. Purification by flash column chromatography (100% hexanes to 25% ethyl acetate/hexanes) gave the desired product (0.247 g, 98%) as a racemic mixture. LCMS calculated for d5H16N (M+H)+: m/z = 210.1 ; found: 210.1.
Step 2. N-Methoxy-2-phenyl-3, 4-dihydroquinoline- 1 (2H)-carboxamide
Figure imgf000155_0001
A solution of 2-phenyl-l,2,3,4-tetrahydroquinoline (2.13 g, 10.2 mmol) and triethylamine (4.26 mL, 30.5 mmol) in tetrahydrofuran (30.0 mL) was added to a solution of triphosgene (3.20 g, 10.8 mmol) in tetrahydrofuran (38.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, treated with methoxylamine hydrochloride (1.70 g, 20.3 mmol) and triethylamine (4.26 mL, 30.5 mmol), and stirred at room temperature for an additional 19 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude oil. Purification by flash column chromatography (100% hexanes to 70% ethyl acetate/hexanes, the ethyl acetate containing 5% methanol) gave the desired product (2.25 g, 78%) as a racemic mixture.
LCMS calculated for Ci7H19 202 (M+H)+: m/z = 283.1; found: 283.1.
Step 3. l-Methoxy-4-phenyl-5, 6-dihydro-4H-imidazo[ 4, 5, l-ij]quinolin-2( lH)-one
Figure imgf000155_0002
A solution of N-methoxy-2-phenyl-3,4-dihydroquinoline-l(2H)-carboxamide (0.869 g, 3.08 mmol) in chloroform (23.2 mL) at 0 °C was with treated with [1,1- bis(trifluoroacetoxy)iodo]benzene (1.59 g, 3.69 mmol) in four portions over 20 min. The resulting mixture was stirred at 0 °C for 30 min and at room temperature for 30 min. The reaction mixture was then diluted with saturated aqueous sodium bicarbonate solution (40 mL) and extracted with dichloromethane (50 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude oil. Purification by flash column chromatography (100% hexanes to 70% ethyl acetate/hexanes, the ethyl acetate containing 5% methanol) gave the desired product (0.576 g, 66%) as a racemic mixture. LCMS calculated for Ci7H17 202 (M+H)+: m/z = 281.1; found: 281.1. Step 4. 4-Phenyl-5, 6-dihydro-4H-imidazo[ 4, 5, l-ij]quinoUn-2( lH)-one
Figure imgf000156_0001
A suspension of l-methoxy-4-phenyl-5,6-dihydro-4H-imidazo[4,5,l- ]quinolin- 2(lH)-one (0.575 g, 2.05 mmol) in ethanol (35.9 niL, 615 mmol) was heated to dissolve residual solids and the resulting solution was cooled to room temperature. The solution was treated with acetic acid (0.233 mL, 4.10 mmol), degassed with nitrogen, treated with palladium catalyst (0.575 g, 100 wt%) (10% Pd on carbon, Degussa type) and hydrogenated for 17 h. The reaction mixture was filtered and the catalyst was washed with ethanol and methanol. The filtrate was then concentrated to give the desired product (0.436 g, 85%) as a racemic mixture that was used without further purification. LCMS calculated for C16H15 2O (M+H)+: m/z = 251.1 ; found: 251.1.
Step 5. 7-Bromo-4-phenyl-5, 6-dihydr -4H-imidazo[ 4, 5, l-ij]quinoUn-2( lH)-one
Figure imgf000156_0002
A suspension of 4-phenyl-5,6-dihydro-4H-imidazo[4,5, l- ]quinolin-2(lH)-one (0.200 g, 0.799 mmol) in acetonitrile (10.0 mL) and acetic acid (2.42 mL) was heated to dissolve residual solids and the resultant solution was cooled to 0 °C. The resulting solution was treated with a solution of N-bromosuccinimide (0.144 g, 0.807 mmol) in acetonitrile (3.0 mL), added dropwise, at 0 °C and subsequently stirred at 0 °C for 1 h. The reaction mixture was concentrated to a residue which was dissolved in chloroform (50 mL) and washed with saturated aqueous sodium bicarbonate (40 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give a crude solid. Purification by flash column chromatography (100% hexanes to 50% ethyl acetate/hexanes, the ethyl acetate containing 5% methanol) gave the desired product (0.177 g, 67%) as a racemic mixture along with an additional other brominated isomer, 8-bromo-4-phenyl-5,6-dihydro- 4H-imidazo[4,5,l-y]quinolin-2(lH)-one (which was not be separated) in a 4.4: 1 ratio.
LCMS calculated for Ci6H14BrN20 (M+H)+: m/z = 329.0, 331.0; found: 329.0, 331.0. Step 6. 7-(3, 5-Dimethylisoxazol-4-yl)-4-phenyl-5, 6-dihydro-4H-imidazo [ 4, 5, l-ijjquinolin- 2(lH)-one
A mixture of 7-bromo-4-phenyl-5,6-dihydro-4H-imidazo[4,5,l-ij]quinolin-2(lH)-one (0.050 g, 0.15 mmol) (4.4:1 mixture of isomers with 8-bromo-4-phenyl-5,6-dihydro-4H- imidazo[4,5,l-y]quinolin-2(lH)-one as the minor isomer), (3,5-dimethylisoxazol-4- yl)boronic acid (10.7 mg, 0.0759 mmol), and cesium carbonate (99.0 mg, 0.304 mmol) in 1, 2-dimethoxyethane (1.21 mL) and water (0.303 mL) was degassed with nitrogen for 5 min. The reaction mixture was treated with PEPPSI-IPr (5.2 mg, 0.0076 mmol) [Aldrich, cat. # 669032], degassed with nitrogen for 5 min, and heated at 90 °C for 1 h. The reaction mixture was then diluted with ethyl acetate (25 mL) and water (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. Purification via preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (14.7 mg, 28%) as a racemic mixture. XH NMR (500 MHz, CDC13) δ 10.00 (s, 1H), 7.34 - 7.20 (m, 3H), 7.08 - 6.95 (m, 3H), 6.88 - 6.76 (m, 1H), 5.54 (s, 1H), 2.45 - 1.96 (m, 10H); LCMS calculated for C2iH2o 302 (M+H)+: m/z = 346.2; found: 346.1.
Example 121
7-(3,5-Dimethylisoxazol-4-yl)-l-methyl-4-phenyl-5,6-dihydro-4H-imidazo[4,5,l- 7/]quinolin-2(lH)-one
Figure imgf000157_0001
A solution of 7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-5,6-dihydro-4H-imidazo[4,5,l- y]quinolin-2(lH)-one (10.7 g, 0.031 mmol) in N,N-dimethylformamide (0.50 mL) was treated with cesium carbonate (20.2 g, 0.062 mmol) followed by methyl iodide (2.9 μί, 46.5 μιηοΐ) and stirred at room temperature for 16 h. Purification via preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (8.2 mg, 74%) as a racemic mixture. XH NMR (400 MHz, CDC13) δ 7.35 - 7.20 (m, 3H), 7.03 (d, J= 6.9 Hz, 2H), 6.99 - 6.93 (m, 1H), 6.93 - 6.84 (m, 1H), 5.53 (s, 1H), 3.49 (s, 3H), 2.48 - 2.11 (m, 7H), 2.09 - 1.84 (m, 3H); LCMS calculated for C22H22 302 (M+H)+: m/z = 360.2; found: 360.1.
Example 122
7-(3,5-Dimethylisoxazol-4-yl)-l-methoxy-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,l- iy]quinolin-2(lH)-one trifluoroacetate
Figure imgf000158_0001
Step 1. 2-Pyridin-2-ylquinoline
Figure imgf000158_0002
A solution of 2-bromoquinoline (1.00 g, 4.81 mmol) [Aldrich, cat. # 716278] in N,N- dimethylformamide (10.0 mL) (degassed with nitrogen) was treated with 2-
(tributylstannyl)pyridine (1.83 mL, 4.81 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.337 g, 0.481 mmol). The reaction mixture was degassed with nitrogen for 5 min and heated at 1 10 °C for 17 h. The reaction mixture was then diluted with water (50 mL) and ether (50 mL) and filtered over Celite. The solids were washed with additional ether (150 mL). The filtrate was washed with water (150 mL) and brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column
chromatography (100% hexanes to 70% ethyl acetate/hexanes, the ethyl acetate containing 5% methanol) gave the desired product (0.771 g, 78%). LCMS calculated for Ci4Hn 2 (M+H)+: m/z = 207.1; found: 207.1. Step 2. 2-Pyridin-2-yl-l,2,3,4-tetrahydroquinoline
Figure imgf000158_0003
A suspension of 2-pyridin-2-ylquinoline (0.767 g, 3.72 mmol), l,4-dihydro-3,5- dicarbethoxy-2,6-dimethylpyridine (2.17 g, 8.55 mmol), and diphenyl hydrogen phosphate (0.0093 g, 0.037 mmol) in benzene (18.6 mL) was heated at 60 °C for 10 h. The reaction mixture was treated with 2-phenylquinoline (0.305 g, 1.49 mmol) and heated at 60 °C for 3 h. The reaction mixture was then concentrated to a crude solid. Purification by flash column chromatography (100% hexanes to 50% ethyl acetate/hexanes [the ethyl acetate contained 5% methanol]) gave the desired product (0. 735 g, 94%) as a racemic mixture. LCMS calculated for Ci4H15N2 (M+H)+: m/z = 21 1.1; found: 21 1.1.
Step 3. N-Methoxy-2-pyridin-2-yl-3, 4-dihydroquinoline- 1 (2H)-carboxamide
Figure imgf000159_0001
A solution of 2-pyridin-2-yl-l,2,3,4-tetrahydroquinoline (0.723 g, 3.44 mmol) in methylene chloride (10.3 mL) was treated with 4-nitrophenyl methoxycarbamate (0.948 g, 4.47 mmol) (Org. Process Res. Dev. 2012, 16, 109-116) followed by the dropwise addition of N,N-diisopropylethylamine (1.20 mL, 6.88 mmol), and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was then poured over water (25 mL) and saturated sodium bicarbonate (25 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a crude oily solid. Purification by flash column chromatography (100% hexanes to 20% ethyl acetate/hexanes [the ethyl acetate contained 5% methanol]) gave the desired product (0.923 g, 95%) as a racemic mixture. LCMS calculated for Ci6Hi8 302 (M+H)+: m/z = 284.1; found: 284.0. Step 4. l-Methoxy-4^yridin-2-yl-5, 6-dih dro-4H midazo[4,5 j]quinoUn-2(lH)-one
Figure imgf000159_0002
This compound was synthesized according to the procedure of Example 120, step 3, using N-methoxy-2-pyridin-2-yl-3,4-dihydroquinoline-l(27i)-carboxamide as the starting material. LCMS calculated for Ci6H16 302 (M+H)+: m/z = 282.1; found: 282.0. Step 5. 7-Bromo-l-methoxy-4-pyridin-2-yl-5, 6-dihydro-4H-imidazo[ 4, 5, l-ij]quinolin-2( 1H)- one
Figure imgf000160_0001
This compound was synthesized according to the procedure of Example 120, step 5, using l-methoxy-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,l- ]quinolin-2(lH)-one as the starting material. LCMS calculated for C^H^Br sCb (M+H)+: m/z = 360.0, 362.0; found: 359.9, 361.9.
Step 6. 7-(3, 5-Dimethylisoxazol-4-yl)-l-methoxy-4-pyridin-2-yl-5, 6-dihydro-4H-imidazo[ 4, 5, l-ij]quinolin-2( lH)-one trifluoroacetate
A suspension of 7-bromo-l-methoxy-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5, l- y]quinolin-2(lH)-one (0.132 g, 0.367 mmol) (as a mixture of brominated isomers), and cesium fluoride (0.195 g, 1.29 mmol) in tert-butyl alcohol (1.22 mL) and water (0.612 mL) degassed with nitrogen for 10 min. The reaction mixture was treated with (3,5- dimethylisoxazol-4-yl)boronic acid (0.0518 g, 0.367 mmol) followed by addition of 4-(di- tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2: 1) (5.2 mg, 7.35 μιηοΐ). The mixture was degassed with nitrogen for an additional 5 min, and heated at 80 °C for 1.5 h, at which time the reaction mixture was treated with cesium fluoride (0.0558 g, 0.367 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.104 g, 0.735 mmol), and 4-(di-ieri- butylphosphino)-N,N-dimethylaniline-dichloropalladium (2: 1) (5.20 mg, 0.00735 mmol), degassed with nitrogen, and stirred at 100 °C for 14 h. The reaction mixture was diluted with ethyl acetate (40 mL) and water (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue.
Purification by flash column chromatography (100% hexanes to 20% ethyl acetate/hexanes, the ethyl acetate containing 5% methanol) yielded a crude product. Further purification via preparative LCMS (XBridge C 18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (95 mg, 53%) as a racemic mixture. XH NMR (500 MHz, DMSO-i¾) δ 8.52 (d, J= 4.3 Hz, 1H), 7.84 (dd, J= 7.5 Hz, 1H), 7.42 - 7.31 (m, 1H), 7.31 - 7.23 (m, 1H), 7.18 (d, J= 7.9 Hz, 1H), 7.04 - 6.90 (m, 1H), 5.44 (s, 1H), 4.02 (s, 3H), 2.54 - 2.46 (m, 3H), 2.45 - 2.31 (m, 2H), 2.29 - 2.16 (m, 2H), 2.08 (d, J= 25.9 Hz, 3H); LCMS calculated for C2iH21 403 (M+H)+: m/z = 377.2; found: 377.0. Example 123
7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,l-^]quinolin- 2(lH)-one trifluoroacetate
Figure imgf000161_0001
Step 1. 4-Pyridin-2-yl-5,6-dihydro-4H midazo 4,5,l-ij]quinoUn-2(lH)-one
Figure imgf000161_0002
This compound was synthesized according to the procedure of Example 120, step 4, using l-methoxy-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,l- ]quinolin-2(lH)-one as the starting material. LCMS calculated for C15H14N30 (M+H)+: m/z = 252.1 ; found: 252.1. Step 2. 7-Bromo-4-pyridin-2-yl-5, 6-dihydro-4H midazo[4,5,1 j]quinoUn-2(lH)-one
Figure imgf000161_0003
This compound was synthesized according to the procedure of example 120, step 5, using 4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5, l- ]quinolin-2(lH)-one as the starting material. LCMS calculated for C15H13BrN30 (M+H)+: m/z = 330.0, 332.0; found: 329.9, 331.9.
Step 3. 7-(3, 5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-5, 6-dihydro-4H-imidazo[ 4,5,1- ij]quinolin-2( lH)-one trifluoroacetate
This compound was synthesized according to the procedure of Example 120, step 6, using 7-bromo-4^yridin-2-yl-5,6-dihydro-4H-imidazo[4,5,l- ]quinolin-2(lH)-one as the starting material. ¾ NMR (500 MHz, DMSO-i¾) δ 10.89 (s, 1H), 8.55 (d, J= 4.3 Hz, 1H), 7.85 (dd, J= 7.3 Hz, 1H), 7.49 - 7.31 (m, 1H), 7.25 - 7.10 (m, 1H), 6.96 (d, J= 7.9 Hz, 1H), 6.90 - 6.72 (m, 1H), 5.41 (s, 1H), 2.55 - 2.28 (m, 5H), 2.27 - 1.89 (m, 5H); LCMS calculated for C2oH19 402 (M+H)+: m/z = 347.1 ; found: 347.1.
Example 124
7-[5-(Hydroxymethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [l,4]benzoxazin-2(lH)-one
Figure imgf000162_0001
Step 1. Prop-2-yn-l-yl benzoate
Figure imgf000162_0002
A solution of 2-propyn- 1 -ol (10.0 mL, 172 mmol) in methylene chloride (496 mL) and triethylamine (47.9 mL, 344 mmol) at 0 °C was treated with benzoyl chloride (20.0 mL, 172 mmol), added over a period of 5 min. The reaction mixture was stirred at 0 °C for 30 min, followed by additional stirring at room temperature for 2 h. The reaction mixture was quenched with water (300 mL). The aqueous layer was separated and extracted with dichloromethane (2 x 200 mL). The combined organic layers were washed with water (2 x 200 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and concentrated to give the desired product (27 g, 98%) which was used without further purification. LCMS calculated for Ci0H9O2 (M+H)+: m/z = 161.1 ; found: 161.0.
Step 2. (3-Methylisoxazol-5-yl)methyl benzoate
Figure imgf000162_0003
A solution of prop-2-yn-l-yl benzoate (26.0 g, 162 mmol) in chloroform (598 mL) was treated with triethylamine (1 1.3 mL, 81.2 mmol) and acetaldoxime (14.4 g, 244 mmol). The reaction mixture was cooled to 0 °C, treated with sodium hypochlorite (551 mL, 487 mmol) (commercial grade ~5% aqueous), and stirred overnight at room temperature. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 200 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (100% hexanes to 30% ethyl acetate/hexanes) gave the desired product (20.1 g, 57%). LCMS calculated for Ci2H12N03 (M+H)+: m/z = 218.1 ; found: 218.1.
Step 3. (4-Bromo-3-methylisoxazol-5-yl)methyl benzoate
Figure imgf000163_0001
A solution of (3-methylisoxazol-5-yl)methyl benzoate (20.1 g, 92.4 mmol) in acetic acid (77.3 mL) was treated with N-bromosuccinimide (19.7 g, 11 1 mmol) and heated in a sealed tube at 90 °C for 4 h. The reaction mixture was diluted with brine and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (100% hexanes to 20% ethyl acetate/hexanes) gave the desired product (21.6 g, 79%). LCMS calculated for C12HnBrN03 (M+H)+: m/z = 296.0, 298.0; found: 296.0, 298.0.
Step 4. {5-[(Benzoyloxy)methyl]-3-methylisoxazol-4-yl}boronic acid
Figure imgf000163_0002
A flask containing bis(acetonitrile)palladium(II) chloride (0.40 g, 1.6 mmol) and 2'- (dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (2.10 g, 5.34 mmol) was evacuated and back-filled with nitrogen (repeated for three cycles). Addition of (4-bromo-3- methylisoxazol-5-yl)methyl benzoate (14.9 g, 50.4 mmol) (as a solution in 1,4-dioxane (32 mL)), was followed by addition of 1.0 M 4,4,5, 5-tetramethyl-l,3,2-dioxaborolane in tetrahydrofuran (85.7 mL), and triethylamine (21.1 mL, 151 mmol). The resulting mixture was bubbled with nitrogen for 5 min and then heated at 100 °C for 1 h. The reaction mixture was then diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude boronate ester. Purification by flash column chromatography (100% hexanes to 40% ethyl acetate/hexanes) gave the intermediate boronate ester. The purified boronate ester was dissolved in tetrahydrofuran (1 10 mL), diluted with water (50 mL), and treated with sodium periodate (20.3 g, 94.7 mmol). The reaction mixture was stirred vigorously for 15 min, treated with 1.0 M hydrogen chloride in water (64.0 mL), and stirred at room temperature for 2 h. The reaction mixture was then extracted with ethyl acetate (3 x 60 mL), washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude boronic acid. Recrystallization from ethyl acetate/hexanes gave the desired product (2.2 g). The filtrate was concentrated and the resulting residue was washed with hexanes to yield additional product (4.85 g) (7.05 g total, 54% combined yield). LCMS calculated for Ci2H13BN05 (M+H)+: m/z = 262.1; found: 262.1.
Step 5. [3-Methyl-4-(2-oxo-4-pyridin-2-yl-l, 2, 4, 5-tetrahydroimidazo[ 1, 5, 4-deJ '[ 1,
4] benzoxazin-7-yl)isoxazol-5-yl] methyl benzoate
Figure imgf000164_0001
A solution of 7-bromo-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-i/e][l,4]benzoxazin- 2(lH)-one (687 mg, 2.07 mmol) and {5-[(benzoyloxy)methyl]-3-methylisoxazol-4- yl}boronic acid (1.08 g, 4.14 mmol) in 1,4-dioxane (15.7 mL) and water (4 mL) was degassed with nitrogen. The reaction mixture was treated with [1, 1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1 : 1) (253 mg, 0.310 mmol), degassed with nitrogen, and heated in a sealed tube at 80 °C for 30 min, at which time the reaction mixture was treated with {5-[(benzoyloxy)methyl]-3- methylisoxazol-4-yl}boronic acid (1.08 g, 4.14 mmol) and [1, 1'- bis(diphenylphosphino)ferrocene]-dichloropalladium(II),complex with dichloromethane (1 : 1) (10 mg, 12.2 μιηοΐ), degassed with nitrogen and heated at 80 °C for a further 30 min. The reaction mixture was then diluted with ethyl acetate and water. The organic layer was separated and washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (30% ethyl acetate/hexanes to 100% ethyl acetate [the ethyl acetate contained 5% methanol]) gave the desired product (0.589 g, 58%) as a racemic mixture. LCMS calculated for C26H21 4O5 (M+H)+: m/z = 469.1; found: 469.1.
Step 6. 7-[ 5-(Hydroxymethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4, 5-dihydroimidazo[ 1, 5, 4-de] [l,4]benzoxazin-2(lH)-one
A solution of [3-methyl-4-(2-oxo-4-pyridin-2-yl-l,2,4,5-tetrahydroimidazo[l,5,4- <ie][l,4]benzoxazin-7-yl)isoxazol-5-yl]methyl benzoate (15.0 mg, 0.0320 mmol) in tetrahydrofuran (1.0 mL) and methanol (1.0 mL) was treated with 2.0 M lithium hydroxide in water (0.10 mL, 0.20 mmol) and stirred at room temperature for 20 min. The reaction mixture was quenched with 6 N hydrogen chloride in water (to pH ~ 2) and then
concentrated. Purification by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) gave the desired product (8 mg, 69%) as a racemic mixture. XH NMR (300 MHz, DMSO-i¾) 5 8.51 (d, J= 4.8 Hz, 1H), 7.77 (ddd, J= 7.7, 7.7, 1.7 Hz, 1H), 7.31 (dd, J= 7.4, 4.9 Hz, 1H), 7.09 (d, J= 7.9 Hz, 1H), 6.85 (d, J= 8.0 Hz, 1H), 6.75 (d, J= 8.0 Hz, 1H), 5.51 (s, 1H), 4.77 (dd, J= 11.4, 1.8 Hz, 1H), 4.42 (dd, J= 11.4, 3.1 Hz, 1H), 4.36 (s, 2H), 3.15 (s, 1H), 2.06 (s, 3H); LCMS calculated for Ci9H17 404 (M+H)+: m/z = 365.1; found: 365.1.
Example 125
7-[5-(Fluoromethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [l,4]benzoxazin-2(lH)-one trifluoroacetate
Figure imgf000165_0001
A solution of 7-[5-(hydroxymethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2(lH)-one (15.0 mg, 0.0412 mmol) in methylene chloride (0.30 mL) was cooled to -78 °C, treated with dimethylaminosulfur trifluoride (6.03 mg, 0.0453 mmol) and was allowed to warm to room temperature overnight. The reaction mixture was then concentrated to give a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 30 mL/min) gave the desired product (8 mg, 40%) as a racemic mixture. ¾ NMR (300 MHz, CD3OD) δ 8.59 (d, J= 4.2 Hz, 1H), 7.89 (ddd, J= 7.8, 7.8, 1.7 Hz, 1H), 7.43 (dd, J= 7.5, 5.0 Hz, 1H), 7.20 (d, J= 7.9 Hz, 1H), 6.97 (d, J= 8.1 Hz, 1H), 6.90 (d, J= 8.1 Hz, 1H), 5.60 (dd, J= 2.7, 2.7 Hz, 1H), 5.37 (s, 1H), 5.21 (s, 1H), 4.82 (dd, J= 11.5, 2.6 Hz, 1H), 4.52 (dd, J= 1 1.5, 3.2 Hz, 1H), 2.19 (s, 3H); LCMS calculated for Ci9H16F 403 (M+H)+: m/z = 367.1; found: 367.1.
Example 126
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4-< ^] [l,
4]benzoxazin-4-yl]pyridine-2-car nitrile
Figure imgf000166_0001
Step 1. 2-Bromo-l-(2-bromopyridin-3-yl)ethanone
Figure imgf000166_0002
A solution of l-(2-bromopyridin-3-yl)ethanone (2.10 g, 10.5 mmol) in acetic acid (28.0 mL) was treated with bromine (595 \L, 11.5 mmol) and heated at 90 °C for 1 h. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was separated and further extracted with ethyl acetate (2 x 80 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (10% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) gave the desired product (2.15 g, 73%). LCMS calculated for C7H6Br2NO (M+H)+: m/z = 277.9, 279.9, 281.9; found: 277.7, 279.7, 281.8.
Step 2. 3-(2-Bromopyridin-3-yl)-5-n l, 4-benzoxazin-3-ol
Figure imgf000166_0003
A solution of 2-bromo-l-(2-bromopyridin-3-yl)ethanone (2.15 g, 7.71 mmol) in methylene chloride (77.1 mL) and water (19.3 mL) was treated with potassium carbonate (2.13 g, 15.4 mmol), tetra-N-butylammonium bromide (500 mg, 1.50 mmol), and 2-amino-3- nitrophenol (1.31 g, 8.48 mmol), and heated at 40 °C for 5 h. The reaction mixture was then diluted with brine. The aqueous layer was separated and extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (100% hexanes to 35% ethyl acetate/hexanes) gave the desired product (2.45 g, 90%) as a racemic mixture. LCMS calculated for Ci3HnBrN304 (M+H)+: m/z = 352.0, 354.0; found: 351.7, 353.8.
Step 3. 3-(2-Bromopyridin-3-yl)-2H- -benzoxazin-5-amine
Figure imgf000167_0001
A suspension of iron (1.71 g, 30.7 mmol) (<10 micron) in ethanol (33.5 mL) was treated with 1.0 M hydrogen chloride in water (3.1 mL, 3.1 mmol) and was stirred at 60 °C for 2 h. The mixture was then cooled to 55-60 °C and treated with 5.0 M ammonium chloride in water (5.3 mL, 26.4 mmol) followed by addition of 3-(2-bromopyridin-3-yl)-5- nitro-3,4-dihydro-2H-l,4-benzoxazin-3-ol (2.16 g, 6.13 mmol, washed with 5 mL ethanol). The resulting suspension was stirred at 60-65 °C for 2 h. The suspension was diluted with acetonitrile to about 100 mL and filtered over Celite. The solid was washed with additional acetonitrile and the filtrate was concentrated to a solid. This solid was dissolved in ethyl acetate which was then dried over magnesium sulfate, filtered, and concentrated to give the desired product (1.85 g, 99%), used without further purification. LCMS calculated for C13HiiBrN30 (M+H)+: m/z = 304.0, 306.0; found: 304.0, 306.0.
Step 4. 3-(2-Bromopyridin-3-yl)-3,4-dihydro-2H-l,4-benzoxazin-5-amine tris- trifluoroacetate
Figure imgf000167_0002
A suspension of 3-(2-bromopyridin-3-yl)-2H-l,4-benzoxazin-5-amine (1.85 g, 6.08 mmol) in ethanol (20.0 mL) and water (4.0 mL) was treated with sodium tetrahydroborate (460 mg, 12.2 mmol) and stirred at room temperature overnight, at which time the mixture was treated with additional sodium tetrahydroborate (200 mg, 5.3 mmol) and heated at 90 °C for 2 h. The reaction mixture was quenched with acetic acid and diluted with ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification via preparative LCMS (XB ridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (1.69 g, 66%) as a racemic mixture. LCMS calculated for Ci3Hi3Br 30 (M+H)+: m/z = 306.0, 308.0; found: 305.9, 307.9. Step 5. 4-(2-Bromopyridin-3-yi)-4,5-dihydroimidazo[l,5,4-deJ[l,4Jbenzoxazin-2(lH)-one
Figure imgf000168_0001
A solution of 3-(2-bromopyridin-3-yl)-3,4-dihydro-2H-l,4-benzoxazin-5-amine tris- trifluoroacetate (1.69 g, 4.01 mmol) in ethyl acetate (17.8 mL) at 50 °C was treated with N,N- carbonyldiimidazole (0.78 g, 4.8 mmol) and stirred at 50 °C for 1 h. The reaction mixture was then cooled to 0 °C. The resulting precipitate was collected via filtration and washed with ether. The filtrate was concentrated to give a crude solid. Purification by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) gave the desired product that was combined with the precipitated material (0.970 g total, 73% combined yield) as a racemic mixture. LCMS calculated for C^HnBr sOz (M+H)+: m/z = 332.0, 334.0; found: 331.8, 333.8.
Step 6. 3-(2-Oxo-l, 2, 4, 5-tetrahydroimidazo[ 1, 5, 4-deJ '[ 1, 4 ] benzoxazin-4-yl)pyridine-2- carbonitrile
Figure imgf000168_0002
A suspension of 4-(2-bromopyridin-3-yl)-4,5-dihydroimidazo[l,5,4-i/e][l,
4]benzoxazin-2(lH)-one (964 mg, 2.90 mmol), zinc cyanide (1.00 g, 8.70 mmol) and tetrakis(triphenylphosphine)palladium(0) (335 mg, 0.290 mmol) in N,N-dimethylformamide (20.4 niL) was degassed and heated in a microwave at 160 °C for 20 min. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium
bicarbonate, water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. The crude product was suspended in hot ethyl acetate and diluted with hexanes to twice the volume, which resulted in the precipitation of a solid. The solid was collected by filtration and washed with ethyl acetate to give the desired product (656 mg). The filtrate was concentrated to a residue which was purified by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product that was combined with the precipitated material (0.709 g total, 88% combined yield) as a racemic mixture. LCMS calculated for C15HiiN402 (M+H)+: m/z = 279.1 ; found: 278.9.
Step 7. 3-(7-Bromo-2-oxo-l, 2, 4, 5-tetrahydroimidazof 1, 5, 4-deJf 1 ,4] benzoxazin-4- yl)pyridine-2-carbonitrile
Figure imgf000169_0001
A solution of 3-(2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazin-4- yl)pyridine-2-carbonitrile (709 mg, 2.548 mmol) in N,N-dimethylformamide (25.0 mL) was treated with N-bromosuccinimide (630 mg, 3.54 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (0.44 g, 48%) as a racemic mixture. LCMS calculated for CisHioBr^C^ (M+H)+: m/z = 357.0, 359.0; found: 356.8, 358.8. Step 8. 3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l ,2,4,5-tetrahydroimidazofl ,5,4-de] [1 , 4]benzoxazin-4-yl]pyridine-2-carbonitrile
A sealed tube containing 4-(di-tert-butylphosphino)-N,N-dimethylaniline - dichloropalladium (2: 1) (1 1.5 mg, 0.0162 mmol), cesium fluoride (574 mg, 3.78 mmol), 3-(7- bromo-2-oxo- 1 ,2,4,5-tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-4-yl)pyridine-2- carbonitrile (386 mg, 1.01 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (533 mg, 3.78 mmol) was placed under vacuum and back-filled with nitrogen (repeated 3x). The sealed tube was charged with 1-butanol (4.92 mL) and water (1.2 mL) and the mixture was degassed by bubbling nitrogen for 15 min and heated at 100 °C for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (342 mg, 85%) as a racemic mixture. XH NMR (300 MHz, DMSO-i¾) δ 11.00 (br s, 1H), 8.81 - 8.66 (m, 1H), 7.80 - 7.62 (m, 2H), 6.90 (d, J= 8.0 Hz, 1H), 6.80 (d, J= 8.0 Hz, 1H), 5.74 - 5.51 (m, 1H), 4.58 (d, J= 3.4 Hz, 2H), 2.29 (s, 3H), 2.12 (s, 3H); LCMS calculated for C2oH16N503
(M+H)+: m/z = 374.1; found: 374.1.
Example 127
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4-</ ] [l,
4] benzoxazin-4-yl] pyridine-2-carboxamide trifluoroacetate
Figure imgf000170_0001
A solution of 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5, 4-i/e][l,4]benzoxazin-4-yl]pyridine-2-carbonitrile (12.0 mg, 0.0321 mmol) in dimethyl sulfoxide (120 μΚ) at 0 °C was treated with hydrogen peroxide (5.36 μί, 0.0524 mmol) (30% solution), followed by potassium carbonate (1 mg, 0.008 mmol) and stirred overnight at room temperature. Purification via preparative LCMS (XBridge C 18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 30 mL/min) gave the desired product (10 mg, 62%) as a racemic mixture. XH NMR (300 MHz, DMSO- d6) δ 11.06 (s, 1H), 8.73 - 8.49 (m, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.49 (dd, J= 8.0, 4.6 Hz, 1H), 7.11 (d, J= 7.9 Hz, 1H), 6.88 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 8.0 Hz, 1H), 6.56 - 6.41 (m, 1H), 4.53 (d, J= 2.1 Hz, 2H), 2.24 (s, 3H), 2.07 (s, 3H); LCMS calculated for
C20H18 5O4 (M+H)+: m/z = 392.1; found: 392.1. Example 128
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4-</ ][l,
4]benzoxazin-4-yl]- V-methylpyridine-2-carboxamide
Figure imgf000171_0001
Step 1. 3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l ,2,4,5-tetrahydroimidazofl ,5,4-de] [1 , 4]benzoxazin-4-yl]pyridine-2-carboxylic acid hydrochloride
Figure imgf000171_0002
A solution of 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5, 4-i/e][l,4]benzoxazin-4-yl]pyridine-2-carbonitrile (342 mg, 0.916 mmol) in 6.0 M hydrogen chloride in water (32.6 mL, 196 mmol) was heated in the microwave at 160 °C for 30 min. The reaction mixture was concentrated to give the desired product (357 mg, 91%) as a racemic mixture which was used without further purification. LCMS calculated for C20H17N4O5 (M+H)+: m/z = 393.1; found: 392.9. Step 2. 3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4-de][l, 4 ] benzoxazin-4-yl J-N-methyipyridine-2-carboxamide
A solution of 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5, 4-i/e][l,4]benzoxazin-4-yl]pyridine-2-carboxylic acid (10.0 mg, 0.026 mmol) in N,N- dimethylformamide (0.50 mL) was treated with methylammonium chloride (4.30 mg, 0.064 mmol) followed by N,N-diisopropylethylamine (22.2 μL, 0.127 mmol) and stirred at room temperature for 5 min. The reaction mixture was treated with benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate [Aldrich #: 226084] (16.9 mg, 0.038 mmol) and stirred at room temperature for 1 h. Purification by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (5 mg, 48%) as a racemic mixture. ¾ NMR (300 MHz, DMSO-i¾) δ 9.06 - 8.91 (m, 1H), 8.57 (d, J= 3.6 Hz, 1H), 7.49 (dd, J= 8.1, 4.6 Hz, 1H), 7.10 (d, J= 7.4 Hz, 1H), 6.93 - 6.74 (m, 2H), 6.47 (s, 1H), 4.65 - 4.37 (m, 2H), 2.62 (d, J= 10.1 Hz, 6H), 2.24 (s, 1.5H), 2.07 (s, 1.5H); LCMS calculated for C21H20N5O4 (M+H)+: m/z = 406.1 ; found: 406.1.
Example 129
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4-< ^] [l,
4] benzoxazin-4-yl] -7V,7V-dimethyl ridine-2-carboxamide
Figure imgf000172_0001
The title compound was synthesized according to the procedure of Example 128, step
2, substituting dimethylamine as the starting material. XH NMR (300 MHz, DMSO-i¾) δ 8.53 (dd, J= 4.6, 1.5 Hz, 1H), 7.40 (dd, J= 8.0, 4.7 Hz, 1H), 7.33 (dd, J= 8.0, 1.5 Hz, 1H), 6.86 (d, J= 8.0 Hz, 1H), 6.78 (d, J= 8.0 Hz, 1H), 5.27 (dd, J= 3.3, 3.3 Hz, 1H), 4.47 - 4.28 (m, 2H), 3.04 (s, 1.5H), 2.86 (s, 1.5H), 2.62 (d, J= 10.1 Hz, 6H), 2.27 (s, 1.5H), 2.10 (s, 1.5H); LCMS calculated for C22H22N5O4 (M+H)+: m/z = 420.2; found: 420.1.
Example 130
4-[2-(Aminomethyl)pyridin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[l,5, 4-de] [l,4]benzoxazin-2(lH)-one
Figure imgf000172_0002
A solution of 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,
4-i/e][l,4]benzoxazin-4-yl]pyridine-2-carbonitrile (50.0 mg, 0.134 mmol) in methanol (25.0 mL) and 6.0 M hydrogen chloride in water (0.250 mL, 1.50 mmol) in a Parr bottle was flushed with nitrogen and treated with palladium catalyst (28.5 mg, 0.013 mmol) (10% Pd on carbon, Degussa type). The reaction vessel was charged to 50 PSI hydrogen and shaken for 5 h. The reaction mixture was then filtered over Celite. The solids were washed with additional methanol (150 mL) and the filtrate was concentrated to give the crude product. Purification via preparative LCMS (XB ridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (39 mg, 48%) as a racemic mixture. XH NMR (300 MHz, DMSO-i¾) δ 11.08 (s, 1H), 8.60 (dd, J= 4.5, 1.8 Hz, 1H), 8.48 - 8.23 (m, 2H), 7.54 - 7.28 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.80 (d, J= 8.0 Hz, 1H), 5.80 - 5.54 (m, 1H), 4.85 - 4.30 (m, 4H), 2.29 (s, 3H), 2.12 (s, 3H); LCMS calculated for C2oH2oN503 (M+H)+: m/z = 378.2; found: 378.1.
Example 131
7V-({3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4-< ^][l, 4]benzoxazin-4-yl]pyridin-2-yl}m thyl)acetamide
Figure imgf000173_0001
A solution of 4-[2-(aminomethyl)pyridin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4,5- dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2(lH)-one bis(trifluoroacetate) (35.0 mg, 0.058 mmol) in methylene chloride (2.0 mL) was treated with N,N-diisopropylethylamine (50.3 μί, 0.289 mmol) and stirred. Once the starting material was completely dissolved, the reaction mixture was treated with acetyl chloride (49.3 μί, 0.069 mmol) (added as a 10% solution in dichloromethane) and stirred at room temperature for 1 h. The reaction mixture was quenched with methanol and the solvent was concentrated to give the crude
product. Purification by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (18 mg, 74%>) as a racemic mixture. XH NMR (500 MHz, DMSO-i¾) δ 10.98 (br s, 1H), 8.50 - 8.47 (m, 1H), 8.44 (dd, J= 5.2, 5.2 Hz, 1H), 7.26 (dd, J= 7.9, 4.7 Hz, 1H), 7.23 - 7.16 (m, 1H), 6.88 (d, J= 8.0 Hz, 1H), 6.78 (d, J= 8.0 Hz, 1H), 5.68 (dd, J= 3.1, 3.1 Hz, 1H), 4.71 (dd, J= 15.1, 6.1 Hz, 1H), 4.55 - 4.47 (m, 2H), 4.44 (dd, J= 11.6, 3.2 Hz, 1H), 2.28 (s, 3H), 2.12 (s, 3H), 1.88 (s, 3H); LCMS calculated for C22H22N504 (M+H)+: m/z = 420.2; found: 420.1. Example 132
Methyl 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4-< ^] [l, 4]benzoxazin-4-yl]pyridine-2-car xylate
Figure imgf000174_0001
A solution of 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,
4-i/e][l,4]benzoxazin-4-yl]pyridine-2-carboxylic acid (294 mg, 0.7493 mmol) in methanol (60.0 mL) was treated with one drop of concentrated sulfuric acid and heated in a sealed tube overnight at 80 °C. The reaction mixture was then concentrated to a crude residue. This residue was diluted with ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution and stirred at room temperature for 1 hour. After dissolution, the aqueous layer was separated and extracted with ethyl acetate (2x). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (300 mg, 99%) as a racemic mixture. XH NMR (400 MHz, DMSO-i¾) δ 8.63 (dd, J= 4.6, 1.5 Hz, 1H), 7.56 (dd, J= 8.1, 4.6 Hz, 1H), 7.29 (dd, J= 8.1, 1.4 Hz, 1H), 6.89 (d, J= 8.0 Hz, 1H), 6.80 (d, J= 8.0 Hz, 1H), 6.00 (dd, J= 2.9, 2.9 Hz, 1H), 4.53 (d, J= 2.9 Hz, 2H), 3.91 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H); LCMS calculated for
C2iH19 405 (M+H)+: m/z = 407.1; found: 407.0.
Example 133
Single enantiomer of 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l, 5,4-< ^] [l,4]benzoxazin-4-yl]-7V- thylpyridine-2-carboxamide
Figure imgf000174_0002
Step 1. Separation of isomers of 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l, 2,4,5- tetrahydroimidazof 1, 5, 4-de][ l,4]benzoxazin-4-yl]pyridine-2-carbonitrile
Figure imgf000175_0001
The racemic mixture of 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazin-4-yl]pyridine-2-carbonitrile was separated by chiral HPLC (Phenomenex Lux Cellulose C2 column, 21.2 x 250 mm, 5 micron particle size, eluting with 60% ethanol in hexanes at 18 mL/min, 90 mg per injection) to give peak 1 (RT = 9.2 min) and peak 2 (RT = 15.9 min). Peak 1 was determined to be more active and was used for the synthesis of subsequent analogs. Step 2. Single enantiomer of 3-[7-(3,5-Dimethyiisoxazoi-4-yi)-2-oxo-l, 2,4,5- tetrahydroimidazof 1, 5, 4-de][ 1, 4]benzoxazin-4-yl]pyridine-2-carboxylic acid
Figure imgf000175_0002
A solution of 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5, 4-i/e][l,4]benzoxazin-4-yl]pyridine-2-carbonitrile (2.23 g, 5.97 mmol) (Peak 1 from step 1) in 6.0 M hydrogen chloride in water (50 mL, 300 mmol) was heated in the microwave at 160 °C for 30 min. The reaction mixture was concentrated to give the crude product. Purification by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (1.41 g, 60%) as a single enantiomer. LCMS calculated for C20H17 4O5 (M+H)+: m/z = 393.1; found: 393.1. Step 3. 3-f ( 4S)-7-(3, 5-Dimethylisoxazol-4-yl)-2-oxo- 1 , 2, 4, 5-tetrahydroimidazof 1, 5, 4-deJf 1, 4 ] benzoxazin-4-yl ] -N-ethylpyridine-2-carboxamide
A solution of 3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5, 4-i/e][l,4]benzoxazin-4-yl]pyridine-2-carboxylic acid (30.0 mg, 0.0764 mmol) (from step 2) in N,N-dimethylformamide (1.0 mL) was treated with ethylamine (10.8 \L, 0.191 mmol) followed by N,N-diisopropylethylamine (66.6 μΐ,, 0.382 mmol) and stirred at room temperature for 5 min. The reaction mixture was subsequently treated with benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate [Aldrich #: 226084] (50.7 mg, 0.115 mmol) and stirred at room temperature for 1 h. Purification by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (23 mg, 71%) as a single enantiomer. XH NMR (400 MHz, DMSO-i¾) δ 9.03 (t, J = 5.9 Hz, 1H), 8.58 (dd, J= 4.6, 1.4 Hz, 1H), 7.49 (dd, J= 8.0, 4.6 Hz, 1H), 7.1 1 (dd, J= 8.0, 1.2 Hz, 1H), 6.87 (d, J= 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.54 - 6.41 (m, 1H), 4.64 - 4.45 (m, 2H), 3.43 - 3.24 (m, 2H), 2.24 (s, 3H), 2.07 (s, 3H), 1.15 (t, J= 7.2 Hz, 3H); LCMS calculated for
C22H22N5O4 (M+H)+: m/z = 420.2; found: 420.2.
Examples 134-136
Examples 134-136 listed in Table 6 were synthesized as single enantiomers according to the procedure of Example 133.
Table 6
Figure imgf000176_0001
Figure imgf000176_0002
Ex. No. Name R
3 -[7-(3 ,5-dimethylisoxazol-4-yl)-2-oxo- 1 ,
136 2,4,5-tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,
4]benzoxazin-4-yl]- V-(2,2,2- H
trifluoroethyl)pyridine-2-carboxamide
Example 137
(4S)-9-(Aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-< ^] [l,4]benzoxazin-2(lH)-one bis(trifluoroacetate)
Figure imgf000177_0001
Step 1. ( 4S)-9-Bromo- 7-(3, 5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4, 5-dihydroimidazo[ 1, 5, 4-deJ '[ l,4]benzoxazin-2( lH)-one
Figure imgf000177_0002
A solution of (45')-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one (2.50 g, 7.18 mmol) in tetrahydrofuran (47 mL) was treated with N-bromosuccinimide (1.40 g, 7.89 mmol) and stirred at room temperature for 1 h, at which time the reaction mixture was treated with additional N- bromosuccinimide (0.70 g, 3.93 mmol) and stirred at 45 °C for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column
chromatography (50% ethyl acetate/hexanes to 100% ethyl acetate) gave the desired product (3.0 g, 98%) as a single enantiomer. LCMS calculated for Ci9Hi6Br 403 (M+H)+: m/z = 427.1, 429.1 ; found: 426.8, 428.8. Step 2. (4S)-7-(3,5-Dimethyiisoxazoi-4-yi)-4^yridin-2-yi-9-vinyi-4,5-dihydroimidazo[l,5,4- dejf l,4]benzoxazin-2(lH)-one
Figure imgf000178_0001
A mixture of (45)-9-bromo-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2(lH)-one (3.00 g, 7.02 mmol), 4,4,5,5- tetramethyl-2-vinyl-l,3,2-dioxaborolane (2.14 mL, 12.6 mmol), [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium(II),complex with dichloromethane (1: 1) (570 mg, 0.70 mmol) and potassium carbonate (2.90 g, 21 mmol) in 1,4-dioxane (40 mL) and water (20 mL) was heated at 80 °C for 1 h. The mixture was then poured over water and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash column chromatography (40% ethyl acetate/hexanes to 90% ethyl acetate/hexanes) gave the desired product (1.69 g, 64%) as a single enantiomer. LCMS calculated for C21H19 4O3 (M+H)+: m/z = 375.1; found: 375.1.
Step 3. (4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl- tetrahydroimidazof 1, 5, 4-de][ 1, 4 Jbenzoxazine-9-carbaidehyde
Figure imgf000178_0002
A mixture of (45)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-9-vinyl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one (1690 mg, 4.51 mmol) in water (7.8 mL) and tetrahydrofuran (104 mL) was treated with sodium metaperiodate (2.90 g, 13.5 mmol) and heated at 60 °C for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) gave the desired product (0.797 g, 47%) as a single enantiomer. LCMS calculated for C2oH17 404 (M+H)+: m/z = 377.1; found: 376.9. Step 4. (4S)-9-{[(2,4-Dimethoxybenzyl)amino]methyl}-7-(3,5-dimethylisoxazol-4-yl)-4- pyridin-2-yl-4, 5-dihydroimidazo[ 1, 5, 4-de][ 1, 4]benzoxazin-2( lH)-one
Figure imgf000179_0001
A solution (45')-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl- 1,2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazine-9-carbaldehyde (250 mg, 0.664 mmol) in ethanol (12.5 mL) was treated with l-(2,4-dimethoxyphenyl)methanamine [Aldrich #:
432725] (150 JL, 0.996 mmol) and acetic acid (20.0 JL, 0.352 mmol) and heated at 60 °C for 1 h. The reaction mixture was cooled to room temperature, treated with sodium
cyanoborohydride (210 mg, 3.3 mmol) and stirred at room temperature for 3 h. The reaction mixture was then quenched with acetic acid (1 mL) and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the desired product (0.40 g, 97%) as a single enantiomer which was used without further purification. LCMS calculated for C29H30 5O5 (M+H)+: m/z = 528.2; found: 528.0.
Step 5. (4S)-9-(Aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazof 1, 5, 4-deJf 1 ,4] benzoxazin-2( lH)-one bis( trifluoroacetate)
A solution of (45)-9- {[(2,4-dimethoxybenzyl)amino]methyl}-7-(3,5- dimethylisoxazol-4-yl)-4^yridin-2-yl-4,5-dihydroimidazo[l,5,4-(ie][l,4]benzoxazin-2(lH)- one (70.0 mg, 0.133 mmol) in trifluoroacetic acid (5 mL) and water (30 \L) was heated in the microwave at 120 °C for 10 min. The reaction mixture was concentrated to give a crude residue. Purification via preparative LCMS (XBridge C 18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (66 mg, 82%) as a single enantiomer. *H NMR (300 MHz, DMSO-i¾) δ 11.28 (s, 1H), 8.48 (d, J = 4.4 Hz, 1H), 8.18 (br s, 2H), 7.80 (ddd, J= 7.7, 7.7, 1.7 Hz, 1H), 7.32 (dd, J= 7.1, 5.0 Hz, 1H), 7.19 (d, J= 7.9 Hz, 1H), 6.94 (s, 1H), 5.59 (s, 1H), 4.89 - 4.73 (m, 1H), 4.44 (dd, J = 1 1.5, 3.0 Hz, 1H), 4.13 (d, J= 5.5 Hz, 2H), 2.24 (s, 3H), 2.07 (s, 3H); LCMS calculated for C2oH2o 503 (M+H)+: m/z = 378.2; found: 378.0. Example 138
7V-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[l,5,4-< ^] [l,4]benzoxazin-9-yl]methyl}acetamide trifluoroacetate
Figure imgf000180_0001
A solution of (45*)-9-(aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one bis(trifluoroacetate) (10.0 mg, 0.0265 mmol) in methylene chloride (1.00 mL) was treated with N,N-diisopropylethylamine (13.8 μΐ,, 0.0795 mmol) followed by acetyl chloride (2.26 μΐ,, 0.0318 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated to give a crude residue.
Purification via preparative LCMS (XB ridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at a flow rate of 60 mL/min) gave the desired product (9 mg, 81%) as a single enantiomer. XH NMR (500 MHz, DMSO-i¾) δ 10.89 (s, 1H), 8.52 (d, J= 4.1 Hz, 1H), 8.31 (dd, J= 5.7, 5.7 Hz, 1H), 7.79 (ddd, J= 7.7, 7.7, 1.8 Hz, 1H), 7.41 - 7.27 (m, 1H), 7.14 (d, J= 7.9 Hz, 1H), 6.70 (s, 1H), 5.53 (dd, J= 2.4, 2.4 Hz, 1H), 4.76 (dd, J= 11.5, 2.0 Hz, 1H), 4.41 (dd, J= 1 1.5, 3.1 Hz, 1H), 4.32 (d, J= 5.8 Hz, 2H), 2.22 (s, 3H), 2.05 (s, 3H), 1.87 (s, 3H); LCMS calculated for C22H22 504 (M+H)+: m/z = 420.2; found: 420.0.
Examples 139-143
Examples 139 to 142 of Table 7 were synthesized as single enantiomers according to the procedure of Example 138.
Example 143 of Table 7 was synthesized according to the procedure of Example 128,
Step 2.
Figure imgf000181_0001
Figure imgf000181_0003
Example 144A
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(l-hydroxyethyl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de] [l,4]benzoxazin-2(lH)-one (Diastereoisomer 1) Example 144B
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(l-hydroxyethyl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-<fe] [l,4]benz xazin-2(lH)-one (Diastereoisomer 2)
Figure imgf000181_0002
A solution of (45')-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazine-9-carbaldehyde (1.30 g, 3.45 mmol) (single enantiomer from Example 137, step 3) in tetrahydrofuran (30.0 mL) was treated with 3.0 M methylmagnesium iodide in diethyl ether (4.03 mL, 12.1 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product as a mixture of diastereoisomers. The diastereoisomers were separated by chiral HPLC (Chiracel AD-H column, 20 x 250 mm, 5 micron particle size, eluting with 50% ethanol in hexanes at 12 mL/min, 45 mg per injection) to give Peak 1 (Diastereoisomer 1, RT = 10.2 min) and Peak 2 (Diastereoisomer 2, RT = 12.6 min).
Diastereoisomer 1, Peak 1 : 1H MR (400 MHz, DMSO-i¾) δ 11.03 (br s, 1H), 8.51 (d, J= 4.7 Hz, 1H), 7.78 (ddd, J= 7.7, 7.7, 1.6 Hz, 1H), 7.31 (dd, J= 7.3, 5.0 Hz, 1H), 7.09 (d, J= 7.9 Hz, 1H), 6.83 (s, 1H), 5.52 (s, 1H), 5.21 (br s, 1H), 4.95 (q, J= 6.3 Hz, 1H), 4.76 (dd, J= 11.4, 1.5 Hz, 1H), 4.42 (dd, J= 11.4, 3.0 Hz, 1H), 2.22 (s, 3H), 2.05 (s, 3H), 1.37 (d, J= 6.4 Hz, 3H); LCMS calculated for C2iH21 404 (M+H)+: m/z = 393.2; found: 393.0.
Diastereoisomer 2, Peak 2: XH NMR (400 MHz, DMSO-i¾) δ 10.97 (br s, 1H), 8.52 (d, J= 4 Hz, 1H), 7.78 (ddd, J= 7.7, 7.7, 1.4 Hz, 1H), 7.32 (dd, J= 7.4, 4.9 Hz, 1H), 7.1 1 (d, J= 7.8 Hz, 1H), 6.80 (s, 1H), 5.50 (s, 1H), 5.20 (br s, 1H), 4.92 (q, J= 6.3 Hz, 1H), 4.75 (dd, J= 11.4, 1.7 Hz, 1H), 4.39 (dd, J= 11.4, 3.0 Hz, 1H), 2.23 (s, 3H), 2.06 (s, 3H), 1.40 (d, J= 6.4 Hz, 3H); LCMS calculated for C2iH21N404 (M+H)+: m/z = 393.2; found: 393.1.
Example 145
(3 ?)-l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- < ^] [l,4]benzoxazin-2-yl]-N-isopropylpyrrolidine-3-carboxamide
Figure imgf000182_0001
Step 1. (3R)-N-Isopropylpyrrolidine-3-carboxamide
Figure imgf000183_0001
To (3R)-l-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (150 mg, 0.70 mmol) in N,N-dimethylformamide (3.0 mL), N,N-diisopropylethylamine (0.25 mL, 1.4 mmol) and 1 -hydroxybenzotriazole (94 mg, 0.70 mmol) were added. The mixture was stirred at room temperature for 5 min, followed by addition of N-(3-dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride (150 mg, 0.77 mmol). The mixture was then stirred for 20 min. 2-Propanamine (59 ΐ^, 0.69 mmol) was added and the mixture was stirred overnight. The mixture was then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated, and purified by preparative LCMS using pH 2 buffer to give desired boc- protected intermediate. The product fractions were concentrated and treated with 4.0 M hydrogen chloride in 1,4-dioxane (2.0 mL) for 30 min, at which time the mixture was concentrated and dissolved in DCM/MeOH and treated with Trisamine resin (Silicycle) for 30 min. The resulting mixture was filtered and the solvents were evaporated to give the desired compound (63 mg, 58%) which was used in the next step without further purification. LCMS calc. for C8H17N20 (M+H)+: m/z = 157.1 ; found: 157.2.
Step 2. ( 3R)-l-[ ( 4S)- 7-( 3, 5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4, 5-dihydroimidazo[ 1, 5, 4- dejf 1, 4 Jbenzoxazin-2-yi J-N-isopropyipyrroiidine-3-carboxamide
Triethylamine (1 10 \L, 0.79 mmol) and (3R)-N-isopropylpyrrolidine-3- carboxamide (120 mg, 0.74 mmol) were added to a solution of (45)-2-chloro-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-(ie][l,4]benzoxazine (66.0 mg, 0.18 mmol) in N-methylpyrrolidinone (1.5 mL), and the resulting mixture was heated in a microwave at 120 °C for 5 min. The mixture was diluted with methanol and
purified twice by preparative LCMS using pH 10 buffer to give the title compound, (8.9 mg, 10%). LCMS calc. for C27H3i 603 (M+H)+: m/z = 487.2; found: 487.3. XH NMR (500 MHz, DMSO) δ 8.54 (dd, J= 4.8, 0.8 Hz, 1H), 7.79 (d, J= 7.6 Hz, 1H), 7.72 (td, J= 7.7, 1.8 Hz, 1H), 7.29 (dd, J= 6.8, 4.9 Hz, 1H), 6.95 (d, J= 8.1 Hz, 1H), 6.80 (d, J= 8.1 Hz, 1H), 6.60 (d, J= 7.9 Hz, 1H), 6.09 (t, 1H), 4.82 (dd, J= 1 1.4, 1.3 Hz, 1H), 4.53 (dd, J= 1 1.5, 2.8 Hz, 1H), 3.85 - 3.71 (m, 3H), 3.43 (dd, J= 9.6, 7.6 Hz, 1H), 3.39 - 3.32 (m, 1H), 2.90 (p, J= 7.8 Hz, 1H), 2.19 (s, 3H), 2.02 (s, 3H), 2.00 - 1.89 (m, 2H), 1.01 (dd, J= 10.1, 6.6 Hz, 6H). Example 146A
l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2-yl]-3-methylpyrrolidin-3-ol (Diastereoisomer 1)
Example 146B
l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2-yl]-3-methylpyrrolidin-3-ol (Diastereoisomer 2)
Example 146C
l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2-yl]-3-methylp ture of diastereoisomers)
Figure imgf000184_0001
Triethylamine (0.76 mL, 5.5 mmol) and 3-methylpyrrolidin-3-ol hydrochloride (563 mg, 4.09 mmol) were added to (45)-2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[l,5,4-i/e][l,4]benzoxazine (100 mg, 0.27 mmol) in N- methylpyrrolidinone (3 mL) and the resulting mixture was heated in a microwave at 150 °C for 20 min. The mixture was then diluted with methanol and purified by preparative LCMS at pH 2 buffer followed by preparative LCMC at pH 10 buffer to give the title compound as a mixture of diastereomers (47.1 mg, 40%). LCMS calc. for C24H26 5O3 (M+H)+: m/z = 432.2; found: 432.2. The isomers were separated by prep chiral column chromatography: Column: phenomenex Lux Cellulose C-2 5 μιη, 21, 2x250 mm, Mobile phase: 20% EtOH/Hexanes, gradient condition: isocratic at 18 mL/min, run time: 30 min, peak time: 23.0 and 25.7 min.
Example 146A, Peak 1, 12.6 mg, 11%, LCMS calc. for C24H26N503 (M+H) : m/z = 432.2; found: 432.2.
Example 146B, Peak 2, 12.6 mg, 1 1%, LCMS calc. for ϋ24Η26 503 (M+H) m/z = 432.2; found: 432.2. Example 147
4-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- <fe] [l,4]benzoxazin-2-yl]-l,4-diazepane-l-sulfonamide
Figure imgf000185_0001
Step 1. tert-Butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l ,5,4-de] [1 ,4] benzoxazin-2-yl] -1 ,4-diazepane-l-carboxylate
Figure imgf000185_0002
The title compound was prepared by methods analogous to Example 146, substituting with tert-butyl 1,4-diazepane-l-carboxylate. The mixture was concentrated and purified by preparative LCMS using pH 10 buffer to give the title compound (63 mg, 36%). LCMS calc. for C29H35 604 (M+H)+: m/z = 531.3; found: 531.3.
Step 2. ( 4S)-2-(l, 4-Diazepan-l-yl)-7-(3, 5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4, 5- dihydroimidazof 1, 5, 4-de][ 1, 4 Jb
Figure imgf000185_0003
tert-Butyl 4-[(45)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2-yl]-l,4-diazepane-l-carboxylate (53 mg, 0.10 mmol) was treated with a solution of 4.0 M hydrogen chloride in 1,4-dioxane (2.0 mL) for 10 min. The mixture was concentrated and purified by preparative LCMS using pH 10 buffer to give the title compound (28.5 mg, 66%). LCMS calc. for C24H27 602 (M+H)+: m/z = 431.2; found: 431.3.
Step 3. 4-[(4S)- 7-(3, 5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4, 5-dihydroimidazof 1, 5, 4- dejf l,4]benzoxazin-2-yl]-l, 4-diazepane-l -sulfonamide
(45)-2-(l,4-diazepan-l-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-ife][l,4]benzoxazine (5.8 mg, 0.013 mmol) and sulfamide (7.8 mg, 0.081 mmol) were dissolved in pyridine (0.71 mL) and the solution was heated at 120 °C for 3 min in a microwave. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound (5.1 mg, 74%). LCMS calc. for
C24H27 704S (M+H)+: m/z = 510.2; found: 509.7.
Example 148
(4S)-2-(4-Acetyl-l,4-diazepan-l-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-<fe] [l,4]benzoxazine
Figure imgf000186_0001
To a solution of (45)-2-(l,4-diazepan-l-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin- 2-yl-4,5-dihydroimidazo[l,5,4-i/e][l,4]benzoxazine (5.0 mg, 0.012 mmol) in methylene chloride (0.44 mL), triethylamine (8.1 μί, 0.058 mmol) was added followed by acetyl chloride (1.6 μί, 0.023 mmol) and the mixture was stirred for 5 min. The mixture was then diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound (3.5 mg, 64%). LCMS calc. for C26H29 603 (M+H)+: m/z = 473.2; found: 473.3. Example 149
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-[4-(methylsulfonyl)-l,4-diazepan-l-yl]-4-pyridin-2- yl-4,5-dihydroimidazo[l,5,4-<fe]
Figure imgf000187_0001
Triethylamine (8.1 \L, 0.058 mmol) was added to a solution of (45*)-2-(l,4-diazepan- l-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- ife][l,4]benzoxazine (5.0 mg, 0.012 mmol) in methylene chloride (0.44 mL), and the mixture was cooled to 0 °C. Methanesulfonyl chloride (1.8 μΐ,, 0.023 mmol) was then added and the mixture was stirred for 5 min at 0 °C. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound (3.8 mg, 64%). LCMS calc. for C25H29 604S (M+H)+: m/z = 509.2; found: 509.2.
Example 150
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-piperazin-l-yl-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-<fe] [l,4]be ride
Figure imgf000187_0002
Step 1. tert-Butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazof 1, 5, 4-de][ 1 ,4] benzoxazin-2-yiJpiperazine-l -carboxylate
Figure imgf000188_0001
The title compound was prepared by methods analogous to Example 146, substituting tert-butyl piperazine- 1 -carboxylate. The mixture was concentrated and purified by preparative LCMS using pH 10 buffer to give the product. LCMS calc. for C28H33 6O4 (M+H)+: m/z = 517.3; found: 517.4.
Step 2. (4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-piperazin-l-yl-4-pyridin-2-yl-4,5- dihydroimidazof 1, 5, 4-de][ 1, 4 Jbenzoxazine trihydrochloride
tert-Butyl 4-[(45)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2-yl]piperazine-l-carboxylate (45 mg, 0.087 mmol) was stirred in 4 N HC1 in dioxanes (3 mL) and methanol (2 mL) for 30 min, at which time the solvent was evaporated to give the title compound (45 mg, 92%). LCMS calc. for C27H32N7O3 (M+H)+: m/z = 417.2; found: 417.3.
Example 151
2-{4-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- < ^] [l,4]benzoxazin-2-yl]piperazin-l-yl}-7V,iV-dimethylacetamide —
Figure imgf000188_0002
To a solution of (45)-7-(3,5-dimethylisoxazol-4-yl)-2-piperazin-l-yl-4-pyridin-2-yl- 4,5-dihydroimidazo[l,5,4-i/e][l,4]benzoxazine trihydrochloride (10 mg, 0.03 mmol) in methylene chloride (1.0 mL), potassium carbonate (18 mg, 0.13 mmol) was added, followed by 2-chloro-N,N-dimethylacetamide (2.7 \L, 0.026 mmol) and the mixture was stirred for 5 min. The mixture was then heated at 60 °C overnight. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound, (3.7 mg, 30%). LCMS calc. for C27H32 703 (M+H)+: m/z = 502.2; found: 502.3.
Example 152
2-Cyano-7V-{(3JR)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-^] [l,4]benzoxazin-2-yl]pyrrolidin-3-yl}-iV-methylacetamide
Figure imgf000189_0001
Triethylamine (8.2 μL, 0.059 mmol) and ethanol (1.0 mL) were added to a solution of
(3R)-l-[(45)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- i/e][l,4]benzoxazin-2-yl]-N-methylpyrrolidin-3-amine (8.5 mg, 0.020 mmol) in methylene chloride (0.50 mL), followed by addition of 3-[(2,5-dioxopyrrolidin-l-yl)oxy]-3- oxopropanenitrile (7.2 mg, 0.039 mmol) and the mixture was stirred overnight at room temperature. The mixture was then diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound (1.4 mg, 14%). LCMS calc. for C27H28 7O3 (M+H)+: m/z = 498.2; found: 498.3.
Example 153
7V-{(3 ?)-l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- < ^][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}morpholine-4-carboxamide
Figure imgf000189_0002
To a solution of (3 ?)-l-[(45)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5 dihydroimidazo[l,5,4-i/e][l,4]benzoxazin-2-yl]pyrrolidin-3-amine trihydrochloride (35 mg, 0.068 mmol) in methylene chloride (1.0 mL), triethylamine (18 \L, 0.13 mmol) was added followed by morpholine-4-carbamoyl chloride (10 \L, 0.1 mmol) and the mixture was stirred for 5 min. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound, (4.1 mg, 30%). LCMS calc. for C28H32 7O4 (M+H)+: m/z = 530.2; found: 530.3.
Example 154
7-(3,5-Dimethylisoxazol-4-yl)-2-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- <fe][l,4]benzoxazine
Figure imgf000190_0001
A mixture of 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-ife][l,4]benzoxazine (45 mg, 0.12 mmol), 2.0 M methylzinc chloride in THF (310 μΚ), and tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006 mmol) in THF (2 mL) under nitrogen was heated in a microwave at 150 °C for 5 min. Purification by preparative LCMS using pH 10 buffer gave the title compound (21 mg, 49%). LCMS calc. for C2oH19 402 (M+H)+: m/z = 347.1; found: 347.2. ¾ NMR (300 MHz, CD3OD) δ 8.58 (d, J= 4.8 Hz, 1H), 7.69 (td, J= 7.8, 1.8 Hz, 1H), 7.32 (dd, J= 7.1, 5.3 Hz, 1H), 7.05 (d, J= 8.1 Hz, 2H), 6.89 (d, J= 8.1 Hz, 2H), 6.59 (d, J= 7.9 Hz, 1H), 6.03 (s, 1H), 4.55 (dd, J= 11.5, 2.8 Hz, 2H), 4.29 - 4.09 (m, 1H), 4.00 - 3.71 (m, 2H), 3.63 - 3.50 (m, 3H), 3.40 (dd, J= 9.8, 4.6 Hz, 1H), 2.23 (s, 3H), 2.23 - 2.11 (m, 1H), 2.08 (s, 3H), 1.98 - 1.83 (m, 1H).
Example 155
Methyl {(3JR)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-< ^] [l,4]benzoxazin-2-yl]pyrrolidin-3-yl}carbamate
Figure imgf000191_0001
Step 1. ( 3R)-l-f ( 4S)- 7-( 3, 5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4, 5-dihydroimidazof 1, 5, 4- dejf 1, 4 Jbenzoxazin-2-yi Jpyrroiidin-3-amine trihydrochloride
Figure imgf000191_0002
(45")-2-Chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-ife][l,4]benzoxazine (300 mg, 0.8 mmol) tert-butyl (3R)-pyrrolidin-3- ylcarbamate (4.57 g, 24.5 mmol) and triethylamine (570 \L, 4.1 mmol) were stirred in N- methylpyrrolidinone (10 mL) and heated to 150 °C in a microwave for 5 min. Purifiication by preparative LCMS (pH 10) gave the desired boc -protected intermediate. Treatment with 4 Ν HC1 in dioxanes/methanol and subsequent evaporation of the solvents afforded the title compound (36 mg, 100%). LCMS calc. for C23H25 602 (M+H)+: m/z = 417.2; found: 417.3.
Step 2. Methyl {(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazof 1, 5, 4-de][ 1, 4 Jbenzoxazin-2-yi ]pyrrolidin-3-yl}carbamate
(3R)-l-[(45)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- i/e][l,4]benzoxazin-2-yl]pyrrolidin-3-amine trihydrochloride (35 mg, 0.068 mmol) was stirred in methylene chloride (1.0 mL) with triethylamine (47 \L, 0.34 mmol), followed by addition of methyl chloroformate (10 μί, 0.14 mmol). The mixture was stirred at room temperature for 30 min and concentrated. Purification by preparative LCMS using pH 10 buffer gave the title compound (24 mg, 75%). LCMS calc. for C25H27 6O4 (M+H)+:
m/z = 475.2; found: 475.3. XH NMR (300 MHz, CD3OD) δ 8.58 (d, J= 4.8 Hz, 1H), 7.69 (td, J= 7.8, 1.8 Hz, 1H), 7.32 (dd, J= 7.1, 5.3 Hz, 1H), 7.05 (d, J= 8.1 Hz, 2H), 6.89 (d, J= 8.1 Hz, 2H), 6.59 (d, J= 7.9 Hz, 1H), 6.03 (s, 1H), 4.55 (dd, J= 1 1.5, 2.8 Hz, 2H), 4.29 - 4 (m, 1H), 4.00 - 3.71 (m, 2H), 3.63 - 3.50 (m, 3H), 3.40 (dd, J= 9.8, 4.6 Hz, 1H), 2.23 ( 3H), 2.23 - 2.11 (m, 1H), 2.08 (s, 3H), 1.98 - 1.83 (m, 1H).
Example 155
7-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-iV,iV-dimethyl-4-pyridin-3-yl-4,5- dihydroimidazo[l,5,4-< ^] [l,4]benzoxazin-2-amine
Figure imgf000192_0001
Step 1. 6-Bromo-4-fluoro-2,3-dinitrophenol
Figure imgf000192_0002
To a solution of 2-bromo-4-fluoro-5-nitrophenol (4.0 g, 17 mmol) in methylene chloride (29.5 mL), 2.0 M nitric acid in DCM (25 mL) was added and the mixture was stirred for 15 min at room temperature. The mixture was poured over cold water and extracted with methylene chloride to give the product. Step 2. 2-Amino-6-bromo-4-fluoro-3-nitrophenol
Figure imgf000192_0003
6-Bromo-4-fluoro-2,3-dinitrophenol (4.4 g, 16 mmol) was stirred in methanol (88 mL) and 12.0 M hydrogen chloride in water (40 mL), followed by addition of stannous chloride dihydrate (11 g, 47 mmol) and the mixture was stirred at room temperature for 15 min. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated and concentrated. Purification on silica gel eluting ethyl acetate in hexanes gave the amine product. Step 3. 8-Bromo-6-fluoro-5-nitro-3-pyridin-3-yl-3, 4-dihydro-2H-l, 4-benzoxazin-3-ol
Figure imgf000193_0001
2-Amino-6-bromo-4-fluoro-3-nitrophenol (500 mg, 2.0 mmol) and potassium carbonate (780 mg, 5.7 mmol) were stirred in acetone (8 mL) for 15 min followed by addition of 2-bromo-l-pyridin-3-ylethanone hydrobromide (530 mg, 1.9 mmol) over a period of 5 min. The mixture was stirred at room temperature for 15 min and poured over water. The aqueous mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification on silica gel elucting ethyl acetate in hexanes afforded the bicyclic product. LCMS calc. for Ci3HioBrF 304 (M+H)+: m/z = 370.0; found: 370.0.
Step 4. 8-Bromo-6-fluoro-3-pyridin- -yl-2H-l, 4-benzoxazin-5-amine
Figure imgf000193_0002
Iron (91 mg, 1.6 mmol) was added to a mixture of 8-bromo-6-fluoro-5-nitro-3- pyridin-3-yl-3,4-dihydro-2H-l,4-benzoxazin-3-ol (121.0 mg, 0.3269 mmol) in acetic acid (3 mL), and heated overnight at 60 °C. The mixture was extracted with ethyl acetate and the organic layer concentrated. Purification on silica gel eluting ethyl acetate in hexanes afforded product. LCMS calc. for Ci3H10BrFN3O (M+H)+: m/z = 322.0; found: 322.0.
Step 5. 8-Bromo-6-fluoro-3-pyridin- -yl-3, 4-dihydro-2H-l, 4-benzoxazin-5-amine
Figure imgf000193_0003
Sodium tetrahydroborate (44 mg, 1.2 mmol) was added to a solution of 8-bromo-6- fluoro-3-pyridin-3-yl-2H-l,4-benzoxazin-5-amine (190 mg, 0.58 mmol) in ethanol (4 mL) and water (1 mL), and heated at 90 °C for 15 minutes. The mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic solvents were evaporated to afford the product. LCMS calc. for Ci3H12BrFN30 (M+H)+: m/z = 324.0; found: 324.0.
Step 6. 7-Bromo-9-fluoro-4-pyridin-3-yl-4, 5-dihydroimidazo[ 1, 5, 4-deJ '[ 1, 4 Jbenzoxazin- 2(lH)-one
Figure imgf000194_0001
Triethylamine (140 \L, 1.0 mmol) was added to a solution of 8-bromo-6-fluoro-3- pyridin-3-yl-3,4-dihydro-2H-l,4-benzoxazin-5 -amine (160 mg, 0.50 mmol)) in THF (6.0 mL), followed by addition of triphosgene (60 mg, 0.2 mmol), and the mixture was subsequently stirred at room temperature for 10 min. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine and concentrated. Purification on silica gel eluting ethyl acetate in hexanes afforded the title compound. LCMS calc. for Ci4H10BrF 3O2 (M+H)+: m/z = 350.0; found: 350.0. Step 7. 7-(3, 5-Dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4, 5-dihydroimidazo[ 1, 5, 4- dejf l,4]benzoxazin-2(lH)-one
Figure imgf000194_0002
7-Bromo-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4-(ie][l,4]benzoxazin- 2(lH)-one (50 mg, 0.14 mmol), potassium (3,5-dimethylisoxazol-4-yl)(trifluoro)borate(l-) (43 mg, 0.21 mmol), [l, r-/?«(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1 : 1) (10 mg, 0.01 mmol) and potassium carbonate (39 mg, 0.28 mmol) were stirred in 1,4-dioxane (1.1 mL) and water (0.28 mL) under a flow of nitrogen gas for 5 min. The mixture was then heated to 90 °C for 6 h. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were collected and evaporated to give the desired compound. LCMS calc. for Ci9Hi6F 403 (M+H) : m/z = 367.1; found
Step 8. 2-Chloro- 7-( 3, 5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4, 5- dihydroimidazof 1, 5, 4-de][ 1, 4 Jb
Figure imgf000195_0001
Phosphoryl chloride (1.5 mL, 16 mmol) was added to a vial charged with 7-(3,5- dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[ l,5,4- de][ l,4]benzoxazin-2(lH)-one (32 mg, 0.087 mmol) and the mixture was stirred overnight at 90 °C. The mixture was quenched with ice-cold water, diluted with aHC03 and extracted with ethyl acetate. The organic extracts were collected and evaporated to afford the title compound. LCMS calc. for Ci9H15ClFN402 (M+H)+: m/z = 385.1; found: 385.1.
Step 9. 7-(3, 5-Dimethylisoxazol-4-yl)-9-fluoro-N,N-dimethyl-4-pyridin-3-yl-4, 5- dihydroimidazof 1, 5, 4-de][ 1, 4 ]benzoxazin-2-amine
Triethylamine (16 μί, 0.12 mmol) and dimethylamine (0.2 mL, 4 mmol) were added to 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- i/e][ l,4]benzoxazine (15 mg, 0.040 mmol) in N-methylpyrrolidinone (0.41 mL) and the mixture was heated in a microwave at 150 °C for 20 min. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to afford the title compound (3.0 mg, 19%). LCMS calc. for C2iH21FN502 (M+H)+: m/z = 394.2; found: 394.1.
Example 157
l-[7-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- <fe][l,4]benzoxazin-2-yl]pyrrolidin-3-ol
Figure imgf000196_0001
Triethylamine (16 \L, 0.12 mmol) and 3-pyrrolidinol (0.2 niL, 3 mmol) were added to 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- ife][l,4]benzoxazine (15 mg, 0.040 mmol) in N-methylpyrrolidinone (0.41 mL) and the mixture was heated in a microwave at 150 °C for 20 min. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to afford the title compound (2.4 mg, 14%). LCMS calc. for CzstfeFNjOs (M+H)+: m/z = 436.2; found: 436.1.
Example 158
7-(3,5-Dimethylisoxazol-4-yl)-7V-ethyl-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- <fe][l,4]benzoxazin-2-amine
Figure imgf000196_0002
Triethylamine (16 μΐ^, 0.12 mmol) and ethylamine (0.2 mL, 3 mmol) were added to 2- chloro-7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- ife][l,4]benzoxazine (15 mg, 0.040 mmol) in N-methylpyrrolidinone (0.41 mL) and the mixture was heated in a microwave at 150 °C for 20 min. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to afford the title compound (3.0 mg, 19%). LCMS calc. for C2iH21FN502 (M+H)+: m/z = 394.2; found: 394.1.
Example 159A
(3 ?)-l-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- <fe][l,4]benzoxazin-2-yl]pyrrolidin-3-ol (Diastereoisomer 1)
Example 159B
(3 ?)-l-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- <fe][l,4]benzoxazin-2-yl]pyrrolidin-3-ol (Diastereoisomer 2A)
Example 159C
(3 ?)-l-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- <fe][l,4]benzoxazin-2-yl]pyrrolidin-3-ol (Diastereoisomer 2B)
Example 159D
(3 ?)-l-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- <fe][l,4]benzoxazin-2-yl]pyrrolidin-3-ol (Diastereoisomer 3)
Example 159E
(3 ?)-l-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazin-2-yl]pyrrolid -3-ol (Mixture of diastereoisomers)
Figure imgf000197_0001
The title compound was prepared by methods analogous to Example 157, substituting 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- ife][l,4]benzoxazine and 3R-pyrrolidinol. The mixture was diluted with methanol and purifed by preparative LCMS using pH 10 buffer to afford the title compound as a mixture of diastereomers (13.3 mg, 75%). LCMS calc. for
Figure imgf000197_0002
(M+H)+: m/z = 418.2; found: 418.2. The isomers were separated by prep chiral column chromatography using the following conditions: Column: phenomenex Lux Cellulose C-2 5 μιη, 21, 2x250 mm, Mobile phase: 45% EtOH/Hexanes, gradient condition: isocratic at 18 mL/min, Loading: 5.0 mg in 900 \L, run time: 18 min, peak time: 12.0, 14.0 and 16.0 min.
Example 159A, Peak 1, LCMS calc. for C23H24N5O3 (M+H)+: m/z = 418.2; found:
418.2.
Peak 2 was isolated as a mixture of 2 diastereomers and further separated by prep chiral column chromatography: Column: phenomenex Lux Cellulose C-4 5 μιη, 21, 2x250 mm, Mobile phase: 30% EtOH/Hexanes, gradient condition: isocratic at 18 mL/min, Loading: 1.5 mg in 900 μί, run time: 23 min, peak time: 18.5 and 20.0 min.
Example 159B, Peak 2A, LCMS calc. for C23H24 503 (M+H)+: m/z = 418.2; found:
418.2. Example 159C, Peak 2B, LCMS calc. for C23H24 5O3 (M+H) : m/z = 418.2; found:
418.2.
Example 159D, Peak 3, LCMS calc. for C23H24 5O3 (M+H)+: m/z = 418.2; found:
418.2.
Examples 160A
l-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]azetidin-3-ol
Examples 160B
l-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]azetidin-3-ol
Examples 160C
l-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]azetidin-3-ol
Examples 160D
l-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl]azetidin-3-
Figure imgf000198_0001
The title compound was prepared by methods analogous to Example 157, substituting 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- ife][l,4]benzoxazine, azetidin-3-ol hydrochloride and extending the reaction time to 60 min. The mixture was diluted with methanol and purifed by preparative LCMS using pH 10 buffer to give the title compound as a racemic mixture (16 mg, 23%). LCMS calc. for C22H22 5O3 (M+H)+: m/z = 404.2; found: 404.2. The isomers were separated by prep chiral column chromatography using the following conditions: Column: phenomenex Lux Cellulose C-2 5 μιη, 21, 2x250 mm, Mobile phase: 45% EtOH/Hexanes, gradient condition: isocratic at 18 mL/min, Loading: 2.0 mg in 900 \L, run time: 24 min, peak time: 12.0, 14.0, 16.0 and 21.0 min. Example 160A, Peak 1, LCMS calc. for C22H22N503 (M+H) : m/z = 404.2; found: 404.2. 'H NMR (500 MHz, DMSO) δ 8.47 (dd, J= 4.8, 1.6 Hz, 1H), 8.43 (d, J= 2.2 Hz, 1H), 7.58 (dt, J= 7.9, 1.9 Hz, 1H), 7.35 (dd, J= 7.9, 4.8 Hz, 1H), 6.74 (d, J= 7.9 Hz, 1H), 6.70 (d, J= 8.0 Hz, 1H), 5.42 (t, 1H), 5.07 (d, J= 3.8 Hz, 1H), 4.61 (dd, J= 11.6, 1.9 Hz, 1H), 4.36 (dd, J= 11.6, 2.9 Hz, 1H), 4.00 (d, J= 3.5 Hz, 1H), 3.91 (dd, J= 11.5, 2.8 Hz, 1H), 3.67 (dd, J= 11.5, 4.2 Hz, 1H), 3.40 - 3.34 (m, 1H), 3.17 (dd, J= 14.3, 4.2 Hz, 1H), 2.24 (s, 3H), 2.07 (s, 3H).
Example 160B, Peak 2, LCMS calc. for C22H22N503 (M+H)+: m/z = 404.2; found: 404.2. 'H NMR (500 MHz, DMSO) δ 8.47 (dd, J= 4.8, 1.6 Hz, 1H), 8.43 (d, J= 2.2 Hz, 1H), 7.58 (dt, J= 7.9, 1.9 Hz, 1H), 7.35 (dd, J= 7.9, 4.8 Hz, 1H), 6.74 (d, J= 7.9 Hz, 1H), 6.70 (d, J= 8.0 Hz, 1H), 5.42 (t, 1H), 5.07 (d, J= 3.8 Hz, 1H), 4.61 (dd, J= 11.6, 1.9 Hz, 1H), 4.36 (dd, J= 11.6, 2.9 Hz, 1H), 4.00 (d, J= 3.5 Hz, 1H), 3.91 (dd, J= 11.5, 2.8 Hz, 1H), 3.67 (dd, J= 11.5, 4.2 Hz, 1H), 3.40 - 3.34 (m, 1H), 3.17 (dd, J= 14.3, 4.2 Hz, 1H), 2.24 (s, 3H), 2.07 (s, 3H).
Example 160C, Peak 3, LCMS calc. for C22H22N503 (M+H)+: m/z = 404.2; found:
404.2. 'H NMR (500 MHz, DMSO) δ 8.47 (dd, J= 4.8, 1.6 Hz, 1H), 8.43 (d, J= 2.2 Hz, 1H), 7.58 (dt, J= 7.9, 1.9 Hz, 1H), 7.35 (dd, J= 7.9, 4.8 Hz, 1H), 6.74 (d, J= 7.9 Hz, 1H), 6.70 (d, J= 8.0 Hz, 1H), 5.42 (t, 1H), 5.07 (d, J= 3.8 Hz, 1H), 4.61 (dd, J= 11.6, 1.9 Hz, 1H), 4.36 (dd, J= 11.6, 2.9 Hz, 1H), 4.00 (d, J= 3.5 Hz, 1H), 3.91 (dd, J= 11.5, 2.8 Hz, 1H), 3.67 (dd, J= 11.5, 4.2 Hz, 1H), 3.40 - 3.34 (m, 1H), 3.17 (dd, J= , 42 nz, 1H), 2.24 (s, 3H), 2.07 (s, 3H).
Example 160D, Peak 4, LCMS calc. for C22H22N503 (M+H)+: m/z = 404.2; found: 404.2. 'H NMR (500 MHz, DMSO) δ 8.47 (dd, J= 4.8, 1.6 Hz, 1H), 8.43 (d, J= 2.2 Hz, 1H), 7.58 (dt, J= 7.9, 1.9 Hz, 1H), 7.35 (dd, J= 7.9, 4.8 Hz, 1H), 6.74 (d, J= 7.9 Hz, 1H), 6.70 (d, J= 8.0 Hz, 1H), 5.42 (t, 1H), 5.07 (d, J= 3.8 Hz, 1H), 4.61 (dd, J= 11.6, 1.9 Hz, 1H), 4.36 (dd, J= 11.6, 2.9 Hz, 1H), 4.00 (d, J= 3.5 Hz, 1H), 3.91 (dd, J= 11.5, 2.8 Hz, 1H), 3.67 (dd, J= 11.5, 4.2 Hz, 1H), 3.40 - 3.34 (m, 1H), 3.17 (dd, J= 14.3, 4.2 Hz, 1H), 2.24 (s, 3H), 2.07 (s, 3H).
Examples 161-251
The compounds of Examples 161 to 251 are set out in Table 8 below.
Table 8
Figure imgf000200_0001
Ex. No. Name R5 Procedure*
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-
161 morpholin-4-yl-4-pyridm-2-yl-4,5- 25 dihydroimidazof 1 ,5,4- del [ 1 ,4~|benzoxazine
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-
162 pyridin-2-yl-2-pyrrolidin- 1 -yl-4,5- 25 dihydroimidazof 1 ,5,4- de][ 1 ,4]benzoxazine
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-
163 methylpiperazin-l-yl)-4-pyridin-2-yl- 25
4 , 5 -dihy droimidazo [1,5,4- de] [ 1 ,4]benzoxazine
(4S)-2-azetidin- 1 -yl-7-(3 ,5-
164 dimethylisoxazol-4-yl)-4-pyridin-2-yl- 25
4 , 5 -dihy droimidazo [1,5,4- de] [ 1 ,4]benzoxazine
l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-
165 pyridin-2-yl-4,5-dihydroimidazo[ 1 ,5,4- ry0H 25 de] [ 1 ,4]benzoxazin-2 -y 1] azetidin-3 -ol
4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-
166 pyridin-2-yl-4,5-dihydroimidazo[l ,5,4- de] [ 1 ,4]benzoxazin-2-yl] - 1 - ΝΛ0 25 methylpiperazin-2-one
ethyl 4-[(4S)-7-(3 ,5-dimethylisoxazol-4- 0
yl)-4-pyridin-2-yl-4,5-
167 dihydroimidazof 1,5,4- 25 de] [ 1 ,4]benzoxazin-2-yl]piperazine- 1 - carboxylate
(3R)-l-[(4S)-7-(3,5-Dimethylisoxazol-4-
168A yl)-4-pyridin-3-yl-4,5- 25
dihydroimidazof 1,5,4- del [ 1 ,4]benzoxazin-2-yllpyrrolidin-3 -ol
(3 S)- 1 -[(4S)-7-(3 ,5-Dimethylisoxazol-4-
168B yl)-4-pyridin-3-yl-4,5- dihydroimidazof 1 ,5,4- de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -ol >N "OH 25 l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-
169 pyridin-2-yl-4,5-dihydroimidazo[ 1 ,5,4- 25 de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-ol rr0H
(3R)-l -[(4S)-7 -(3 ,5 -dimethy lisoxazol-4-
170A yl)-4-pyridin-2-yl-4,5- dihydroimidazof 1,5,4- ,0 0H 25 del [ 1 ,4~|benzoxazin-2-yllpiperidin-3 -ol
(3 S)- 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4-
170B yl)-4-pyridin-2-yl-4,5- 25
dihydroimidazof 1 ,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperidin-3 -ol Ex. No. Name Procedure* l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-
171 pyridin-2-yl-4,5-dihydroimidazo[l,5,4- 25 de] [ 1 ,4]benzoxazin-2-yl] -N,N- dimethylpiperidin-4-amine
4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-
172 pyridin-2-yl-4,5-dihydroimidazo[l,5,4- 25 de] [ 1 ,4]benzoxazin-2-yl]piperazin-2-one
Figure imgf000201_0001
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-
173 (methylsulfonyl)piperazin-l-yl]-4- 25 pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazine
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-
174 isopropylpiperazin- 1 -yl)-4-pyridin-2-yl- 25
4 , 5 -dihy droimidazo [1,5,4- de] [ 1 ,4]benzoxazine
l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-
175 pyridin-2-yl-4,5-dihydroimidazo[l,5,4- 25 de] [ 1 ,4]benzoxazin-2-yl]piperidine-4- carbonitrile
{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-
4-pyridin-2-yl-4,5-
176 dihydroimidazof 1 ,5,4- 25 de] [ 1 ,4]benzoxazin-2-yl]piperidin-4- yl} methanol
2-{4-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
177 dihydroimidazof 1 ,5,4- 25 de] [ 1 ,4]benzoxazin-2-yl]piperazin- 1 - yljethanol
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-
178 phenylpiperazin- 1 -yl)-4-pyridin-2-yl- 25
4 , 5 -dihy droimidazo [1,5,4- de] [ 1 ,4]benzoxazine
(4S)-2-(4-benzylpiperazin-l-yl)-7-(3,5-
179 dimethylisoxazol-4-yl)-4-pyridin-2-yl- 25
4 , 5 -dihy droimidazo [1,5,4- de] [ 1 ,4]benzoxazine
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
180A dihydroimidazof 1 ,5,4- 25
de] [ 1 ,4]benzoxazin-2-yl] -N,N- dimethylpyrrolidin-3 -amine
(3 S)- 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
180B dihydroimidazof 1 ,5,4- 25
de] [ 1 ,4]benzoxazin-2-yl] -N,N- dimethylpyrrolidin-3 -amine
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
181A dihydroimidazof 1 ,5,4- N 5
de] [ 1 ,4]benzoxazin-2-yl] -N- 0^n x h 2 methylpyrrolidin-3 -amine Ex. No. Name R5 Procedure*
(3 S)- 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
181B dihydroimidazof 1,5,4- de] [ 1 ,4]benzoxazin-2-yl]-N- N "'N X H 25 methylpyrrolidin-3 -amine
tert-butyl {(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-
182A 4 , 5 -dihy droimidazo [1,5,4- 25 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - 0
yljcarbamate
tert-butyl {(3S)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-
182B ' H
4 , 5 -dihy droimidazo [1,5,4- N - Y- 25 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - 0
yl} carbamate
(4S)-2-[4-(cyclopropylmethyl)piperazin-
183 l-yl]-7-(3,5-dimethylisoxazol-4-yl)-4- 25 pyridin-2-yl-4,5-dihydroimidazo[l ,5,4- de] [ 1 ,4]benzoxazine
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-
184 (2 -methoxyethyl)piperazin- 1 -y 1] -4- 25 pyridin-2-yl-4,5-dihydroimidazo[l ,5,4- de] [ 1 ,4]benzoxazine
2-[[7-(3,5-dimethylisoxazol-4-yl)-4- 1 OH
185 pyridin-2-yl-4,5-dihydroimidazo[ 1 ,5,4- 25 de] [ 1 ,4]benzoxazin-2- yl](methyl)amino]ethanol
7-(3,5-dimethylisoxazol-4-yl)-N-methyl-
186 4-pyridin-2-yl-4,5- H
25 dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-amine
7-(3,5-dimethylisoxazol-4-yl)-N,N-
1
187 dimethyl-4-pyridin-2-yl-4,5- 25 dihydroimidazof 1 ,5,4- de] [ 1 ,4]benzoxazin-2-amine
O
l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-
188 pyridin-2-yl-4,5-dihydroimidazo[ 1 ,5,4- 25 de] [ 1 ,4]benzoxazin-2-yl]piperidine-4- carboxamide
l -[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-
189 pyridin-2-yl-4,5-dihydroimidazo[l ,5,4- 25 de] [ 1 ,4]benzoxazin-2-yl] -N- methylpiperidine-4-carboxamide
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
190 dihydroimidazof 1,5,4- 25 de] [ 1 ,4]benzoxazin-2-yl]piperidin-4- yl}acetamide
2- {4-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
191 dihydroimidazo[l,5,4- 25 de] [ 1 ,4]benzoxazin-2-yl]piperazin- 1 - yl} acetamide
Figure imgf000203_0001
Ex. No. Name R Procedure*
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
202A dihydroimidazof 1 ,5,4- 150
de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -
Figure imgf000204_0001
amine trihydrochloride
(3 S)- 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
202B dihydroimidazof 1 ,5,4- de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - N "NH2 150 amine trihydrochloride
N-{(3R)-l-[(4S)-7-(3,5- O p p
dimethylisoxazol-4-yl)-4-pyridin-2-yl-
203 4 , 5 -dihy droimidazo [1,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yl} -2,2,2-trifluoroacetamide
N-{(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl- ° n
205 4 , 5 -dihy droimidazo [1,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yl} -2-methoxyacetamide
N-{(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-
206 4 , 5 -dihy droimidazo [1,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yljcyclopropanecarboxamide
N-{(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl- ° o
207 4 , 5 -dihy droimidazo [1,5,4- 149 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yl } methanesulfonamide
N-{(3R)-l-[(4S)-7-(3,5- O
dimethylisoxazol-4-yl)-4-pyridin-2-yl-
208 4 , 5 -dihy droimidazo [1,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yljpropanamide
N-{(3R)-l-[(4S)-7-(3,5- 0
dimethylisoxazol-4-yl)-4-pyridin-2-yl-
209 4 , 5 -dihy droimidazo [1,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yl} -2-methylpropanamide
N-{(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-
210 4 , 5 -dihy droimidazo [1,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yl } cyclobutanecarboxamide
2-cyano-N-{(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-
211 4 , 5 -dihy droimidazo [1,5,4- 152 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yljacetamide
N-{(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-
213 4 , 5 -dihy droimidazo [1,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yl}tetrahydro-2H-pyran-4-carboxamide Ex. No. Name R Procedure*
N-{(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-
214 4 , 5 -dihy droimidazo [1,5,4- 149 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yl } ethanesulfonamide
N-{(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl- ° n
215 4 , 5 -dihy droimidazo [1,5,4- 149 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yl}propane- 1 -sulfonamide
N'-{(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-
216 4 , 5 -dihy droimidazo [1,5,4- 153 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yl} -N,N-dimethylurea
N-{(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl- 0 O
217 4 , 5 -dihy droimidazo [1,5,4- 149 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yl}propane-2-sulfonamide
N-{(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-
218 4 , 5 -dihy droimidazo [1,5,4- 149 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -
Figure imgf000205_0001
yl}cyclopropanesulfonamide
methyl {(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-
219 4 , 5 -dihy droimidazo [1,5,4- 155 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - y 1 } methylc arb amate
N-{(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-
220 4 , 5 -dihy droimidazo [1,5,4- 149 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yl} -N-methylmethanesulfonamide
N-{(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl- ° n
221 4 , 5 -dihy droimidazo [1,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yl} -2-methoxy-N-methylacetamide
N-{(3R)-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-
222 4 , 5 -dihy droimidazo [1,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -
Figure imgf000205_0002
yl } -N-methylacetamide
(4S)-2-(4-acetylpiperazin-l-yl)-7-(3,5-
224 dimethylisoxazol-4-yl)-4-pyridin-2-yl- 148 4 , 5 -dihy droimidazo [1,5,4- de] [ 1 ,4]benzoxazine
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-
225 propionylpiperazin- 1 -yl)-4-pyridin-2-yl- 148 4 , 5 -dihy droimidazo [1,5,4- de] [ 1 ,4]benzoxazine Ex. No. Name R Procedure*
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-
226 (ethylsulfonyl)piperazin- 1 -yl]-4-pyridin- 149 2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazine
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4- (2-oxo-2-pyrrolidin- 1 -ylethyl)piperazin-
228 1 -yl]-4-pyridin-2-yl-4,5- 151 dihydroimidazof 1 ,5,4- de] [ 1 ,4]benzoxazine
4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4- 1 Δ
229 pyridin-2-yl-4,5-dihydroimidazo[l,5,4- I 147 de] [ 1 ,4]benzoxazin-2-yl]piperazine- 1 - N I I O
sulfonamide
l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-
230 pyridin-2-yl-4,5-dihydroimidazo[l,5,4- 150 de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 - amine trihydrochloride
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
231 dihydroimidazof 1 ,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 -
Figure imgf000206_0001
yljacetamide
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
232 dihydroimidazof 1 ,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 - yl}propanamide
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
233 dihydroimidazof 1 ,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 -yl } -
2 -me thy lprop an amide
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
234 dihydroimidazof 1 ,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 -yl } -
2-methoxyacetamide
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
235 dihydroimidazof 1 ,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 - yl}cyclopropanecarboxamide
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
236 dihydroimidazof 1 ,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 - yl } cyclobutanecarboxamide
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
237 dihydroimidazof 1 ,5,4- N 149 de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 - N " ¾"
yl } methanesulfonamide Ex. No. Name R Procedure*
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- H
yl)-4-pyridin-2-yl-4,5-
238 dihydroimidazof 1 ,5,4- 149 de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 - yl } ethanesulfonamide
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
239 dihydroimidazof 1 ,5,4- de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 - iff °i 149 yl}propane-2-sulfonamide
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
240 dihydroimidazof 1 ,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperidin-4- yl } methanesulfonamide rrNH 149
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
241 dihydroimidazof 1 ,5,4- 149 de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-yl } - rrNH
2-methoxyacetamide
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
242 dihydroimidazof 1 ,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-yl } -
2,2,2-trifluoroacetamide
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
243 dihydroimidazof 1 ,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl]piperidin-4- yl}propanamide
N- { 1 -[(4S)-7-(3 ,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
244 dihydroimidazof 1 ,5,4- 148 de] [ 1 ,4]benzoxazin-2-yl]piperidin-4- rrNH
yl}propanamide
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-
246 propionyl-1 ,4-diazepan- 1 -yl)-4-pyridin- 148 2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazine
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-
248 (ethylsulfonyl)- 1 ,4-diazepan- 1 -yl] -4- 149 pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazine
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
249 dihydroimidazof 1 ,5,4- 145 de] [ 1 ,4]benzoxazin-2-yl] -N-
Figure imgf000207_0001
methylpyrrolidine-3 -carboxamide Ex. No. Name R Procedure*
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-
250 dihydroimidazof 1 ,5,4- 145
de] [ 1 ,4]benzoxazin-2-yl] -N- ethylpyrrolidine-3-carboxamide
(3R)-N-cyclopropyl-l-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-
251 4 , 5 -dihy droimidazo [1,5,4- 145
de] [ 1 ,4]benzoxazin-2-yl]pyrrolidine-3 - carboxamide
*The number in this column indicates the Example number of the procedure used to prepare the compound.
Example 252
(4S)-8,9-dichloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [l,4]benzoxazin-2(lH)-one bistrifluoroacetate
Figure imgf000208_0001
A mixture of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one (35 mg, 0.10 mmol) N- chlorosuccinimide (15 mg, 0.1 1 mmol) and tetrahydrofuran (1.0 mL) was stirred at 60 °C for 3hrs. The mixture was extracted with EtOAc, dried, concentrated, purified on silicagel and eluted with 40% EtOAc in hexane. Purification by preparative LCMS using pH 2 buffer gave the title compound as a bistrifluoroacetate salt. LCMS calc. for C19H15CI2 4O3 (M+H)+: m/z = 417.0; found: 417.2.
Example 253
7-(3,5-Dimethylisoxazol-4-yl)-9-[(isopropylamino)methyl]-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-<fe] [l,4]benzoxazin-2(lH)-one
Figure imgf000209_0001
7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5-tetrahydroimidazo[l,5,4- ife][l,4]benzoxazine-9-carbaldehyde (15 mg, 0.04 mmol) from Example 137, Step 3 was stirred in methanol (1.0 mL) with 2-propanamine (10. \L, 0.12 mmol), followed by addition of sodium cyanoborohydride (7.5 mg, 0.12 mmol). The mixture was heated at 60
°C overnight, then diluted with methanol. Purification by preparative LCMS (pH 10) afforded the title compound. LCMS calc. for C23H26 5O3 (M+H)+: m/z = 420.2; found: 420.1.
Example 254
7-(3,5-Dimethylisoxazol-4-yl)-9-(hydroxymethyl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-< ^] [l,4]benzoxazin-2(lH)-one
Figure imgf000209_0002
7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5-tetrahydroimidazo[ 1,5,4- ife][l,4]benzoxazine-9-carbaldehyde (15 mg, 0.040 mmol) from Example 137, Step 3 was stirred in ethanol (0.58 mL), followed by addition of sodium tetrahydroborate (2.3 mg, 0.060 mmol). The mixture was stirred at room temperature for 1 h. Purification by preparative LCMS (pH 10) afforded the title compound. LCMS calc. for C2oH19 404 (M+H)+:
m/z = 379.1 ; found: 379.2. Example 255
7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de\ [l,4]benzoxazine-2(lH)-thione
Figure imgf000210_0001
7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- ife][l,4]benzoxazin-2(lH)-one (50 mg, 0.1 mmol) from Example 13 was stirred in 1,4- dioxane (2 mL) and 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-l,3,2,4-dithiadiphosphetane [Aldrich #: 227439] (58 mg, 0.14 mmol) was added. The mixture was heated to 100 °C for 3 h and concentrated. Purification by preparative LCMS (pH 10) afforded the title compound. LCMS calc. for CwHnN-jCfeS (M+H)+: m/z = 365.1 ; found: 365.1.
Examples 256-269B
The experimental procedures used to prepare the compounds of Examples 256 to
269B are summarized in Table 9 below.
Figure imgf000210_0002
Figure imgf000210_0003
Figure imgf000211_0001
*The number in this column indicates the Example number of the procedure used to prepare the compound. Analytical Data
lH NMR data (Varian Inova 500 spectrometer, a Mercury 400 spectrometer, or a Varian (or Mercury) 300 spectrometer) and LCMS mass spectral data (MS) for the compounds of Examples 47A-51, 75-87, 104-108, 110-1 19, 134-136, and 139-143 are provided below in Table 10.
Table 10
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Biological Assay Protocols: Example Al
BRD4 AlphaScreen™ Assay
BRD4-BD1 and BRD4-BD2 assays were conducted in white 384-well polystyrene plate in a final volume of 20 μϊ^ for BD1 and 40 μϊ^ for BD2. Inhibitors were first serially diluted in DMSO and added to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 1.25% (BD1) and 0.83% (BD2). The assays were carried out at room temperature for 75 min. in the assay buffer (50 mM HEPES, pH 7.4, 100 mM NaCl, 0.05% CHAPS, 0.01% BSA), containing 50 nM Biotin-labeled tetra-acetylated histone H4 peptide (H4Ac4), 3.8 nM (BRD4-BD1, BPS
Bioscience #31040) or 20 nM (BRD4-BD2, BPS Bioscience # 31041). The reaction followed by the addition of 20 of assay buffer supplemented with Streptavidin donor beads (PerkinElmer 6760002) and GSH Acceptor beads (PerkinElmer-AL109C) at 4 μg/mL under reduced light. After plate sealing, the plate was incubated in the dark at room temperature for 75 min. before reading on a PHERAstar FS plate reader (BMG Labtech). IC50 determination was performed by fitting the curve of percent control activity versus the log of the inhibitor concentration using the GraphPad Prism 5.0 software.
IC50 data for the compounds of the Examples as determined by Assay Al is presented in Table 11.
Table 11
Figure imgf000223_0002
Example BRD4 BD-1 enzyme BRD4 BD-2 enzyme No. ICso (nM)* ICso (nM)*
4 + +
5 + +
6 + +
7 + +
8 + +
9 + +
10 ++ +
11 +++ ++
12 ++ +
13 + +
14 +++ +++
15 + +
17 + +
18A ++ +
18B ++ +
21 + +
22 + +
23 + +
24A ++ +
24B ++ +
25 + +
26 + +
27 + +
28 + +
29 + +
30 + +
31 + +
32 + +
33 +++ ++
34 + +
35 ++ +
36 ++ +
37 ++ +
38 +++ ++ Example BRD4 BD-1 enzyme BRD4 BD-2 enzyme
No. ICso (nM)* ICso (nM)*
39 + +
40 ++ +
49 + +
50 + +
51 + +
53 + +
54 + +
55 + +
56 + +
57 + +
58 + +
59 + +
60 + +
*Symbols used:
+ : IC50 < 100 nM
++: 100 nM < IC50 < 1000 nM
+++: 1000 nM to 10000 nM
NT = not tested
Example A2
BRD4 AlphaScreen™ Assay
BRD4-BD1 and BRD4-BD2 assays were conducted in white 384-well polystyrene plate in a final volume of 40 μϊ^ for BD1 and 60 μϊ^ for BD2. Inhibitors were first serially diluted in DMSO and added to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 1.25% (BD1) and 0.83% (BD2). The assays were carried out at room temperature in the assay buffer (50 mM Tris- HC1, pH 7.5, 0.01% Tween-20, 0.01% BSA, 5 mM DTT), containing 50 nM Biotin-labeled tetra-acetylated histone H4 peptide (H4Ac4) and BRD4-BD1 or BRD4-BD2 protein at concentration less than 1 nM. The incubation for 75 min. was followed by the addition of 20 μΐ, of assay buffer supplemented with Streptavidin donor beads (PerkinElmer 6760002) and GSH Acceptor beads (PerkinElmer-AL109C) at final concentration 2-4 μg/mL under reduced light. After plate sealing, the plate was incubated in the dark at room temperature for 75 min. before reading on a PHERAstar FS plate reader (BMG Labtech). IC50 determination was performed by fitting the curve of percent control activity versus the log of the inhibitor concentration using the GraphPad Prism 5.0 software.
IC50 data for the compounds of the Examples as determined by Assay A2 is presented in Table 12.
Table 12
Figure imgf000226_0001
Example BRD4 BD-1 enzyme BRD4 BD-2 enzyme No. ICso (nM)* ICso (nM)*
80 +++ +++
81 ++ +
82 ++ +
83 + +
84 ++ +
85 +++ ++
86 ++ +
87 ++ +
88 + +
89 + +
90 + +
91 + +
92 + +
93 + +
94 + +
95 + +
96 + +
97 + +
98 + +
99 + +
100 + +
101A + +
101B + +
102 NT NT
103 + +
104 + +
105 + +
106A + +
106B + +
107 + +
108 NT NT
109 + +
110 + +
11 1 + + Example BRD4 BD-1 enzyme BRD4 BD-2 enzyme No. ICso (nM)* ICso (nM)*
112 + +
113A + +
113B + +
114A + +
114B + +
115 + +
116 + +
117 + +
118 + +
119 + +
120 + +
121 ++ +
122 ++ +
123 ++ +
124 +++ ++
125 +++ +
126 ++ +
127 + +
128 + +
129 ++ +
130 + +
131 + +
132 + +
133 + +
134 + +
135 + +
136 + +
137 +++ +
138 + +
139 + +
140 + +
141 + +
142 ++ +
143 ++ + Example BRD4 BD-1 enzyme BRD4 BD-2 enzyme No. ICso (nM)* ICso (nM)*
144A ++ +
144B ++ +
145 + +
146A + +
146B + +
146C + +
147 + +
148 + +
149 + +
150 + +
151 + +
152 + +
153 + +
154 + +
155 + +
156 ++ +
157 + +
158 + +
159A +++ ++
159B + +
159C ++ +
159D + +
159E + +
160A +++ ++
160B +++ +++
160C +++ +++
160D +++ +++
161 + +
162 + +
163 + +
164 + +
165 + +
166 + +
167 + + Example BRD4 BD-1 enzyme BRD4 BD-2 enzyme No. ICso (nM)* ICso (nM)*
168A + +
168B + +
169 + +
170A + +
170B + +
171 + +
172 + +
173 + +
174 + +
175 + +
176 + +
177 + +
178 + +
179 + +
180A + +
180B + +
181A + +
181B + +
182A + +
182B + +
183 + +
184 + +
185 ++ +
186 + +
187 + +
188 + +
189 + +
190 + +
191 + +
192 + +
193 A + +
193B + +
194 + +
195 + + Example BRD4 BD-1 enzyme BRD4 BD-2 enzyme No. ICso (nM)* ICso (nM)*
196 + +
197 + +
198 +++ +
199 ++ +
200 ++ +
201A + +
201B + +
202A + +
202B + +
203 + +
205 + +
206 + +
207 + +
208 + +
209 + +
210 + +
21 1 + +
213 + +
214 + +
215 + +
216 + +
217 + +
218 + +
219 + +
220 + +
221 + +
222 + +
224 + +
225 + +
226 + +
228 + +
229 + +
230 + +
231 + + Example BRD4 BD-1 enzyme BRD4 BD-2 enzyme No. ICso (nM)* ICso (nM)*
232 + +
233 + +
234 + +
235 + +
236 + +
237 + +
238 + +
239 + +
240 + +
241 + +
242 + +
243 + +
244 + +
246 + +
248 + +
249 + +
250 + +
251 + +
252 ++ ++
253 ++ ++
254 + +
255 + +
256 + +
257 ++ +
258 +++ ++
259 ++ +
260 ++ +
261 ++ +
262 +++ +
263 ++ +
264 ++ +
265A +++ +++
265B + +
266A ++ + Example BRD4 BD-1 enzyme BRD4 BD-2 enzyme
No. ICso (nM)* ICso (nM)*
266B +++ ++
267A +++ +++
267B + +
268 +++ ++
269A + +
269B +++ +++
*Symbols used:
Figure imgf000233_0001
++: 100 nM < IC50 < 1000 nM
+++: 1000 nM to 10000 nM
NT = not tested
Example Bl: KMS.12.BM Cell Viability Assay
KMS.12.BM cell line (human myeloma) was purchased from JCRB (Osaka, Japan) and maintained in RPMI with 10% FBS culture medium. To measure the cytotoxic activity of the compounds through ATP quantitation, the KMS.12.BM cells are plated in the RPMI culture medium at 5000 cells / well/ per 100 μΐ, into a 96-well polystyrene clear black tissue culture plate (Greiner-bio-one through VWR, NJ), in the presence or absence of a concentration range of test compounds. After 3 days, 100 mL Cell Titer-GLO Luminescent (Promega, Madison, WI) cell culture agent is added to each well for 10 min. at room temperature to stabilize the luminescent signal. This determines the number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells. Luminescence is measured with the Top Count 384 (Packard Bioscience through Perkin Elmer, Boston, MA). Compound inhibition is determined relative to cells cultured with no drug and the IC50 reported as the compound concentration required for 50% cell death.
IC50 data for the compounds of the Examples as determined by Assay Bl is presented in Table 13.
Table 13
Figure imgf000233_0002
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
*Symbols used:
+ : IC50 < 1000 nM
++: 1000 nM < IC50 < 10000 nM
NT = not tested Example CI
KMS.12.BM C-myc ELISA Assay
KMS.12.BM cell line (human myeloma) was purchased from JCRB (Osaka, Japan) and maintained in RPMI with 10% FBS culture medium. To measure the C-myc inhibitory activity of the compounds, the KMS.12.BM cells are plated in the RPMI culture medium at 75000 cells / well/ per 200 μΐ, into a 96-well flat bottom polystyrene tissue culture plate (Corning through VWR, NJ), in the presence or absence of a concentration range of test compounds. After 2 h, cells are pelleted and lysed with Cell Extraction Buffer (BioSource, Carlsbad, CA) in the presence of protease inhibitors (Life Technologies, Grand Island, NY and Sigma, St Louis, MO). Clarified lyses are tested in a C-myc commercial ELISA (Life Technologies, Grand Island, NY). Compound inhibition is determined relative to cells cultured with no drug and the IC50 reported as the compound concentration required for 50% C-myc inhibition.
IC50 data for the compounds of the Examples as determined by Assay CI is presented in Table 14.
Table 14
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
*Symbols used:
+ : IC50 < 1000 nM
++: 1000 nM < IC50 < 10000 nM
NT = not tested
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present disclosure, including all patent, patent applications, and publications, is incorporated herein by reference in its entirety.

Claims

What is claimed is:
1. A compound of Formula (I):
Figure imgf000247_0001
or a pharmaceutically acceptable salt thereof, wherein:
represents a single bond or a double bond;
L is CR9R9a , 0, S, SO, or S02;
Cy1 is selected from phenyl or a 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said phenyl or 5-6 membered heteroaryl of Cy1 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R11;
R1 and R2 are independently selected from H, halo, CN, OH, Ci_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl,
C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl,
NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl, NRclS(=0)2Rbl and S(=0)2NRclRdl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl of R1 and R2 are optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl, C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl, NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl, NRclS(=0)2Rbl and
S(=0)2NRclRdl;
provided neither R1 nor R2 are CI, Br, I, CN, or OH when L is O or S;
alternatively, R1 and R2 together with the carbon atom to which they are attached are combined to form a C3-7 cycloalkyl group, wherein said cycloalkyl group is optionally substituted with 1, 2, 3, or 4 groups independently selected from R20;
Cy3 is selected from phenyl, C3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R , wherein a ring- forming nitrogen atom of said 5-10 membered heteroaryl group or a ring- forming nitrogen atom of said 4-10 membered heterocycloalkyl group is optionally oxidized;
R4 is H, C(=0)NR14aR14b, C(=0)R14a, C(=0)OR14a, or Ci_6 alkyl optionally substituted by 1, 2, or 3 substituents independently selected from halo, NR14aR14b, OR14a, SR14a, CN, C(=0)R14a, C(=0)NR14aR14b, C(=0)OR14a, OC(=0)R14b,
OC(=0)NR14aR14b, NR14aC(=0)R14b, NR14aC(=0)NR14aR14b, NR14aC(=0)OR14b, S(=0)R14a, S(=0)NR14aR14b, S(=0)2R14a, NR14aS(=0)2R14b , and S(=0)2NR14aR14b;
R5 is selected from =0 and =S when C=-^N is a single bond,
alternatively, when C^^N is a double bond then R5 is selected from H, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, NR15aR15b, -C(=0)NR15aR15b, - C(=0)OR15a, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4- 10 membered heterocycloalkyl of R5 is optionally substituted by 1, 2, 3, or 4 groups independently selected from R15;
R6 is selected from H, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 alkoxy, and Ci-6 haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R16;
alternatively, R6 is selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20;
R7 is selected from H, halo, CN, ORa, NRcRd, SRb, C(=0)NRcRd, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 4-7 membered heterocycloalkyl group of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17; R8 is selected from H, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd, wherein said Ci_3 alkyl of R8 is optionally substituted with 1 , 2, or 3 groups independently selected from R18;
R9 and R9a are independently selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
R11 is independently at each occurrence selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd, wherein said Ci_3 alkyl is optionally substituted by OH;
R13 is independently at each occurrence selected from H, halo, CN, OH, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, OR33, SRa3, C(=0)Rb3,
C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3, NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of R13 is optionally substituted with 1 , 2, or 3 groups independently selected from halo, CN, OH, ORa3, SR33, C(=0)Rb3, C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3, NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3;
R15 is independently at each occurrence selected from H, C e alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, CN, ORa5, SRa5, C(=0)Rb5, C(=0)NRc5Rd5, C(=0)ORa5, OC(=0)Rb5,
OC(=0)NRc5Rd5, NRc5Rd5, NRc5C(=0)Rb5, NRc5C(=0)NRc5Rd5, NRc5C(=0)ORa5, S(=0)Rb5, S(=0)NRc5Rd5, S(=0)2Rb5, NRc5S(=0)2Rb5, and S(=0)2NRc5Rd5, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa5, SRa5, C(=0)Rb5, C(=0)NRc5Rd5, C(=0)ORa5, OC(=0)Rb5, OC(=0)NRc5Rd5, NRc5Rd5, NRc5C(=0)Rb5,
NRc5C(=0)NRc5Rd5, NRc5C(=0)ORa5, S(=0)Rb5, S(=0)NRc5Rd5, S(=0)2Rb5, NRc5S(=0)2Rb5, S(=0)2NRc5Rd5, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl, and C3-7 cycloalkyl;
R14a and R14b are independently at each occurrence selected from H and Ci_6 alkyl, wherein said Ci_6 alkyl of R14a and R14b is optionally substituted with 1, 2, or 3 substituents selected from R20; or R a and R together with the N atom to which they are attached form a 4- 7 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents selected from R20;
R15a and R15b are independently at each occurrence selected from H and Ci_6 alkyl, wherein said Ci_6 alkyl of R15a and R15b is optionally substituted with 1, 2, or 3 substituents selected from R20;
or R15a and R15b together with the N atom to which they are attached form a 4- 7 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents selected from R20;
R16 is independently at each occurrence selected from halo, CN, OH, ORa6, SRa6, C(=0)Rb6, C(=0)NRc6Rd6, C(=0)ORa6, OC(=0)Rb6, OC(=0)NRc6Rd6, NRc6Rd6, NRc6C(=0)Rb6, NRc6C(=0)NRc6Rd6, NRc6C(=0)ORa6, S(=0)Rb6, S(=0)NRc6Rd6, S(=0)2Rb6, NRc6S(=0)2Rb6 and S(=0)2NRc6Rd6, C6_i0 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R16 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20;
R17 and R18 are independently at each occurrence selected from halo, C1-4 alkyl, CN, ORa, NRcRd, SRb, C(=0)NRcRd, C(=0)ORa, and NRcC(=0)Ra;
Ra, Rc, and Rd are independently at each occurrence selected from H, Ci-6 alkyl, C(0)Re, S(=0)2Rf, C(=0)NRsRh, and phenyl optionally substituted by Ci_4 alkoxy;
Rb is at each occurrence Ci_6 alkyl;
Re is at each occurrence Ci_4 alkyl optionally substituted by a group selected from phenyl, Ci_4 alkoxy, amino, Ci_4 alkylamino, and C2_8 dialkylamino;
Rf is Ci_4 alkyl;
Rs and Rh are independenetly at each occurrence selected from H and Ci_4 alkyl;
Ral, Rbl, Rcl and Rdl are independently at each occurrence selected from H, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl forming Ral, Rbl, Rcl and Rdl are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; Ra , R , Rc and R are independently at each occurrence selected from H, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl forming Ra3, Rb3, Rc3 and Rd3 are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, ORa4, SRa4, C(=0)RM, C(=0)NRc4Rd4, C(=0)ORa4, OC(=0)RM,
OC(=0)NRc4Rd4, R^R134, NRc4C(=0)RM, NRc4C(=0)NRc4Rd4, NRc4C(=0)ORa4, S(=0)RM, S(=0)NRc4Rd4, S(=0)2RM, NRc4S(=0)2RM and S(=0)2NRc4Rd4;
Ra4, RM, Rc4 and Rd4 are independently at each occurrence selected from H, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl forming Ra4, RM, R04 and Rd4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra5, Rb5, Rc5 and Rd5 are independently at each occurrence selected from H, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, 5-6 membered heterocycloalkyl, and Ci-6 haloalkyl wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl forming Ra5, Rb5, Rc5 and Rd5 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
or Rc5 and Rd5 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra6, Rc6 and Rd6 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl wherein said Ci-6 alkyl, C2-6 alkenyl, and C2_6 alkynyl forming Ra6, Rc6 and Rd6 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
alternatively, Rc6 and Rd6 together with the nitrogen atom to which they are attached form a 4-7 membered heterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2 additional heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Rb6 is independently at each occurrence selected from Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; and
R20 is at each occurrence independently selected from H, halo, OH, CN, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl, Ci_4 haloalkoxy, Ci_4 alkyl-C(=0)-, Ci_4 alkyl-C(=0)0-, Ci_4 alkyl-OC(=0)-, HOC(=0)-, H2NC(=0)-, Ci_4 alkyl-NHC(=0)-, di(Ci_4 alkyl)NC(=0)-, Ci_4 alkyl- C(=0)NH-, Ci_4 alkyl-0-C(=0)NH-, Ci_4 alkyl-S(=0)-, H2NS(=0)-, Ci_4 alkyl- NHS(=0)-, di(Ci_4 alkyl)NS(=0)-, Ci_4 alkyl-S(=0)2-, Ci_4 alkyl-S(=0)2NH-,
H2NS(=0)2-, Ci_4 alkyl-NHS(=0)2-, and di(Ci_4 alkyl)NS(=0)2-.
2. A compound of Formula (I):
Figure imgf000252_0001
or a pharmaceutically acceptable salt thereof, wherein:
represents a single bond or a double bond;
L is CR9R9a , 0, S, SO, or S02;
Cy1 is selected from phenyl or a 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said phenyl or 5-6 membered heteroaryl of Cy1 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R11;
R1 and R2 are independently selected from H, halo, CN, OH, Ci_6 alkyl, C2_6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl,
C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl,
NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl,
NRclS(=0)2Rbl and S(=0)2NRclRdl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl of R1 and R2 are optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl, C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl, NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl, NRclS(=0)2Rbl and
S(=0)2NRclRdl;
provided neither R1 nor R2 are CI, Br, I, CN, or OH when L is O or S; alternatively, R1 and R2 together with the carbon atom to which they are attached may be combined to form a C3-7 cycloalkyl group, wherein said cycloalkyl group is optionally substituted with 1, 2, 3, or 4 groups independently selected from R20;
Cy3 is selected from phenyl, C3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13, wherein a ring-forming nitrogen atom of said 5-10 membered heteroaryl group or a ring- forming nitrogen atom of said 4-10 membered heterocycloalkyl group is optionally oxidized;
R4 is H or Ci_6 alkyl;
R5 is selected from =0 and =S when C=^=N is a single bond,
alternatively, when C=^=N is a double bond then R5 is selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, NR15aR15b, phenyl, C3-7 cycloalkyl, 5- 6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R5 is optionally substituted by 1, 2, 3, or 4 groups independently selected from R15;
R6 is selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R16;
alternatively, R6 is selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20;
R7 is selected from H, halo, CN, ORa, NRcRd, SRb, C(=0)NRcRd, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 4-7 membered heterocycloalkyl group of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17;
R8 is selected from H, C1-3 alkyl, C2_3 alkenyl, C2_3 alkynyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd, wherein said Ci_3 alkyl of R8 is optionally substituted with 1 , 2, or 3 groups independently selected from R18;
R9 and R9a are independently selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
R11 is independently at each occurrence selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
R13 is independently at each occurrence selected from H, halo, CN, OH, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, OR33, SRa3, C(=0)Rb3,
C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3, NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl of R13 is optionally substituted with 1 , 2, or 3 groups independently selected from halo, CN, OH, ORa3, SR33, C(=0)Rb3, C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3, NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3;
R15 is independently at each occurrence selected from H, halo, CN, OH, ORa5, SRa5, C(=0)Rb5, C(=0)NRc5Rd5, C(=0)ORa5, OC(=0)Rb5, OC(=0)NRc5Rd5, NRc5Rd5, NRc5C(=0)Rb5, NRc5C(=0)NRc5Rd5, NRc5C(=0)ORa5, S(=0)Rb5, S(=0)NRc5Rd5, S(=0)2Rb5, NRc5S(=0)2Rb5 and S(=0)2NRc5Rd5;
R15a and R15b are independently selected from H and Ci_6 alkyl, wherein said alkyl of R15a and R15b is optionally substituted with 0, 1 , 2, or 3 substituents selected from R20;
R16 is independently at each occurrence selected from halo, CN, OH, ORa6, SRa6, C(=0)Rb6, C(=0)NRc6Rd6, C(=0)ORa6, OC(=0)Rb6, OC(=0)NRc6Rd6, NRc6Rd6, NRc6C(=0)Rb6, NRc6C(=0)NRc6Rd6, NRc6C(=0)ORa6, S(=0)Rb6, S(=0)NRc6Rd6, S(=0)2Rb6, NRc6S(=0)2Rb6 and S(=0)2NRc6Rd6, C6_i0 aryl, C3_7 cycloalkyl, 5- 10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said Ce-w aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20;
R17 and R18 are independently at each occurrence selected from halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
Ra, Rc, and Rd are independently at each occurrence selected from H and C e alkyl;
Rb is at each occurrence Ci_6 alkyl;
Ral, Rbl, Rcl and Rdl are independently at each occurrence selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ral, Rbl, Rcl and Rdl are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra3, Rb3, Rc3 and Rd3 are independently at each occurrence selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra3, Rb3, Rc3 and Rd3 are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, ORa4, SRa4, C(=0)RM, C(=0)NRc4Rd4, C(=0)ORa4, OC(=0)RM, OC(=0)NRc4Rd4, NR^R134, NRc4C(=0)RM, NRc4C(=0)NRc4Rd4, NRc4C(=0)ORa4, S(=0)RM, S(=0)NRc4Rd4,
Figure imgf000255_0001
Ra4, RM, Rc4 and Rd4 are independently at each occurrence selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra4, Rb4, R04 and Rd4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra5, Rb5, Rc5 and Rd5 are independently at each occurrence selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra5, Rb5, Rc5 and Rd5 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra6, Rc6 and Rd6 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra6, Rc6 and Rd6 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
alternatively, Rc6 and Rd6 together with the nitrogen atom to which they are attached may be combined to form a 4-7 membered heterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2 additional heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Rb6 is independently at each occurrence selected from Ci_6 alkyl, C2_6 alkenyl, C2-6 alkynyl, C e haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; and
R20 is at each occurrence independently selected from H, halo, OH, CN, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl-C(=0)-, C1-4 alkyl-C(=0)0-, C1-4 alkyl-OC(=0)-, HOC(=0)-, H2NC(=0)-, Ci_4 alkyl-NHC(=0)-, di(Ci_4 alkyl)NC(=0)-, Ci_4 alkyl- C(=0)NH-, Ci_4 alkyl-S(=0)-, H2NS(=0)-, Ci_4 alkyl-NHS(=0)-, di(Ci_4
alkyl)NS(=0)-, Ci_4 alkyl-S(=0)2-, Ci_4 alkyl-S(=0)2NH-, H2NS(=0)2-, Ci_4 alkyl- NHS(=0)2-, and di(Ci_4 alkyl)NS(=0)2-.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:
represents a single bond or a double bond;
L is CR9R9a , 0, S, SO, or S02;
Cy1 is selected from phenyl or a 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said phenyl or 5-6 membered heteroaryl of Cy1 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R11;
R1 is selected from H, halo, CN, OH, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl, C(=0)ORal, OC(=0)Rbl,
OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl, NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl, NRclS(=0)2Rbl and S(=0)2NRclRdl, wherein said Ci-6 alkyl, C2_6 alkenyl, and C2_6 alkynyl of R1 and R2 are optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl, C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl, NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl, NRclS(=0)2Rbl and S(=0)2NRclRdl; R2 is selected from H, halo, CN, OH, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 alkyl-O-, and
Ci-6 haloalkyl-O-;
provided neither R1 nor R2 are CI, Br, I, CN, or OH when L is O or S;
Cy3 is selected from phenyl, C3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13; additionally, wherein a ring- forming nitrogen atom of said 5-10 membered heteroaryl group or a ring-forming nitrogen atom of said 4-10 membered heterocycloalkyl group is optionally oxidized;
R4 is H or Ci_6 alkyl;
R5 is selected from =0 and =S when C^^N is a single bond,
alternatively, when C^^N is a double bond then R5 is selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, NR15aR15b, phenyl, C3-7 cycloalkyl, 5- 6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R5 is optionally substituted by 1, 2, 3, or 4 groups independently selected from R15;
R6 is selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R16;
alternatively, R6 is selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20;
R7 is selected from H, halo, CN, ORa, NRcRd, SRb, C(=0)NRcRd, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 4-7 membered heterocycloalkyl group of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17;
R8 is selected from H, halo, CN, OH, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 alkyl-O-, and Ci-6 haloalkyl-O-;
R9 and R9a are independently selected from H and C1-3 alkyl;
R11 is independently at each occurrence selected from H, C1-3 alkyl,
Ci_3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
R13 is independently at each occurrence selected from H, halo, CN, OH, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, OR33, SRa3, C(=0)Rb3,
C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3, NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl of R13 is optionally substituted with 1 , 2, or 3 groups independently selected from halo, CN, OH, ORa3, SR33, C(=0)Rb3, C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3, NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3;
R15 is independently at each occurrence selected from H, halo, CN, OH, ORa5, SRa5, C(=0)Rb5, C(=0)NRc5Rd5, C(=0)ORa5, OC(=0)Rb5, OC(=0)NRc5Rd5, NRc5Rd5, NRc5C(=0)Rb5, NRc5C(=0)NRc5Rd5, NRc5C(=0)ORa5, S(=0)Rb5, S(=0)NRc5Rd5, S(=0)2Rb5, NRc5S(=0)2Rb5 and S(=0)2NRc5Rd5;
R15a and R15b are independently selected from H and Ci_6 alkyl, wherein said alkyl of R15a and R15b is optionally substituted with 0, 1 , 2, or 3 substituents selected from R20;
R16 is independently at each occurrence selected from halo, CN, OH, ORa6, SRa6, C(=0)Rb6, C(=0)NRc6Rd6, C(=0)ORa6, OC(=0)Rb6, OC(=0)NRc6Rd6, NRc6Rd6, NRc6C(=0)Rb6, NRc6C(=0)NRc6Rd6, NRc6C(=0)ORa6, S(=0)Rb6, S(=0)NRc6Rd6, S(=0)2Rb6, NRc6S(=0)2Rb6 and S(=0)2NRc6Rd6, C6_i0 aryl, C3-7 cycloalkyl, 5- 10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C6-10 aryl, C3-7 cycloalkyl, 5- 10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R16 are each optionally substituted by 1 , 2, 3, or 4 groups independently selected R20; R17 is independently at each occurrence selected from halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
Ra, Rc, and Rd are independently at each occurrence selected from H and C e alkyl;
Rb is at each occurrence Ci_6 alkyl;
Ral, Rbl, Rcl and Rdl are independently at each occurrence selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ral, Rbl, Rcl and Rdl are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra3, Rb3, Rc3 and Rd3 are independently at each occurrence selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra3, Rb3, Rc3 and Rd3 are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, ORa4, SRa4, C(=0)RM, C(=0)NRc4Rd4, C(=0)ORa4, OC(=0)RM, OC(=0)NRc4Rd4, NR'V4, NRc4C(=0)RM, NRc4C(=0)NRc4Rd4, NRc4C(=0)ORa4, S(=0)RM, S(=0)NRc4Rd4,
Figure imgf000259_0001
Ra4, RM, Rc4 and Rd4 are independently at each occurrence selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra4, RM, R04 and Rd4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra5, Rb5, Rc5 and Rd5 are independently at each occurrence selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra5, Rb5, Rc5 and Rd5 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra6, Rc6 and Rd6 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl wherein said Ci_6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra6, Rc6 and Rd6 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
alternatively, Rc6 and Rd6 together with the nitrogen atom to which they are attached may be combined to form a 4-7 membered heterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2 additional heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R20; R is independently at each occurrence selected from Ci_6 alkyl, C2_6 alkenyl, C2-6 alkynyl, C e haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; and
R20 is at each occurrence independently selected from H, halo, OH, CN, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl, Ci_4 haloalkoxy, Ci_4 alkyl-C(=0)-, Ci_4 alkyl-C(=0)0-, Ci_4 alkyl-OC(=0)-, HOC(=0)-, H2NC(=0)-, Ci_4 alkyl-NHC(=0)-, di(Ci_4 alkyl)NC(=0)-, Ci_4 alkyl- C(=0)NH-, Ci-4 alkyl-S(=0)-, H2NS(=0)-, C1-4 alkyl-NHS(=0)-, di(C1-4
alkyl)NS(=0)-, Ci_4 alkyl-S(=0)2-, Ci_4 alkyl-S(=0)2NH-, H2NS(=0)2-, Ci_4 alkyl- NHS(=0)2-, and di(Ci_4 alkyl)NS(=0)2-.
4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein:
represents a single bond or a double bond;
L is O;
Cy1 is a five membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said five membered heteroaryl of Cy1 is optionally substituted with 1, 2, or 3 groups independently selected from R11;
R1 is selected from H, F, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl, C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl, NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl,
S(=0)NRclRdl, S(=0)2Rbl, NRclS(=0)2Rbl and S(=0)2NRclRdl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl of R1 and R2 are optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, ORal, SRal, C(=0)Rbl, C(=0)NRclRdl, C(=0)ORal, OC(=0)Rbl, OC(=0)NRclRdl, NRclRdl, NRclC(=0)Rbl, NRclC(=0)NRclRdl, NRclC(=0)ORal, S(=0)Rbl, S(=0)NRclRdl, S(=0)2Rbl,
NRclS(=0)2Rbl and S(=0)2NRclRdl;
R2 is selected from H, F, and Ci_6 alkyl;
Cy3 is selected from phenyl, C3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13; additionally, wherein a ring- forming nitrogen atom of said 5-10 membered heteroaryl group or a ring-forming nitrogen atom of said 4-10 membered heterocycloalkyl group is optionally oxidized;
R4 is H or Ci_6 alkyl;
R5 is selected from =0 and =S when C^^N is a single bond,
alternatively, when C^^N is a double bond then R5 is selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, NR15aR15b, phenyl, C3-7 cycloalkyl, 5- 6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R5 is optionally substituted by 1, 2, 3, or 4 groups independently selected from R15;
R6 is selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R16;
R7 is selected from H, halo, CN, ORa, NRcRd, SRb, C(=0)NRcRd, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 4-7 membered heterocycloalkyl group of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17;
R8 is selected from H, halo, CN, OH, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 alkyl-O-, and Ci-6 haloalkyl-O-;
R11 is independently at each occurrence selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
R13 is independently at each occurrence selected from H, halo, CN, OH, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, OR33, SRa3, C(=0)Rb3,
C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3, NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of R is optionally substituted with 1 , 2, or 3 groups independently selected from halo, CN, OH, ORa3, SR33, C(=0)Rb3, C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3, NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3;
R15 is independently at each occurrence selected from H, halo, CN, OH, ORa5, SRa5, C(=0)Rb5, C(=0)NRc5Rd5, C(=0)ORa5, OC(=0)Rb5, OC(=0)NRc5Rd5, NRc5Rd5, NRc5C(=0)Rb5, NRc5C(=0)NRc5Rd5, NRc5C(=0)ORa5, S(=0)Rb5, S(=0)NRc5Rd5, S(=0)2Rb5, NRc5S(=0)2Rb5 and S(=0)2NRc5Rd5;
R15a and R15b are independently selected from H and Ci_6 alkyl, wherein said alkyl of R15a and R15b is optionally substituted with 0, 1 , 2, or 3 substituents selected from R20;
R16 is independently at each occurrence selected from halo, CN, OH, ORa6, SRa6, C(=0)Rb6, C(=0)NRc6Rd6, C(=0)ORa6, OC(=0)Rb6, OC(=0)NRc6Rd6, NRc6Rd6, NRc6C(=0)Rb6, NRc6C(=0)NRc6Rd6, NRc6C(=0)ORa6, S(=0)Rb6, S(=0)NRc6Rd6, S(=0)2Rb6, NRc6S(=0)2Rb6 and S(=0)2NRc6Rd6, C6_i0 aryl, C3-7 cycloalkyl, 5- 10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C6-10 aryl, C3-7 cycloalkyl, 5- 10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R16 are each optionally substituted by 1 , 2, 3, or 4 groups independently selected R20;
R17 is independently at each occurrence selected from halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
Ra, Rc, and Rd are independently at each occurrence selected from H and Ci_6 alkyl;
Rb is at each occurrence Ci_6 alkyl;
Ral, Rbl, Rcl and Rdl are independently at each occurrence selected from H, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl forming Ral, Rbl, Rcl and Rdl are each optionally substituted with 1 , 2, or 3 substituents independently selected from R20;
Ra3, Rb3, Rc3 and Rd3 are independently at each occurrence selected from H, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl forming Ra3, Rb3, Rc3 and Rd3 are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, CN, OH, ORa4, SRa4, C(=0)RM, C(=0)NRc4Rd4, C(=0)ORa4, OC(=0)RM, OC(=0)NRc4Rd4, NR^R134, NRc4C(=0)RM, NRc4C(=0)NRc4Rd4, NRc4C(=0)0Ra4, S(=0)RM, S(=0)NRc4Rd4, S(=0)2RM, NRc4S(=0)2RM and S(=0)2NRc4Rd4;
Ra4, RM, Rc4 and Rd4 are independently at each occurrence selected from H, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, and Ci_6 haloalkyl, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl forming Ra4, Rb4, R04 and Rd4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra5, Rb5, Rc5 and Rd5 are independently at each occurrence selected from H, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, and Ci_6 haloalkyl wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl forming Ra5, Rb5, Rc5 and Rd5 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra6, Rc6 and Rd6 are independently at each occurrence selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl wherein said Ci-6 alkyl, C2-6 alkenyl, and C2_6 alkynyl forming Ra6, Rc6 and Rd6 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
alternatively, Rc6 and Rd6 together with the nitrogen atom to which they are attached may be combined to form a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Rb6 is independently at each occurrence selected from Ci_6 alkyl, C2_6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; and
R20 is at each occurrence independently selected from H, halo, OH, CN, amino, C1-4 alkyl, Ci_4 alkoxy, Ci_4 alkylthio, Ci_4 alkylamino, di(Ci_4 alkyl)amino, Ci_4 haloalkyl, Ci_4 haloalkoxy, Ci_4 alkyl-C(=0)-, Ci_4 alkyl-C(=0)0-, Ci_4 alkyl-OC(=0)-, HOC(=0)-, H2NC(=0)-, Ci_4 alkyl-NHC(=0)-, di(Ci_4 alkyl)NC(=0)-, Ci_4 alkyl- C(=0)NH-, Ci_4 alkyl-S(=0)-, H2NS(=0)-, Ci_4 alkyl-NHS(=0)-, di(Ci_4
alkyl)NS(=0)-, Ci_4 alkyl-S(=0)2-, Ci_4 alkyl-S(=0)2NH-, H2NS(=0)2-, Ci_4 alkyl- NHS(=0)2-, and di(Ci_4 alkyl)NS(=0)2-.
5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: represents a single bond or a double bond;
L is O;
Cy1 is a five membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said five membered heteroaryl of Cy1 is optionally substituted with 1, 2, or 3 groups independently selected from R11;
R1 is selected from H, F, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, ORal, C(=0)Rbl, C(=0)NRclRdl, and C(=0)ORal;
R2 is selected from H, F, and Ci_6 alkyl;
Cy3 is selected from phenyl, C3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl, C3_7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13; additionally, wherein a ring- forming nitrogen atom of said 5-10 membered heteroaryl group or a ring-forming nitrogen atom of said 4-10 membered heterocycloalkyl group is optionally oxidized;
R4 is H or Ci_6 alkyl;
R5 is selected from =0 and =S when C^^ N is a single bond, alternatively, when C^^ N is a double bond then R5 is selected from H, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, NR15aR15b, phenyl, C3-7 cycloalkyl, 5- 6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R5 is optionally substituted by 1, 2, 3, or 4 groups independently selected from R15;
R6 is selected from H and Ci_6 alkyl, wherein said alkyl of R6 is optionally substituted by 1, 2, or 3 groups independently selected R16;
R7 is selected from H, halo, CN, Ci_6 alkyl, Ci_6 alkoxy, phenyl, and 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, or 5-6 membered heteroaryl group, of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17;
R8 is selected from H, halo, CN, OH, and Ci_6 alkyl; R11 is independently at each occurrence selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
R13 is independently at each occurrence selected from H, halo, CN, OH, C e alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, OR33, SRa3, C(=0)Rb3,
C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3, NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3, wherein said Ci_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl of R13 is optionally substituted with 1 , 2, or 3 groups independently selected from halo, CN, OH, ORa3, SR33, C(=0)Rb3, C(=0)NRc3Rd3, C(=0)ORa3, OC(=0)Rb3, OC(=0)NRc3Rd3, NRc3Rd3, NRc3C(=0)Rb3, NRc3C(=0)NRc3Rd3, NRc3C(=0)ORa3, S(=0)Rb3, S(=0)NRc3Rd3, S(=0)2Rb3, NRc3S(=0)2Rb3 and S(=0)2NRc3Rd3;
R15 is independently at each occurrence selected from H, halo, CN, OH, ORa5, C(=0)Rb5, C(=0)NRc5Rd5, C(=0)ORa5, NRc5Rd5, and NRc5C(=0)Rb5;
R15a and R15b are independently selected from H and C e alkyl, wherein said alkyl of R15a and R15b is optionally substituted with 0, 1 , 2, or 3 substituents selected from R20;
R16 is independently at each occurrence selected from halo, CN, OH, ORa6, C(=0)Rb6, C(=0)NRc6Rd6, C(=0)ORa6, OC(=0)Rb6, NRc6Rd6, NRc6C(=0)Rb6, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl of R16 is optionally substituted by 1 , 2, 3, or 4 groups independently selected R20;
R17 is independently at each occurrence selected from halo, CN, ORa, NRcRd, SRb, and C(=0)NRcRd;
Ra, Rc, and Rd are independently at each occurrence selected from H and C e alkyl;
Rb is at each occurrence Ci_6 alkyl;
Ral, Rbl, Rcl and Rdl are independently at each occurrence selected from H, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, and Ci_6 haloalkyl, wherein said C e alkyl, C2_6 alkenyl, and C2_6 alkynyl forming Ral, Rbl, Rcl and Rdl are each optionally substituted with 1 , 2, or 3 substituents independently selected from R20;
Ra3, Rb3, Rc3 and Rd3 are independently at each occurrence selected from H and Ci_6 alkyl, wherein said Ci_6 alkyl forming R33, Rb3, Rc3 and Rd3 is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, ORa4, SRa4, C(=0)RM, C(=0)NRc4Rd4, C(=0)ORa4, OC(=0)RM, OC(=0)NRc4Rd4, M R , NRC4C(=0)R , NRc4C(=0)NRc4Rd4, NRc4C(=0)0Ra4, S(=0)R ,
S(=0)NRc4Rd4, S(=0)2RM, NRc4S(=0)2RM and S(=0)2NRc4Rd4;
Ra4, RM, Rc4 and Rd4 are independently at each occurrence selected from H and Ci-6 alkyl, wherein said Ci_6 alkyl forming Ra4, Rb4, Rc4 and Rd4 is optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra5, Rb5, Rc5 and Rd5 are independently at each occurrence selected from H and Ci-6 alkyl, wherein said Ci_6 alkyl forming Ra5, Rb5, Rc5 and Rd5 is optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra6, Rc6 and Rd6 are independently at each occurrence selected from H and Ci_6 alkyl;
alternatively, Rc6 and Rd6 together with the nitrogen atom to which they are attached may be combined to form a 4-7 membered heterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2 additional heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Rb6 is independently at each occurrence selected from Ci_6 alkyl; and
R20 is at each occurrence independently selected from H, halo, OH, CN, amino, Ci_4 alkyl, Ci_4 alkoxy, Ci_4 alkylthio, Ci_4 alkylamino, di(Ci_4 alkyl)amino, Ci_4 haloalkyl, Ci_4 haloalkoxy, Ci_4 alkyl-C(=0)-, Ci_4 alkyl-C(=0)0-, Ci_4 alkyl-OC(=0)-, HOC(=0)-, H2NC(=0)-, Ci_4 alkyl-NHC(=0)-, di(Ci_4 alkyl)NC(=0)-, Ci_4 alkyl- C(=0)NH-, Ci-4 alkyl-S(=0)-, H2NS(=0)-, C1-4 alkyl-NHS(=0)-, di(C1-4
alkyl)NS(=0)-, Ci_4 alkyl-S(=0)2-, Ci_4 alkyl-S(=0)2NH-, H2NS(=0)2-, Ci_4 alkyl- NHS(=0)2-, and di(Ci_4 alkyl)NS(=0)2-.
6. The compound of claim 1 or 2 having Formula (la):
Figure imgf000266_0001
or a pharmaceutically acceptable salt thereof, wherein:
represents a single bond or a double bond;
Cy1 is selected from isoxazolyl and pyrazolyl, wherein said isoxazolyl and pyrazolyl of Cy1 is optionally substituted with 1 or 2 groups independently selected from R11; R1 is selected from H, methyl, -C(=0)OCH2CH3, -C(=0)N(H)CH2CH3, - C(=0)N(H)CH2CH2OH, and -C(=0)N(CH3)2;
Cy3 is selected from phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl, wherein said phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13;
R5 is =0 when C is a single bond,
alternatively, when C=^=N is a double bond then R5 is H, methyl, -CH=CH2, -N(H)CH3, -N(H)CH2CH3, -N(H)CH(CH3)2, -N(CH3)2, -N(H)CH2CH2OH, - N(H)CH(CH3)CH2OH, -N(H)CH2CH(OH)CH3, -N(H)C(CH3)2CH2OH, - N(CH3)CH2CH2OH, morpholinyl, pyrrolidinyl, hydroxypyrrolidinyl, piperidinyl, hydroxypiperidinyl, azetidinyl, hydroxyazetidinyl, piperazinyl,
butoxycarbonylpiperazinyl, and phenyl;
R6 is selected from H, methyl, ethyl, and propyl wherein said methyl, ethyl, and propyl of R6 are each optionally substituted by 1, 2, or 3 groups independently selected R16;
R7 is selected from H, F, CI, Br, methyl, methoxy, ethoxy, CN, phenyl, and pyridinyl;
R11 is independently at each occurrence selected from H, methyl, ethyl, chloro, and methoxy;
R13 is independently at each occurrence selected from H, F, CN, methoxy, -CF3, -OCH2C(=0)OH, -OCH2C(=0)N(H)CH2CH3, -OCH2C(=0)N(H)CH2CH2OH, and -OCH2C(=0)N(CH3)2; and
R16 is independently at each occurrence selected from H, morpholinyl, and piperidinyl.
The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein L is O.
The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein L is S.
The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein L is CR9R9a .
10. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein L is CH2.
11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Cy1 is isoxazolyl substituted with 1 or 2 groups independently selected from R11.
12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Cy1 is pyrazolyl substituted with 1 or 2 groups independently selected from R11.
13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, methyl, -CH2OH, -C(=0)OCH2CH3,
-C(=0)N(H)CH2CH3, -C(=0)N(H)CH3, -C(=0)NH2, -C(=0)N(H)CH2CH2OH, and - C(=0)N(CH3)2.
14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, methyl, -C(=0)OCH2CH3, - C(=0)N(H)CH2CH3, -C(=0)N(H)CH2CH2OH, and -C(=0)N(CH3)2.
15. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R1 is H.
16. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R1 is methyl.
17. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R1 is -C(=0)OCH2CH3.
18. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R1 is C(=0)N(H)CH2CH3.
19. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R1 is C(=0)N(H)CH2CH2OH.
20. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R1 is -C(=0)N(CH3)2.
21. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R1 is -C(=0)N(H)CH3.
22. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R1 is -C(=0)NH2.
23. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R1 is -CH2OH.
24. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R2 is H.
25. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl.
26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein Cy3 is selected from phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl, tetrahydrofuranyl, and piperinyl, wherein said phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl, tetrahydrofuranyl, and piperidinyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
27. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein Cy3 is selected from phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl, wherein said phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
28. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein Cy3 is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
29. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein Cy3 is pyridinyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
30. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein Cy3 is oxidopyridinyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
31. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein Cy3 is thiazolyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
32. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein Cy3 is cyclohexyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
33. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein Cy3 is dihydrobenzofuranyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
34. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein Cy3 is tetrahydrofuranyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
35. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein Cy3 is piperidinyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R13.
36. The compound of any one of claims 1 and 7 to 35, or a pharmaceutically acceptable salt thereof, wherein R4 is H, -C(=0)NH2, -CH2NH2, -CH2N(H)C(=0)CH3,
-C(=0)N(H)CH3, -CH2CH3, or -CH3.
37. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R4 is H.
38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R5 is =0 when C^^N is a single bond.
39. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R5 is =S when C=^=N is a single bond.
40. The compound of any one of claims 1 and 7 to 37, or a pharmaceutically acceptable salt thereof, wherein when C=-^N is a double bond then R5 is selected from H, C1-4 alkyl,
-CH=CH2, NR15aR15b, -C(=0)NR15aR15b, phenyl, and a 4-10 membered
heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, and 4-10 membered heterocycloalkyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
41. The compound of any one of claims 1 and 7 to 37, or a pharmaceutically acceptable salt thereof, wherein when C=-^N is a double bond then R5 is selected from H, C1-4 alkyl,
-CH=CH2, NR15aR15b, -C(=0)R15aR15b, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,2,3, 6-tetrahydropyridinyl, 2,5-dihydro-lH-pyrrolyl, 1,4-diazepanyl, morpholinyl, and octahydropyrrolo[l,2-a]pyrazinyl, wherein said C1-4 alkyl, phenyl, azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, 1,2,3, 6-tetrahydropyridinyl, 2,5- dihydro-lH-pyrrolyl, 1,4-diazepanyl, morpholinyl, and octahydropyrrolo[l,2- a]pyrazinyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
42. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein when C^^ N is a double bond then R5 is H, methyl, -CH=CH2, - N(H)CH3, -N(H)CH2CH3, -N(H)CH(CH3)2, -N(CH3)2, -N(H)CH2CH2OH, - N(H)CH(CH3)CH2OH, -N(H)CH2CH(OH)CH3, -N(H)C(CH3)2CH2OH, - N(CH3)CH2CH2OH, morpholinyl, pyrrolidinyl, hydroxypyrrolidinyl, piperidinyl, hydroxypiperidinyl, azetidinyl, hydroxyazetidinyl, piperazinyl,
butoxycarbonylpiperazinyl or phenyl.
43. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein when C is a double bond then R5 is selected from a 4-6 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said 4-6 membered heterocycloalkyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
44. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein when C=-^N is a double bond then R5 is pyrrolidinyl, piperidinyl, azetidinyl, or piperazinyl, wherein said pyrrolidinyl, piperidinyl, azetidinyl, or piperazinyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
45. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein when C is a double bond then R5 is pyrrolidinyl, wherein said pyrrolidinyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
46. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein when C=-^N is a double bond then R5 is piperidinyl, wherein said piperidinyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
47. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein when C=^=N is a double bond then R5 is azetidinyl, wherein said azetidinyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
48. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein when C^^N is a double bond then R5 is piperazinyl, wherein said piperazinyl of R5 is optionally substituted by 1 or 2 groups independently selected from R15.
49. The compound of any one of claims 1 and 7 to 48, or a pharmaceutically acceptable salt thereof, wherein R15 is independently at each occurrence selected from Ci_6 alkyl, CN, ORa5, C(=0)Rb5, C(=0)NRc5Rd5, C(=0)ORa5, NRc5Rd5, NRc5C(=0)Rb5, NRc5C(=0)NRc5Rd5, NRc5C(=0)ORa5, S(=0)2Rb5, NRc5S(=0)2Rb5, and
Figure imgf000272_0001
wherein said Ci_6 alkyl, is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa5, SRa5, C(=0)Rb5,
C(=0)NRc5Rd5, C(=0)ORa5, OC(=0)Rb5, OC(=0)NRc5Rd5, NRc5Rd5, NRc5C(=0)Rb5, NRc5C(=0)NRc5Rd5, NRc5C(=0)ORa5, S(=0)Rb5, S(=0)NRc5Rd5, S(=0)2Rb5, NRc5S(=0)2Rb5, S(=0)2NRc5Rd5, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl, and C3-7 cycloalkyl.
50. The compound of any one of claims 1 and 7 to 49, or a pharmaceutically acceptable salt thereof, wherein R6 is H, C1-4 alkyl, or C1-4 alkoxy.
51. The compound of any one of claims 1 and 7 to 49, or a pharmaceutically acceptable salt thereof, wherein R6 is H, methyl, or methoxy.
52. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein R6 is H.
53. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from H, halo, CN, NRcRd, Ci_6 alkyl, C2-6 alkenyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 5-6 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, 5-6 membered heteroaryl group, and 5-6 membered heterocycloalkyl group of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17.
54. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from H, F, CI, Br, CN, NRcRd, Ci_4 alkyl, C2-4 alkenyl, pyrazolyl, pyridinyl, pyrimidinyl, and 1,2,3,6-tetrahydropyridinyl, wherein said C e alkyl, C2-6 alkenyl, pyrazolyl, pyridinyl, pyrmimidinyl, and 1,2,3,6- tetrahydropyridinyl of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17.
55. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from H, halo, C1-4 alkyl, and CN.
56. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from H, Br, methyl, and CN.
57. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R7 is H.
58. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R7 is Br.
59. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R7 is methyl.
60. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R7 is CN.
61. The compound of any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, wherein R8 is selected from H, halo, C1-4 alkyl, and CN.
62. The compound of any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, wherein R8 is H.
63. The compound of any one of claims 1 to 38 and 50 to 62, or a pharmaceutically acceptable salt thereof, having Formula (Ila):
Figure imgf000274_0001
64. The compound of any one of claims 1-6, 12-23, 26-35, and 50-60, or a
pharmaceutically acceptable salt thereof, having Formula (Ilia):
Figure imgf000274_0002
65. The compound of any one of claims 1-6, 26-35, and 50-52, or a pharmaceutically acceptable salt thereof, having Formula (IVa):
Figure imgf000275_0001
The compound of any one of claims 1 to 37 and 40 to 62, or a pharmaceutically acceptable salt thereof, having Formula (lib):
Figure imgf000275_0002
67. The compound of any one of claims 1-6, 12-23, 26-35, 38-49, and 53-60, or a pharmaceutically acceptable salt thereof, having Formula (Illb):
Figure imgf000275_0003
The compound of any one of claims 1-6, 26-35, and 38-48, or a pharmaceutically acceptable salt thereof, having Formula (IVb):
Figure imgf000275_0004
69. The compound of claim 1 selected from:
7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
(4R)-7-(3 ,5 -dimethy lisoxazol-4-yl)-4-phenyl-4,5 -dihydroimidazo [1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
(4/S)-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-l-methyl-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-5-methyl-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
4-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-4-yl]benzonitrile;
7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(3-methoxyphenyl)-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2(7H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(2-methoxyphenyl)-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(2,4-difluorophenyl)-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-2-methyl-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine;
7-(3,5-dimethylisoxazol-4-yl)-l-(2-morpholin-4-ylethyl)-4-phenyl-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethyl-7H-pyrazol-4-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3-methyl-7H-pyrazol-4-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
(4R)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
(45,)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(l-oxidopyridin-2-yl)-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2( H)-one;
4-cyclohexyl-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(tetrahydrofuran-2-yl)-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(5-fluoropyridin-2-yl)-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2( H)-one;
Ethyl 7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l, 2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazine-5-carboxylate;
7-(3 ,5 -dimethylisoxazol-4-yl)-4-( 1 ,3 -thiazol-2-yl)-4,5 -dihydroimidazo [1,5,4- de] [ 1 ,4]benzoxazin-2(77i)-one;
2- {2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-4-yl]phenoxy } -N-ethylacetamide;
ethyl7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-phenyl- 1,2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazine-5-carboxylate;
7-(3,5-dimethylisoxazol-4-yl)-N-ethyl-2-oxo-4-phenyl-l, 2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazine-5-carboxamide;
7-(3,5-Dimethylisoxazol-4-yl)-N-isopropyl-4-phenyl-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-amine;
7-(3,5-Dimethylisoxazol-4-yl)-N-methyl-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-amine;
7-(3,5-Dimethylisoxazol-4-yl)-N-ethyl-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2-amine;
7-(3,5-Dimethylisoxazol-4-yl)-N,N-dimethyl-4-phenyl-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-amine;
2- {[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]amino} ethanol;
2- {[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl] amino }propan- 1 -ol;
1- {[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2-yl] amino }propan-2-ol;
2- {[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl] amino } -2-methylpropan- 1 -ol;
2-[[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- i/e][l,4]benzoxazin-2-yl](methyl)amino]ethanol;
7-(l-Methyl-7H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
9-Bromo-7-(l-methyl-7H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2(77i)-one;
9-Methyl-7-(l -methyl- 7H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(4-Chloro-l -methyl- 7H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine;
7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-2-piperazin-l-yl-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazine;
7-(3,5-dimethylisoxazol-4-yl)-2,4-diphenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazine;
7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-phenyl- 1,2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazine-9-carbonitrile;
7-(3,5-Dimethylisoxazol-4-yl)-4,9-diphenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(l,4-dimethyl-7H-pyrazol-5-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
9-Bromo-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-9-methyl-4-phenyl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-N,N-dimethyl-2-oxo-4-phenyl- 1,2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazine-5-carboxamide;
7-(3,5-Dimethylisoxazol-4-yl)-N-(2-hydroxyethyl)-2-oxo-4-phenyl- 1,2,4,5- tetrahydroimidazo[l,5,4-i/e][l,4]benzoxazine-5-carboxamide;
7-(3,5-Dimethylisoxazol-4-yl)-4-(4-fluorophenyl)-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2( H)-one;
2- {2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-4-yl]phenoxy } -N-(2-hydroxyethyl)acetamide;
2- {2-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-4-yl]phenoxy } -N,N-dimethylacetamide;
7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-9-pyridin-3-yl-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2( H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-2-morpholin-4-yl-4-phenyl-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazine;
7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-2-pyrrolidin-l-yl-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazine;
l-[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3-ol;
7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-2-piperidin-l-yl-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazine;
l-[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- i/e][l,4]benzoxazin-2-yl]piperidin-4-ol;
l-[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperidin-3 -ol;
l-[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 -ol; and
4-[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazin-2-yl]piperazine- 1 -carboxylate;
or a pharmaceutically acceptable salt thereof.
70. A compound of claim 1, selected from:
7-(3,5-Dimethylisoxazol-4-yl)-5,5-dimethyl-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2( lH)-one;
7-(3,5-Dimethylisoxazol-4-yl)-5-(hydroxymethyl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2( lH)-one;
7-(3,5-Dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( lH)-one;
4-(l-Acetylpiperidin-2-yl)-7-(3,5-dimethylisoxazol-4-yl)-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2( lH)-one;
[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-4-yl]methyl acetate; 7-(3,5-Dimethylisoxazol-4-yl)-4-(hydroxymethyl)-4,5-dihydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-2( lH)-one;
7-(3,5-Dimethylisoxazol-4-yl)-4-methyl-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-4-ethyl-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2( lH)-one;
7-(3,5-Dimethylisoxazol-4-yl)-N-methyl-2-oxo-4-pyridin-2-yl- 1,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine-4-carboxamide;
N-{[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-4-yl]methyl} acetamide;
4- (Aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5,4-de] [ 1 ,4]benzoxazin-2( lH)-one;
7-(3, 5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l, 2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine-4-carboxamide;
7-(3,5-dimethylisoxazol-4-yl)-5-methyl-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-dimethylisoxazol-4-yl)-N-methyl-2-oxo-4-pyridin-2-yl- 1,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ l,4]benzoxazine-5-carboxamide;
7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl- 1,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ l,4]benzoxazine-5-carboxamide;
7-(3,5-dimethylisoxazol-4-yl)-4-(5-fluoropyridin-3-yl)-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-[l-(methylsulfonyl)piperidin-2-yl]-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-4-yl] -N-isopropylpiperidine- 1 -carboxamide;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(l -methyl- 1 H-pyrazol-4-yl)-4-pyridin-2- yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one;
5- [(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[l,5,4-de][l,4]benzoxazin-9-yl]-N,N-dimethylpyridine-2- carboxamide;
tert-butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-9-yl]-3 ,6-dihydropyridine- 1 (2H)- carboxylate; (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-9-pyrimidin-5-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(l-methyl-lH-pyrazol-5-yl)-4-pyridin-2- yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one;
ethyl (2E)-3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l,2,4,5- tetrahydroimidazo[l,5,4-de][l,4]benzoxazin-9-yl]acrylate;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-9-(l,2,3,6- tetrahydropyridin-4-yl)-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one;
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-vinyl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
(lR)-l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]ethane- 1 ,2-diol;
l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]ethanol;
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-N,N-dimethyl-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazine-2-carboxamide;
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazine;
tert-Butyl (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazine-2-carboxylate;
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-(morpholin-4-ylcarbonyl)-4-pyridin-2- yl-4,5 -dihydroimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
(4 S)-7 -(3 , 5 -D imethy lis oxazol-4-y l)-N-methy l-4-pyridin-2 -y 1-4, 5 - dihydroimidazo[l,5,4-de][l,4]benzoxazine-2-carboxamide;
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de] [ 1 ,4]benzoxazine-2-carboxamide;
tert-Butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl] -3 ,6-dihydropyridine- 1 (2H)- carboxylate;
tert-Butyl 3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl] -2,5 -dihydro- 1 H-pyrrole- 1 - carboxylate; tert-Butyl 5-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl] -3 ,6-dihydropyridine- 1 (2H)- carboxylate;
tert-Butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]piperidine-l-carboxylate;
tert-Butyl 3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidine- 1 -carboxylate;
tert-Butyl 3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]piperidine-l-carboxylate;
(4S)-2-(l-Acetylpiperidin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-(l,2,3,6- tetrahydropyridin-4-yl)-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-2-(2,5-dihydro-lH-pyrrol-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin- 2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-pyrrolidin-3-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-(l,2,5,6- tetrahydropyridin-3 -yl)-4,5 -dihydroimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-piperidin-3-yl-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
(4S)-2-(l-Acetylpiperidin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-2-(l -acetyl- l,2,3,6-tetrahydropyridin-4-yl)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-2-[l-(cyclopropylcarbonyl)piperidin-4-yl]-7-(3,5-dimethylisoxazol-4-yl)- 4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[l-(methylsulfonyl)piperidin-4-yl]-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-2-(l-acetylpyrrolidin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-2-[l-(cyclopropylcarbonyl)pyrrolidin-3-yl]-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine; (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[l-(methylsulfonyl)pyrrolidin-3-yl]-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-2-(l -acetyl- l,2,5,6-tetrahydropyridin-3-yl)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-2-(l-acetylpiperidin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-2- [ 1 -(cyclopropylcarbonyl)piperidin-3 -yl] -7-(3 ,5 -dimethylisoxazol-4-yl)- 4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[l-(methylsulfonyl)piperidin-3-yl]-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-5,6-dihydro-4H-imidazo[4,5,l- ij]quinolin-2(lH)-one;
7-(3,5-Dimethylisoxazol-4-yl)-l-methyl-4-phenyl-5,6-dihydro-4H- imidazo[4,5,l-ij]quinolin-2(lH)-one;
7-(3,5-Dimethylisoxazol-4-yl)-l-methoxy-4-pyridin-2-yl-5,6-dihydro-4H- imidazo[4,5,l-ij]quinolin-2(lH)-one;
7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,l- ij]quinolin-2(lH)-one;
7-[5-(Hydroxymethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-[5-(Fluoromethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-4-yl]pyridine-2-carbonitrile;
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[ 1,5,4- de] [ 1 ,4]benzoxazin-4-yl]pyridine-2-carboxamide;
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de][l,4]benzoxazin-4-yl]-N-methylpyridine-2-carboxamide;
3- [7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[ 1,5,4- de][l,4]benzoxazin-4-yl]-N,N-dimethylpyridine-2-carboxamide;
4- [2-(Aminomethyl)pyridin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
N-({3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[ 1 ,5,4- de] [ 1 ,4]benzoxazin-4-yl]pyridin-2-yl} methyl)acetamide; Methyl 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5- tetrahydroimidazo[l,5,4-de][l,4]benzoxazin-4-yl]pyridine-2-carboxylate;
3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de][l,4]benzoxazin-4-yl]-N-ethylpyridine-2-carboxamide;
N-Cyclopropyl-3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo- 1,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-4-yl]pyridine-2-carboxamide;
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de][l,4]benzoxazin-4-yl]-N-(2-hydroxyethyl)pyridine-2-carboxamide;
3- [7-(3,5-dimethylisoxazol-4-yl)-2-oxo-l,2,4,5-tetrahydroimidazo[l,5,4- de][l,4]benzoxazin-4-yl]-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide;
(4S)-9-(Aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
N- { [(4S)-7-(3 ,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl- 1 ,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-9-yl]methyl} acetamide;
N- { [(4S)-7-(3 ,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl- 1 ,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-9-yl]methyl} -2-phenylacetamide;
N- { [(4S)-7-(3 ,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl- 1 ,2,4,5- tetrahydroimidazo[l,5,4-de][l,4]benzoxazin-9-yl]methyl}-2-methoxyacetamide;
N- { [(4S)-7-(3 ,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl- 1 ,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-9-yl]methyl} methanesulfonamide;
N- { [(4S)-7-(3 ,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl- 1 ,2,4,5- tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-9-yl]methyl} -N'-isopropylurea;
2-(Dimethylamino)-N- {[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin- 2-yl- 1 ,2,4,5 -tetrahydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-9-yl]methyl} acetamide;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(l-hydroxyethyl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
(3R)-l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl] -N-isopropylpyrrolidine-3 - carboxamide;
l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [1 ,4]benzoxazin-2-yl]-3-methylpyrrolidin-3-ol;
4- [(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl] - 1 ,4-diazepane- 1 -sulfonamide; (4S)-2-(4-Acetyl-l,4-diazepan-l-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin- 2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-[4-(methylsulfonyl)-l,4-diazepan-l-yl]- 4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-piperazin-l-yl-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
2- {4-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]piperazin- 1 -yl} -N,N- dimethylacetamide;
2-Cyano-N- {(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N-methylacetamide;
N-{(3R)-l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -yl} morpholine-4- carboxamide;
7-(3,5-Dimethylisoxazol-4-yl)-2-methyl-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
Methyl {(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}carbamate;
7-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-N,N-dimethyl-4-pyridin-3-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-amine;
l-[7-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -ol;
7-(3,5-Dimethylisoxazol-4-yl)-N-ethyl-9-fluoro-4-pyridin-3-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-amine;
(3R)-l-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -ol;
l-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[ 1 ,5,4- de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 -ol;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-morpholin-4-yl-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-pyrrolidin-l-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-l-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine; (4S)-2-azetidin-l-yl-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 -ol;
4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]-l-methylpiperazin-2-one;
ethyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]piperazine- 1 -carboxylate;
(3R)-l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -ol;
(3S)-l-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -ol;
l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-ol;
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]piperidin-3 -ol;
(3S)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]piperidin-3 -ol;
l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]-N,N-dimethylpiperidin-4-amine;
4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]piperazin-2-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(methylsulfonyl)piperazin-l-yl]-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-isopropylpiperazin-l-yl)-4-pyridin-2- yl-4,5 -dihydroimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
1- [(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]piperidine-4-carbonitrile;
{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-yl} methanol;
2- {4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]piperazin- 1 -yl} ethanol;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-phenylpiperazin-l-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine; (4S)-2-(4-benzylpiperazin-l-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]-N,N-dimethylpyrrolidin-3-amine;
(3S)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]-N,N-dimethylpyrrolidin-3-amine;
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]-N-methylpyrrolidin-3 -amine;
(3S)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]-N-methylpyrrolidin-3 -amine;
tert-butyl {(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}carbamate;
tert-butyl {(3S)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}carbamate;
(4S)-2-[4-(cyclopropylmethyl)piperazin-l-yl]-7-(3,5-dimethylisoxazol-4-yl)- 4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(2-methoxyethyl)piperazin-l-yl]-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
2-[[7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4- de][l,4]benzoxazin-2-yl](methyl)amino]ethanol;
7-(3,5-dimethylisoxazol-4-yl)-N-methyl-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-amine;
7-(3,5-dimethylisoxazol-4-yl)-N,N-dimethyl-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-amine;
l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]piperidine-4-carboxamide;
1- [(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]-N-methylpiperidine-4-carboxamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-yl} acetamide;
2- {4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]piperazin-l-yl} acetamide;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-ethylpiperazin-l-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine; (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin- 2(lH)-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[(8aR)-hexahydropyrrolo[l,2-a]pyrazin- 2(lH)-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
1- [(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]-4-methylpiperidin-4-ol;
4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]-3-methylpiperazin-2-one;
tert-butyl { l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [1 ,4]benzoxazin-2-yl]azetidin-3-yl}carbamate;
tert-butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]- 1 ,4-diazepane- 1 -carboxylate;
2- {[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]amino} ethanol;
tert-butyl (2- {[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]amino}ethyl)carbamate;
N-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]ethane- 1 ,2-diamine;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -yl} acetamide;
N-{(3S)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -yl} acetamide;
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -amine;
(3S)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -amine;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3-yl} -2,2,2- trifluoroacetamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2-methoxyacetamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [1 ,4]benzoxazin-2-yl]pyrrolidin-3 - yl}cyclopropanecarboxamide; N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}methanesulfonamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}propanamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2- methylpropanamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [1 ,4]benzoxazin-2-yl]pyrrolidin-3- yl}cyclobutanecarboxamide;
2-cyano-N- { (3 R) - 1 - [(4S)-7-(3 ,5 -dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5 - dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -yl} acetamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [1 ,4]benzoxazin-2-yl]pyrrolidin-3-yl}tetrahydro-2H-pyran- 4-carboxamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l ,5,4-de] [1 ,4]benzoxazin-2-yl]pyrrolidin-3-yl} ethanesulfonamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3 -yl} propane- 1 - sulfonamide;
N'- {(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N,N-dimethylurea;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}propane-2- sulfonamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [1 ,4]benzoxazin-2-yl]pyrrolidin-3- yl}cyclopropanesulfonamide;
methyl {(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}methylcarbamate;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidin-3-yl} -N- methylmethanesulfonamide; N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2-methoxy-N- methylacetamide;
N-{(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N-methylacetamide;
(4S)-2-(4-acetylpiperazin-l-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-propionylpiperazin-l-yl)-4-pyridin-2- yl-4,5 -dihydroimidazo[ 1 ,5 ,4-de] [ 1 ,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(ethylsulfonyl)piperazin-l-yl]-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(2-oxo-2-pyrrolidin-l- ylethyl)piperazin-l-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]piperazine- 1 -sulfonamide;
l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 -amine;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]azetidin-3-yl} acetamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]azetidin-3-yl}propanamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 -yl} -2-methylpropanamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l ,5,4-de] [1 ,4]benzoxazin-2-yl]azetidin-3-yl} -2-methoxyacetamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]azetidin-3- yl}cyclopropanecarboxamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]azetidin-3- yl}cyclobutanecarboxamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]azetidin-3 -yl} methanesulfonamide; N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]azetidin-3 -yl} ethanesulfonamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl] azetidin-3 -yl} propane-2-sulfonamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]piperidin-4-yl}methanesulfonamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]piperidin-4-yl}-2-methoxyacetamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-yl} -2,2,2- trifluoroacetamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-yl}propanamide;
N-{ l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[ 1 ,5,4-de] [ 1 ,4]benzoxazin-2-yl]piperidin-4-yl}propanamide;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-propionyl- 1 ,4-diazepan- 1 -yl)-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(ethylsulfonyl)-l,4-diazepan-l-yl]-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazine;
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]-N-methylpyrrolidine-3-carboxamide;
(3R)-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[l,5,4-de][l,4]benzoxazin-2-yl]-N-ethylpyrrolidine-3-carboxamide;
(3R)-N-cyclopropyl-l-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2-yl]pyrrolidine-3 -carboxamide;
(4S)-8,9-dichloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-9-[(isopropylamino)methyl]-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-9-(hydroxymethyl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[ 1 ,5,4- de] [ 1 ,4]benzoxazine-2( 1 H)-thione; 7-(3,5-dimethylisoxazol-4-yl)-9-(lH-pyrazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-(3-methyl-lH-pyrazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-(3,5-dimethyl-lH-pyrazol-4-yl)-4-pyridin-2- yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(6-hydroxypyridin-3-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(2-hydroxypyridin-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(2-hydroxypyridin-3-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one;
9-(anilinomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-{[(4-methoxybenzyl)amino]methyl}-4- pyridin-2-yl-4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-(l-hydroxy-2-methylpropyl)-4-pyridin-2-yl- 4,5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lH)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
9-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
9-bromo-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-methyl-4-pyridin-2-yl-4,5- dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one; and
7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-l, 2,4,5- tetrahydroimidazo[l,5,4-de][l,4]benzoxazine-9-carbonitrile;
or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
72. A method of inhibiting a BET protein comprising contacting a compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, with said BET protein.
73. A method of treating a disease or condition that is associated with a BET protein, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof.
74. A method of treating a proliferative disorder comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof.
75. The method of claim 74, wherein the proliferative disorder is cancer.
76. The method of claim 75, wherein the cancer is adenocarcinoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, ocular cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer, spinal tumor, small intestine cancer, stomach cancer, T-cell leukemia, T-cell lymphoma, testicular cancer, thyroid cancer, throat cancer, urogenital cancer, urothelial carcinoma, uterine cancer, vaginal cancer, or Wilms' tumor.
77. The method of claim 74, wherein the proliferative disorder is a non-cancerous
proliferative disorder.
78. A method of treating an autoimmune or inflammatory disease comprising
administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof.
79. The method of claim 78, wherein the autoimmune or inflammatory disease is selected from allergy, allergic rhinitis, arthritis, asthma, chronic obstructive pulmonary disease, degenerative joint disease, dermatitis, organ rejection, eczema, hepatitis, inflammatory bowel disease, multiple sclerosis, myasthenia gravis, psoriasis, sepsis, sepsis syndrome, septic shock, systemic lupus erythematosus, tissue graft rejection, type I diabetes.
80. A method of treating a viral infection comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof.
81. The method of claim 80, wherein the viral infection is infection with adenovirus, Epstein-Barr virus, hepatitis B virus, hepatitis C virus, a herpes virus, human immunodeficiency virus, human papilloma virus or a pox virus.
PCT/US2014/027872 2013-03-15 2014-03-14 Tricyclic heterocycles as bet protein inhibitors WO2014143768A1 (en)

Priority Applications (22)

Application Number Priority Date Filing Date Title
JP2016502650A JP6243003B2 (en) 2013-03-15 2014-03-14 Tricyclic heterocycles as BET protein inhibitors
SG11201506924YA SG11201506924YA (en) 2013-03-15 2014-03-14 Tricyclic heterocycles as bet protein inhibitors
CN201480025137.0A CN105164131B (en) 2013-03-15 2014-03-14 Tricyclic heterocyclic as BET protein inhibitor
EP19189853.5A EP3581576B1 (en) 2013-03-15 2014-03-14 Tricyclic heterocycles as bet protein inhibitors for use in the treatment of a proliferative disease in combination with a janus kinase inhibitor
AU2014228175A AU2014228175B2 (en) 2013-03-15 2014-03-14 Tricyclic heterocycles as BET protein inhibitors
CA2903881A CA2903881C (en) 2013-03-15 2014-03-14 Tricyclic heterocycles as bet protein inhibitors
EA201591785A EA035469B1 (en) 2013-03-15 2014-03-14 Tricyclic heterocycles as bet protein inhibitors
BR112015022942-5A BR112015022942B1 (en) 2013-03-15 2014-03-14 Tricyclic heterocycle compounds, method for inhibiting bet protein in vitro and pharmaceutical composition comprising said compounds
NZ712453A NZ712453A (en) 2013-03-15 2014-03-14 Tricyclic heterocycles as bet protein inhibitors
KR1020157029800A KR102216288B1 (en) 2013-03-15 2014-03-14 Tricyclic heterocycles as bet protein inhibitors
UAA201510087A UA119848C2 (en) 2013-03-15 2014-03-14 Tricyclic heterocycles as bet protein inhibitors
EP14721642.8A EP2970282B1 (en) 2013-03-15 2014-03-14 Tricyclic heterocycles as bet protein inhibitors
KR1020217003659A KR102355670B1 (en) 2013-03-15 2014-03-14 Tricyclic heterocycles as bet protein inhibitors
MX2015013149A MX366703B (en) 2013-03-15 2014-03-14 Tricyclic heterocycles as bet protein inhibitors.
ES14721642T ES2755827T3 (en) 2013-03-15 2014-03-14 Tricyclic heterocycles as BET protein inhibitors
IL241158A IL241158B (en) 2013-03-15 2015-09-03 Tricyclic heterocycles as bet protein inhibitors
PH12015502157A PH12015502157A1 (en) 2013-03-15 2015-09-15 Trycyclic heterocycles as bet protein inhibitors
CR20150513A CR20150513A (en) 2013-03-15 2015-09-30 TRICYCLIC HETEROCICLES AS INHIBITORS OF BET PROTEIN
ZA2015/07255A ZA201507255B (en) 2013-03-15 2015-09-30 Tricyclic heterocycles as bet protein inhibitors
HK16106622.5A HK1218650A1 (en) 2013-03-15 2016-06-08 Tricyclic heterocycles as bet protein inhibitors bet
IL267609A IL267609B (en) 2013-03-15 2019-06-24 Bet protein inhibitors in combination with janus kinase inhibitors for the treatment of proliferative diseases
PH12019502318A PH12019502318A1 (en) 2013-03-15 2019-10-10 Trycyclic heterocycles as bet protein inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361794812P 2013-03-15 2013-03-15
US61/794,812 2013-03-15

Publications (1)

Publication Number Publication Date
WO2014143768A1 true WO2014143768A1 (en) 2014-09-18

Family

ID=50639971

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/027872 WO2014143768A1 (en) 2013-03-15 2014-03-14 Tricyclic heterocycles as bet protein inhibitors

Country Status (25)

Country Link
US (6) US9227985B2 (en)
EP (2) EP2970282B1 (en)
JP (3) JP6243003B2 (en)
KR (2) KR102216288B1 (en)
CN (2) CN105164131B (en)
AR (1) AR095326A1 (en)
AU (1) AU2014228175B2 (en)
BR (1) BR112015022942B1 (en)
CA (1) CA2903881C (en)
CL (1) CL2015002734A1 (en)
CR (1) CR20150513A (en)
EA (2) EA038494B1 (en)
EC (1) ECSP15043772A (en)
ES (2) ES2909778T3 (en)
HK (1) HK1218650A1 (en)
IL (2) IL241158B (en)
MX (2) MX366703B (en)
NZ (1) NZ712453A (en)
PE (1) PE20151990A1 (en)
PH (2) PH12015502157A1 (en)
SG (2) SG10201707487VA (en)
TW (2) TWI719464B (en)
UA (1) UA119848C2 (en)
WO (1) WO2014143768A1 (en)
ZA (2) ZA201507255B (en)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9290514B2 (en) 2013-07-08 2016-03-22 Incyte Holdings Corporation Tricyclic heterocycles as BET protein inhibitors
WO2016044130A1 (en) * 2014-09-15 2016-03-24 Incyte Corporation Tricyclic heterocycles for use as bet protein inhibitors
US9309246B2 (en) 2013-12-19 2016-04-12 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US9315501B2 (en) 2013-11-26 2016-04-19 Incyte Corporation Bicyclic heterocycles as BET protein inhibitors
WO2016061144A1 (en) 2014-10-14 2016-04-21 The Regents Of The University Of California Use of cdk9 and brd4 inhibitors to inhibit inflammation
US9399640B2 (en) 2013-11-26 2016-07-26 Incyte Corporation Substituted pyrrolo[2,3-c]pyridines and pyrazolo[3,4-c]pyridines as BET protein inhibitors
WO2016146755A1 (en) 2015-03-19 2016-09-22 Glaxosmithkline Intellectual Property Development Limited Covalent conjugates of bet inhibitors and alpha amino acid esters
CN105985282A (en) * 2015-01-28 2016-10-05 中国科学院广州生物医药与健康研究院 2-oxo-1,2-dihydrobenzo[cd]indole compound and application thereof
US9540368B2 (en) 2014-04-23 2017-01-10 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US9540347B2 (en) 2015-05-29 2017-01-10 Incyte Corporation Pyridineamine compounds useful as Pim kinase inhibitors
US9550765B2 (en) 2013-01-15 2017-01-24 Incyte Holdings Corporation Thiazolecarboxamides and pyridinecarboxamide compounds useful as Pim kinase inhibitors
US9624241B2 (en) 2013-03-15 2017-04-18 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US9676750B2 (en) 2013-01-14 2017-06-13 Incyte Corporation Bicyclic aromatic carboxamide compounds useful as pim kinase inhibitors
US9822124B2 (en) 2014-07-14 2017-11-21 Incyte Corporation Bicyclic heteroaromatic carboxamide compounds useful as Pim kinase inhibitors
US9862705B2 (en) 2015-09-09 2018-01-09 Incyte Corporation Salts of a pim kinase inhibitor
US9890162B2 (en) 2014-07-14 2018-02-13 Incyte Corporation Bicyclic aromatic carboxamide compounds useful as pim kinase inhibitors
US9920032B2 (en) 2015-10-02 2018-03-20 Incyte Corporation Heterocyclic compounds useful as pim kinase inhibitors
US10000507B2 (en) 2013-08-23 2018-06-19 Incyte Corporation Furo- and thieno-pyridine carboxamide compounds useful as pim kinase inhibitors
CN108349996A (en) * 2015-09-08 2018-07-31 豪夫迈·罗氏有限公司 Tricyclic PI3K inhibitor compounds and its application method
US10189832B2 (en) 2016-06-20 2019-01-29 Incyte Corporation Crystalline solid forms of a BET inhibitor
US10329305B2 (en) 2015-10-29 2019-06-25 Incyte Corporation Amorphous solid form of a BET protein inhibitor
US10596161B2 (en) 2017-12-08 2020-03-24 Incyte Corporation Low dose combination therapy for treatment of myeloproliferative neoplasms
EP3873896A4 (en) * 2018-12-14 2022-08-31 Jiangsu Hengrui Medicine Co., Ltd. Tricyclic compounds as sting agonists, and preparation methods and medicinal uses thereof
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9073878B2 (en) 2012-11-21 2015-07-07 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
WO2014080291A2 (en) 2012-11-21 2014-05-30 Rvx Therapeutics Inc. Biaryl derivatives as bromodomain inhibitors
AU2013365926B9 (en) 2012-12-21 2019-01-17 Zenith Epigenetics Ltd. Novel heterocyclic compounds as bromodomain inhibitors
CN109939113B (en) 2013-06-21 2022-02-15 恒翼生物医药科技(上海)有限公司 Bicyclic bromodomain inhibitors
EP3010917B1 (en) 2013-06-21 2018-01-31 Zenith Epigenetics Ltd. Novel substituted bicyclic compounds as bromodomain inhibitors
US9855271B2 (en) 2013-07-31 2018-01-02 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
US10710992B2 (en) 2014-12-01 2020-07-14 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
WO2016087942A1 (en) 2014-12-01 2016-06-09 Zenith Epigenetics Corp. Substituted pyridines as bromodomain inhibitors
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
CA2966450A1 (en) 2014-12-17 2016-06-23 Olesya KHARENKO Inhibitors of bromodomains
JP2019508494A (en) * 2016-02-05 2019-03-28 チーア タイ ティエンチン ファーマシューティカル グループ カンパニー，リミティド Tricyclic compounds of bromo domain protein inhibitors and their preparation, pharmaceutical compositions and uses
CA3019342A1 (en) 2016-03-30 2017-10-05 Wisconsin Alumni Research Foundation Methods and compositions for modulating frataxin expression
US11759533B2 (en) 2017-03-29 2023-09-19 Wisconsin Alumni Research Foundation Methods and compositions for modulating gene expression
WO2019246273A1 (en) * 2018-06-20 2019-12-26 Progenity, Inc. Treatment of a disease of the gastrointestinal tract with a jak or other kinase inhibitor
JP2021534250A (en) * 2018-08-24 2021-12-09 アドライ・ノーティ・バイオファーマ・カンパニー・リミテッドAdlai Nortye Biopharma Co., Ltd. Highly active STING protein agonist
CN110879294A (en) * 2018-09-05 2020-03-13 成都市第三人民医院 Use of protein marker in product for diagnosing irritable bowel syndrome and kit for diagnosing irritable bowel syndrome
CN111349094B (en) * 2020-04-23 2021-02-02 杭州师范大学 6H-imidazo [4,5,1-ij ] quinolone and synthesis method and application thereof
AU2022217309A1 (en) * 2021-02-03 2023-09-14 Tuojie Biotech (Shanghai) Co., Ltd. Fused tricyclic cyclin-dependent kinase inhibitor, and preparation method therefor and pharmaceutical use thereof
CN117794546A (en) * 2021-08-10 2024-03-29 葛兰素史密斯克莱有限责任公司 Molotinib combination therapy
CN113975278B (en) * 2021-10-29 2023-04-07 中国科学院昆明动物研究所 Application of bromocriptine in preparation of product for treating African swine fever

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0732334A1 (en) * 1995-03-13 1996-09-18 Synthelabo Piperidine derivatives, process for their preparation and their therapeutic application
WO2002000196A2 (en) 2000-06-28 2002-01-03 Smithkline Beecham P.L.C. Wet milling process
WO2010144679A1 (en) * 2009-06-10 2010-12-16 Janssen Pharmaceutica Nv Benzimidazole derivatives useful as trpm8 channel modulators

Family Cites Families (158)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59170313A (en) 1983-03-14 1984-09-26 Kurimoto Iron Works Ltd Screen gate
JPS6085739U (en) 1983-11-18 1985-06-13 クラリオン株式会社 Pinch roller device in tape recorder
JPH0314566A (en) * 1989-06-09 1991-01-23 Sankyo Co Ltd Benzimidazole derivative
US5244912A (en) * 1991-03-28 1993-09-14 Eli Lilly And Company 6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz(cd)indoles and pharmaceutical use thereof
FR2710915B1 (en) 1993-10-04 1995-11-24 Synthelabo Piperidine derivatives, their preparation and their therapeutic use.
GB9410469D0 (en) * 1994-05-25 1994-07-13 Erba Farmitalia Imidazolylalkyl derivatives of imidazo (5,1-c) (1,4) benzoxazin-1-one and process for their preparation
FR2747678B1 (en) 1996-04-22 1998-05-22 Synthelabo COMPOUNDS DERIVED FROM IMIDAZOBENZOXAZINE, PROCESSES FOR THEIR PREPARATION AND THERAPEUTIC USES
US6287693B1 (en) 1998-02-25 2001-09-11 John Claude Savoir Stable shaped particles of crystalline organic compounds
WO2001081343A2 (en) * 2000-04-21 2001-11-01 Pharmacia & Upjohn Company Compounds for treating fibromyalgia and chronic fatigue syndrome
FR2816619B1 (en) 2000-11-15 2003-01-31 Sanofi Synthelabo BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
PL365080A1 (en) * 2000-08-08 2004-12-27 Sanofi-Aventis Benzimidazole derivatives, preparation and therapeutic use thereof
US6919334B2 (en) 2002-09-12 2005-07-19 Wyeth Antidepressant azaheterocyclymethyl derivatives of 4,5-dihydroimidazo[1,4,5-de][1,4]benzoxazine
MXPA05005425A (en) * 2002-11-22 2005-11-23 Japan Tobacco Inc Fused bicyclic nitrogen-containing heterocycles.
EP1462103A1 (en) 2003-03-25 2004-09-29 Faust Pharmaceuticals NO donors, combination products and uses as modulators of neurotransmitter release
AU2005214258A1 (en) 2004-02-23 2005-09-01 Dainippon Sumitomo Pharma Co., Ltd. Novel heterocyclic compound
US7713954B2 (en) 2004-09-30 2010-05-11 Roche Palo Alto Llc Compositions and methods for treating cognitive disorders
DE102005011058A1 (en) 2005-03-10 2006-09-14 Merck Patent Gmbh Substituted tetrahydro-pyrrolo-quinoline derivatives
EP1912989A2 (en) 2005-08-05 2008-04-23 AstraZeneca AB Tricyclic benzimidazoles and their use as metabotropic glutamate receptor modulators
WO2009020677A2 (en) 2007-04-27 2009-02-12 University Of Rochester Compositions and methods for inhibiting g protein signaling
US8633186B2 (en) 2007-06-08 2014-01-21 Senomyx Inc. Modulation of chemosensory receptors and ligands associated therewith
US9603848B2 (en) 2007-06-08 2017-03-28 Senomyx, Inc. Modulation of chemosensory receptors and ligands associated therewith
US7928111B2 (en) 2007-06-08 2011-04-19 Senomyx, Inc. Compounds including substituted thienopyrimidinone derivatives as ligands for modulating chemosensory receptors
WO2009020559A2 (en) 2007-08-03 2009-02-12 The J. David Gladstone Institutes Agents that inhibit p-tefb interactions and methods of use thereof
KR101600634B1 (en) 2007-12-28 2016-03-07 미쓰비시 타나베 파마 코퍼레이션 Antitumor agent
DE102008052618A1 (en) 2008-10-21 2010-04-22 Henkel Ag & Co. Kgaa Tricyclic aldehydes and C, H-acidic compounds
JP5730281B2 (en) 2009-03-27 2015-06-10 武田薬品工業株式会社 Poly (ADP-ribose) polymerase (PARP) inhibitor
TW201103941A (en) 2009-06-10 2011-02-01 Janssen Pharmaceutica Nv Benzimidazole derivatives useful as TRPM8 channel modulators
GB0919431D0 (en) 2009-11-05 2009-12-23 Glaxosmithkline Llc Novel compounds
GB0919426D0 (en) 2009-11-05 2009-12-23 Glaxosmithkline Llc Novel compounds
GB0919423D0 (en) 2009-11-05 2009-12-23 Glaxosmithkline Llc Novel compounds
EP2955524A3 (en) 2009-11-05 2016-03-23 GlaxoSmithKline LLC Novel process
ES2563057T3 (en) 2009-11-05 2016-03-10 Glaxosmithkline Llc Benzodiazepine Bromodomain Inhibitor
GB0919432D0 (en) 2009-11-05 2009-12-23 Glaxosmithkline Llc Use
GB0919434D0 (en) 2009-11-05 2009-12-23 Glaxosmithkline Llc Novel compounds
EP3050885B1 (en) 2009-11-05 2017-10-18 GlaxoSmithKline LLC Benzodiazepine bromodomain inhibitor
US8927561B2 (en) 2010-04-23 2015-01-06 Kineta, Inc. Pyrimidinedione anti-viral compounds
BR112012029057A2 (en) 2010-05-14 2020-10-13 Dana-Farber Cancer Institute, Inc. leukemia compositions and treatment methods
JP6022442B2 (en) 2010-05-14 2016-11-09 ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド Male contraceptive compositions and methods of use
US20130252331A1 (en) 2010-05-14 2013-09-26 James Elliott Bradner Compositions and methods for modulating metabolism
SI2902030T1 (en) 2010-05-14 2017-01-31 Dana-Farber Cancer Institute, Inc. Thienotriazolodiazepine compounds for treating neoplasia
ES2526671T3 (en) 2010-06-22 2015-01-14 Glaxosmithkline Llc Compounds of benzotriazoldiazepine bromodomain inhibitors
AR084070A1 (en) 2010-12-02 2013-04-17 Constellation Pharmaceuticals Inc BROMODOMINIUM INHIBITORS AND USES OF THE SAME
US9249161B2 (en) 2010-12-02 2016-02-02 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
RU2013138835A (en) 2011-02-09 2015-03-20 Ф. Хоффманн-Ля Рош Аг HETEROCYCLIC COMPOUNDS AS PI3 KINASE INHIBITORS
EP2677865A4 (en) 2011-02-23 2015-04-22 Icahn School Med Mount Sinai Inhibitors of bromodomains as modulators of gene expression
RU2013143747A (en) * 2011-03-21 2015-04-27 Ф. Хоффманн-Ля Рош Аг BENZOXAZEPINE COMPOUNDS SELECTIVE FOR PI3K P110 DELTA AND METHODS OF APPLICATION
GB201106750D0 (en) 2011-04-21 2011-06-01 Glaxosmithkline Llc Novel compounds
GB201106799D0 (en) 2011-04-21 2011-06-01 Glaxosmithkline Llc Novel compounds
GB201106743D0 (en) 2011-04-21 2011-06-01 Glaxosmithkline Llc Novel compounds
GB201107325D0 (en) 2011-05-04 2011-06-15 Glaxosmithkline Llc Novel compounds
US9422292B2 (en) 2011-05-04 2016-08-23 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
EP2721031B1 (en) 2011-06-17 2016-01-20 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
WO2012178208A2 (en) 2011-06-24 2012-12-27 The Trustees Of The Stevens Institute Of Technology Selective inhibitors of histone deacetylase isoform 6 and methods thereof
JP2013010719A (en) 2011-06-30 2013-01-17 Dainippon Sumitomo Pharma Co Ltd Benzimidazolone and oxindole derivative, and pharmaceutical application of them
JP2014524409A (en) 2011-07-29 2014-09-22 ザ・チルドレンズ・ホスピタル・オブ・フィラデルフィア Compositions and methods for the treatment of HIV
GB201114103D0 (en) 2011-08-17 2011-09-28 Glaxosmithkline Llc Novel compounds
WO2013027168A1 (en) 2011-08-22 2013-02-28 Pfizer Inc. Novel heterocyclic compounds as bromodomain inhibitors
WO2013033269A1 (en) 2011-08-29 2013-03-07 Coferon, Inc. Bioorthogonal monomers capable of dimerizing and targeting bromodomains and methods of using same
WO2013033270A2 (en) 2011-08-29 2013-03-07 Coferon, Inc. Bromodomain ligands capable of dimerizing in an aqueous solution, and methods of using same
MX371361B (en) * 2011-08-31 2020-01-27 Otsuka Pharma Co Ltd Quinolone compound.
DE102011082013A1 (en) 2011-09-01 2013-03-07 Bayer Pharma AG 6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepines
US9012642B2 (en) 2011-09-22 2015-04-21 Viiv Healthcare Uk Limited Pyrrolopyridinone compounds and methods for treating HIV
WO2013044511A1 (en) 2011-09-30 2013-04-04 沈阳蓝桑医药生物技术研发有限公司 Pharmaceutical composition containing riligustilide and use thereof
WO2013060636A1 (en) 2011-10-25 2013-05-02 Sanofi 6-(4-hydroxy-phenyl)-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
JP5992049B2 (en) 2011-11-01 2016-09-14 レスバーロジックス コーポレイション Oral immediate release formulations for substituted quinazolinones
WO2013097052A1 (en) 2011-12-30 2013-07-04 Abbott Laboratories Bromodomain inhibitors
US20150133434A1 (en) 2012-03-28 2015-05-14 The J. David Gladstone Institutes Compositions and Methods for Reactivating Latent Immunodeficiency Virus
US20130281396A1 (en) 2012-04-19 2013-10-24 Rvx Therapeutics Inc. Treatment of diseases by epigenetic regulation
US20130281399A1 (en) 2012-04-19 2013-10-24 Rvx Therapeutics Inc. Treatment of diseases by epigenetic regulation
US20130281397A1 (en) 2012-04-19 2013-10-24 Rvx Therapeutics Inc. Treatment of diseases by epigenetic regulation
US20130281398A1 (en) 2012-04-19 2013-10-24 Rvx Therapeutics Inc. Treatment of diseases by epigenetic regulation
JP5989229B2 (en) 2012-04-20 2016-09-07 アッヴィ・インコーポレイテッド Isoindolone derivatives
EP2864336B1 (en) 2012-06-06 2016-11-23 Constellation Pharmaceuticals, Inc. Benzo[b]isoxazoloazepine bromodomain inhibitors and uses thereof
TWI602820B (en) 2012-06-06 2017-10-21 星宿藥物公司 Bromodomain inhibitors and uses thereof
WO2013185284A1 (en) 2012-06-12 2013-12-19 Abbott Laboratories Pyridinone and pyridazinone derivatives
IN2014DN11269A (en) 2012-06-25 2015-10-09 Oncoethix Sa
US9610332B2 (en) 2012-07-18 2017-04-04 Massachusetts Institute Of Technology Compositions and methods for modulating BRD4 bioactivity
EA201590356A1 (en) 2012-08-16 2015-07-30 Байер Фарма Акциенгезельшафт 2,3-benzodiazepines
CA2880578A1 (en) 2012-08-16 2014-02-20 Glaxosmithkline Llc Benzodiazepines for treating small cell lung cancer
MX2015003771A (en) 2012-09-28 2016-03-04 Oncoethix Gmbh Pharmaceutical formulation containing thienotriazolodiazepine compounds.
EP2900672B1 (en) 2012-09-28 2017-02-22 Bayer Pharma Aktiengesellschaft Bet-protein inhibitory 5-aryl-triazolo-azepines
KR20150079968A (en) 2012-11-09 2015-07-08 자코버스 파마슈티컬 컴패니, 인코포레이티드 Heteroaryl derivatives and uses thereof
US9422290B2 (en) 2012-11-13 2016-08-23 Boehringer Ingelheim International Gmbh Triazolopyridazine
WO2014078257A1 (en) 2012-11-14 2014-05-22 Glaxosmithkline Llc Thieno[3,2-c]pyridin-4(5h)-ones as bet inhibitors
WO2014080291A2 (en) 2012-11-21 2014-05-30 Rvx Therapeutics Inc. Biaryl derivatives as bromodomain inhibitors
US9073878B2 (en) 2012-11-21 2015-07-07 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
EP2935261A1 (en) 2012-12-20 2015-10-28 Bayer Pharma Aktiengesellschaft Bet-protein-inhibiting dihydroquinoxalinones
WO2014095774A1 (en) 2012-12-20 2014-06-26 Bayer Pharma Aktiengesellschaft Bet-protein-inhibiting dihydropyridopyrazinones
AU2013365926B9 (en) 2012-12-21 2019-01-17 Zenith Epigenetics Ltd. Novel heterocyclic compounds as bromodomain inhibitors
WO2014128655A1 (en) 2013-02-25 2014-08-28 Aurigene Discovery Technologies Limited Substituted imidazo[4,5-c]quinoline derivatives as bromodomain inhibitors
WO2014134267A1 (en) 2013-02-27 2014-09-04 Bristol-Myers Squibb Company Carbazole compounds useful as bromodomain inhibitors
US9492460B2 (en) 2013-02-27 2016-11-15 Bristol-Myers Squibb Company Carbazole compounds useful as bromodomain inhibitors
US9050346B2 (en) 2013-03-11 2015-06-09 Abbvie Inc. Bromodomain inhibitors
CN105189504B (en) 2013-03-11 2017-07-18 艾伯维公司 Fused tetracyclic bromine domain inhibitor
CA2903463A1 (en) 2013-03-11 2014-10-09 The Regents Of The University Of Michigan Bet bromodomain inhibitors and therapeutic methods using the same
KR102224992B1 (en) 2013-03-12 2021-03-10 애브비 인코포레이티드 Tetracyclic bromodomain inhibitors
EP2970276A1 (en) 2013-03-12 2016-01-20 AbbVie Inc. Dihydro-pyrrolopyridinone bromodomain inhibitors
CN105164113B (en) 2013-03-12 2018-03-02 艾伯维公司 Pyrrole amides inhibitor
AU2014230816B9 (en) 2013-03-14 2016-12-15 Glaxosmithkline Intellectual Property (No.2) Limited Furopyridines as bromodomain inhibitors
WO2014159837A1 (en) 2013-03-14 2014-10-02 Convergene Llc Methods and compositions for inhibition of bromodomain-containing proteins
WO2014159392A1 (en) 2013-03-14 2014-10-02 Dana-Farber Cancer Institute, Inc. Bromodomain binding reagents and uses thereof
PE20151596A1 (en) 2013-03-14 2015-11-24 Glaxosmithkline Intellectual Property N 2 Ltd DERIVATIVES OF 1-ACIL-4-AMINO-1,2,3,4-TETRAHIDROQUINOLINA 2,3-DISUSTITUIDOS AND THEIR USE AS INHIBITORS OF BROMODOMINIUM
PE20151997A1 (en) 2013-03-15 2016-01-13 Plexxikon Inc HETEROCYCLIC COMPOUNDS AND USES OF THEM
EP2968311A4 (en) 2013-03-15 2016-07-20 Epigenetix Inc Oxazolo[5,4-c]quinolin-2-one compounds as bromodomain inhibitors
WO2014143768A1 (en) * 2013-03-15 2014-09-18 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
WO2014154762A1 (en) 2013-03-27 2014-10-02 Boehringer Ingelheim International Gmbh Dihydroquinazolinone analogues as brd4 inhibitors
JP6370368B2 (en) 2013-03-27 2018-08-08 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Indolinone analogs as BRD4 inhibitors
TWI530499B (en) 2013-03-28 2016-04-21 吉李德科學股份有限公司 Benzimidazolone derivatives as bromodomain inhibitors
WO2014170350A1 (en) 2013-04-17 2014-10-23 Albert Ludwigs Universität Freiburg Compounds for use as bromodomain inhibitors
EA027139B1 (en) 2013-04-26 2017-06-30 Бейджин, Лтд. Substituted 5-(3,5-dimethylisoxazol-4-yl)indoline-2-ones
TWI527811B (en) 2013-05-09 2016-04-01 吉李德科學股份有限公司 Benzimidazole derivatives as bromodomain inhibitors
MX2015016344A (en) 2013-05-27 2016-03-01 Novartis Ag Imidazopyrrolidinone derivatives and their use in the treatment of disease.
US8975417B2 (en) 2013-05-27 2015-03-10 Novartis Ag Pyrazolopyrrolidine derivatives and their use in the treatment of disease
EA028175B1 (en) 2013-05-28 2017-10-31 Новартис Аг Pyrazolo-pyrrolidin-4-one derivatives as bet inhibitors and their use in the treatment of disease
MX2015016425A (en) 2013-05-28 2016-03-03 Novartis Ag Pyrazolo-pyrrolidin-4-one derivatives and their use in the treatment of disease.
WO2014202578A1 (en) 2013-06-17 2014-12-24 Bayer Pharma Aktiengesellschaft Substituted phenyl-2,3-benzodiazepines
ITMI20130991A1 (en) 2013-06-17 2014-12-18 Industrie De Nora Spa CURRENT MEASUREMENT SYSTEM PRESENT IN ELECTRODES IN INTERCONNECTED ELECTROLYTIC CELLS.
EP3010917B1 (en) 2013-06-21 2018-01-31 Zenith Epigenetics Ltd. Novel substituted bicyclic compounds as bromodomain inhibitors
CN109939113B (en) 2013-06-21 2022-02-15 恒翼生物医药科技(上海)有限公司 Bicyclic bromodomain inhibitors
AR096758A1 (en) 2013-06-28 2016-02-03 Abbvie Inc BROMODOMINIUM CRYSTAL INHIBITORS
MX2015017963A (en) 2013-06-28 2016-11-10 Abbvie Inc Bromodomain inhibitors.
CA2917319A1 (en) 2013-07-08 2015-01-15 Incyte Holdings Corporation Tricyclic heterocycles as bet protein inhibitors
BR112015033042B1 (en) 2013-07-16 2020-10-13 Basf Se azine compound, processes for the preparation of azine compound, agrochemical composition, process for the preparation of agrochemical compositions, method for controlling vegetation and use of the azine compound
BR112016001457A2 (en) 2013-07-25 2017-08-29 Dana Farber Cancer Inst Inc TRANSCRIPTION FACTOR INHIBITORS AND THEIR USES
KR101672096B1 (en) 2013-09-30 2016-11-02 주식회사 엘지화학 Heterocyclic compound and organic light emitting device comprising the same
AU2014337064B2 (en) 2013-10-18 2019-03-14 Celgene Quanticel Research, Inc. Bromodomain inhibitors
US9399640B2 (en) 2013-11-26 2016-07-26 Incyte Corporation Substituted pyrrolo[2,3-c]pyridines and pyrazolo[3,4-c]pyridines as BET protein inhibitors
WO2015081189A1 (en) 2013-11-26 2015-06-04 Incyte Corporation Bicyclic heterocycles as bet protein inhibitors
US20150148372A1 (en) 2013-11-26 2015-05-28 Incyte Corporation Bicyclic heterocycles as bet protein inhibitors
US9428514B2 (en) 2013-12-09 2016-08-30 Abbvie Inc. Bromodomain inhibitors
US9309246B2 (en) 2013-12-19 2016-04-12 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
WO2015095445A1 (en) 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
SI3092227T1 (en) 2014-01-09 2018-10-30 Orion Corporation Bicyclic heterocyclic derivatives as bromodomain inhibitors
US9580430B2 (en) 2014-02-28 2017-02-28 The Regents Of The University Of Michigan 9H-pyrimido[4,5-B]indoles and related analogs as BET bromodomain inhibitors
WO2015162169A1 (en) 2014-04-23 2015-10-29 Basf Se Diaminotriazine compounds as herbicides
JP6517239B2 (en) 2014-04-23 2019-05-22 武田薬品工業株式会社 Isoindoline-1-one derivatives as cholinergic muscarinic M1 receptor positive allosteric modulator activity for the treatment of Alzheimer's disease
BR112016024626B1 (en) 2014-04-23 2023-03-21 Incyte Holdings Corporation COMPOUNDS 1H-PIRROLO[2,3-C]PYRIDIN-7(6H)-ONES AND PIRAZOLO[3,4-C]PYRIDIN-7 (6H)-ONES, THEIR USE, PHARMACEUTICAL COMPOSITION INCLUDING THEM AND INHIBITION METHOD FROM A BET PROTEIN
KR20170002550A (en) 2014-05-02 2017-01-06 온코에틱스 게엠베하 Method of treating resistant non-hodgkin lymphoma, medulloblastoma, and/or alk+ non-small cell lung cancer using thienotriazolodiazepine compounds
AU2015252844A1 (en) 2014-05-02 2016-11-03 Kay NOEL Method of treating acute myeloid leukemia and/or acute lymphoblastic leukemia using thienotriazolodiazepine compounds
WO2015169953A1 (en) 2014-05-08 2015-11-12 Oncoethix Gmbh Method of treating glioma using thienotriazolodiazepine compounds
JP2017519727A (en) 2014-05-08 2017-07-20 オンコエシックス ゲーエムベーハー Method for treating three types of negative breast cancer using thienotriazolodiazepine compounds
EP3148543B1 (en) 2014-05-30 2020-04-08 Icahn School of Medicine at Mount Sinai Small molecule transcription modulators of bromodomains
CA2952830C (en) 2014-06-20 2022-11-01 Constellation Pharmaceuticals, Inc. Crystalline forms of 2-((4s)-6-(4-chlorophenyl)-1-methyl-4h-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide
EP3194406B8 (en) 2014-09-15 2021-03-31 Incyte Corporation Tricyclic heterocycles for use as bet protein inhibitors
SG11201703188QA (en) 2014-10-24 2017-05-30 Bristol Myers Squibb Co Indole carboxamides compounds useful as kinase inhibitors
MA40943A (en) 2014-11-10 2017-09-19 Constellation Pharmaceuticals Inc SUBSTITUTED PYRROLOPYRIDINES USED AS BROMODOMA INHIBITORS
EP3253756B1 (en) 2015-02-03 2021-09-22 Trillium Therapeutics Inc. Fluorinated imidazo[4,5-c]quinoline derivatives as inhibitors of bromodomain containing proteins
WO2016186453A1 (en) 2015-05-20 2016-11-24 Kainos Medicine, Inc. Quinoline derivatives as bromodomain inhibitors
JP6614585B2 (en) 2015-05-29 2019-12-04 塩野義製薬株式会社 Nitrogen-containing tricyclic derivatives having HIV replication inhibitory action
CN105039258B (en) 2015-07-03 2018-04-17 北京大学 Method and composition by non-neuronal cell reprogramming for neuron cell
TW201722966A (en) 2015-10-29 2017-07-01 英塞特公司 Amorphous solid form of a BET protein inhibitor
CN105254635A (en) 2015-10-30 2016-01-20 中国药科大学 Imidazo pyrazine compound, medicine composition of imidazo pyrazine compound and purpose of imidazo pyrazine compound
US20170127985A1 (en) 2015-11-11 2017-05-11 Medtronic Minimed, Inc. Sensor set
CA3007168A1 (en) 2015-12-14 2017-06-22 Zenith Epigenetics Ltd. 1h-imidazo[4,5-b]pyridinyl and 2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridinyl heterocyclic bet bromodomain inhibitors
WO2017127930A1 (en) 2016-01-28 2017-08-03 Neomed Institute Substituted [1,2,4]triazolo[4,3-a]pyridines, their preparation and their use as pharmaceuticals
JP2019508494A (en) 2016-02-05 2019-03-28 チーア タイ ティエンチン ファーマシューティカル グループ カンパニー，リミティド Tricyclic compounds of bromo domain protein inhibitors and their preparation, pharmaceutical compositions and uses
PE20190623A1 (en) 2016-06-20 2019-04-26 Incyte Corp SOLID CRYSTAL FORMS OF A BET INHIBITOR
CN108069958A (en) 2016-11-10 2018-05-25 凯惠科技发展(上海)有限公司 A kind of nitrogen-containing hetero cyclics, its preparation method, pharmaceutical composition and application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0732334A1 (en) * 1995-03-13 1996-09-18 Synthelabo Piperidine derivatives, process for their preparation and their therapeutic application
WO2002000196A2 (en) 2000-06-28 2002-01-03 Smithkline Beecham P.L.C. Wet milling process
WO2010144679A1 (en) * 2009-06-10 2010-12-16 Janssen Pharmaceutica Nv Benzimidazole derivatives useful as trpm8 channel modulators

Non-Patent Citations (38)

* Cited by examiner, † Cited by third party
Title
"Advances in Heterocyclic Chemistry", vol. 1-107, 1963, ELSEVIER
"Comprehensive Heterocyclic Chemistry", 1984, PERGAMON PRESS
"Comprehensive Organic Functional Group Transformations II", 2004, ELSEVIER
"Comprehensive Organic Functional Group Transformations", 1996, PERGAMON PRESS
"Comprehensive Organic Synthesis", 1991, PERGAMON PRESS
"Knowledge Updates KU2010/1-4; 2011/1-4; 2012/1-2", 2001, THIEME
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY, pages: 1418
"Science of Synthesis", vol. 1-48, 2001
BELKINA ET AL., J. IMMUNOL., 18 February 2013 (2013-02-18), pages 102838
BERGE ET AL., J. PHARM. SCI., vol. 66, no. 1, 1977, pages 1 - 19
DANIEL GALLENKAMP ET AL: "Bromodomains and Their Pharmacological Inhibitors", CHEMMEDCHEM, vol. 9, no. 3, 4 March 2014 (2014-03-04), pages 438 - 464, XP055124420, ISSN: 1860-7179, DOI: 10.1002/cmdc.201300434 *
DAVID S. HEWINGS ET AL: "Progress in the Development and Application of Small Molecule Inhibitors of Bromodomain-Acetyl-lysine Interactions", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 22, 26 November 2012 (2012-11-26), pages 9393 - 9413, XP055124430, ISSN: 0022-2623, DOI: 10.1021/jm300915b *
DELMORE ET AL., CELL, vol. 146, 2011, pages 904 - 917
DEVAIAH ET AL., PROC. NAT. ACAD. SCI., USA, vol. 109, 2012, pages 6927 - 6932
FILIPPAKOPOULOS ET AL., NATURE, vol. 468, 2010, pages 1068 - 1073
FRENCH ET AL., CANCER RES., vol. 63, 2003, pages 304 - 307
FRENCH ET AL., J. CLIN. ONCOL., vol. 22, 2004, pages 4135 - 4139
HUANG ET AL., MOL. CELL BIOL., vol. 29, 2009, pages 1375 - 1387
JANG ET AL., MOL. CELL, vol. 19, 2005, pages 523 - 534
JEAN-MARC GARNIER ET AL: "BET bromodomain inhibitors: a patent review", EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 24, no. 2, 1 February 2014 (2014-02-01), pages 185 - 199, XP055121821, ISSN: 1354-3776, DOI: 10.1517/13543776.2014.859244 *
JOURNAL OFHETEROCYCLIC CHEMISTRY, vol. 1-49, 1964
KARL F. BLOM; BRIAN GLASS; RICHARD SPARKS; ANDREW P. COMBS: "Preparative LCMS Purification: Improved Compound Specific Method Optimization", J. COMBI. CHEM., vol. 6, no. 6, 2004, pages 874 - 883
KATRITZKY ET AL.: "Comprehensive Heterocyclic Chemistry II", 1996, PERGAMON PRESS
KOCIENSKI: "Protecting Groups", 2007, THIEME
LAMONICA ET AL., PROC. NAT. ACAD. SCI., USA, vol. 108, 2011, pages E159 - 168
LAROCK: "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 1999, WILEY
LEROY ET AL., MOL. CELL, vol. 30, 2008, pages 51 - 60
MOCHIZUKI ET AL., J. BIOL. CHEM., vol. 283, 2008, pages 9040 - 9048
ORG. PROCESS RES. DEV., vol. 16, 2012, pages 109 - 116
PETURSSION ET AL.: "Protecting Groups in Carbohydrate Chemistry", J. CHEM. EDUC., vol. 74, no. 11, 1997, pages 1297
ROBERTSON: "Protecting Group Chemistry", 2000, OXFORD UNIVERSITY PRESS
SMITH ET AL.: "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2007, WILEY
STAHL ET AL.: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY
WANG ET AL., BIOCHEM. J., vol. 425, 2009, pages 71 - 83
WUTS ET AL.: "Protective Groups in Organic Synthesis", 2006, WILEY
YOU ET AL., CELL, vol. 117, 2004, pages 349 - 60
ZHU ET AL., CELL REPORTS, vol. 2, 2012, pages 807 - 816
ZUBER ET AL., NATURE, vol. 478, 2011, pages 524 - 528

Cited By (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9676750B2 (en) 2013-01-14 2017-06-13 Incyte Corporation Bicyclic aromatic carboxamide compounds useful as pim kinase inhibitors
US9550765B2 (en) 2013-01-15 2017-01-24 Incyte Holdings Corporation Thiazolecarboxamides and pyridinecarboxamide compounds useful as Pim kinase inhibitors
US10517858B2 (en) 2013-01-15 2019-12-31 Incyte Holdings Corporation Thiazolecarboxamides and pyridinecarboxamide compounds useful as PIM kinase inhibitors
US9849120B2 (en) 2013-01-15 2017-12-26 Incyte Holdings Corporation Thiazolecarboxamides and pyridinecarboxamide compounds useful as Pim kinase inhibitors
US10265307B2 (en) 2013-01-15 2019-04-23 Incyte Corporation Thiazolecarboxamides and pyridinecarboxamide compounds useful as Pim kinase inhibitors
US10828290B2 (en) 2013-01-15 2020-11-10 Incyte Corporation Thiazolecarboxamides and pyridinecarboxamide compounds useful as pim kinase inhibitors
US11229631B2 (en) 2013-01-15 2022-01-25 Incyte Corporation Thiazolecarboxamides and pyridinecarboxamide compounds useful as Pim kinase inhibitors
US10464947B2 (en) 2013-03-15 2019-11-05 Incyte Holdings Corporation Tricyclic heterocycles as BET protein inhibitors
US10919912B2 (en) 2013-03-15 2021-02-16 Incyte Holdings Corporation Tricyclic heterocycles as BET protein inhibitors
US9938294B2 (en) 2013-03-15 2018-04-10 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US11498926B2 (en) 2013-03-15 2022-11-15 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US9624241B2 (en) 2013-03-15 2017-04-18 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US9290514B2 (en) 2013-07-08 2016-03-22 Incyte Holdings Corporation Tricyclic heterocycles as BET protein inhibitors
US9533997B2 (en) 2013-07-08 2017-01-03 Incyte Holdings Corporation Tricyclic heterocycles as BET protein inhibitors
US9850257B2 (en) 2013-07-08 2017-12-26 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US10000507B2 (en) 2013-08-23 2018-06-19 Incyte Corporation Furo- and thieno-pyridine carboxamide compounds useful as pim kinase inhibitors
US9737516B2 (en) 2013-11-26 2017-08-22 Incyte Corporation Bicyclic heterocycles as bet protein inhibitors
US9918990B2 (en) 2013-11-26 2018-03-20 Incyte Corporation Substituted pyrrolo[2,3-c]pyridines and pyrazolo[3,4-c]pyridines as BET protein inhibitors
US9399640B2 (en) 2013-11-26 2016-07-26 Incyte Corporation Substituted pyrrolo[2,3-c]pyridines and pyrazolo[3,4-c]pyridines as BET protein inhibitors
US9315501B2 (en) 2013-11-26 2016-04-19 Incyte Corporation Bicyclic heterocycles as BET protein inhibitors
US10442803B2 (en) 2013-12-19 2019-10-15 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
US9777003B2 (en) 2013-12-19 2017-10-03 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
US11091484B2 (en) 2013-12-19 2021-08-17 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US9309246B2 (en) 2013-12-19 2016-04-12 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US9957268B2 (en) 2014-04-23 2018-05-01 Incyte Corporation 1H-pyrrolo[2,3,c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US10781209B2 (en) 2014-04-23 2020-09-22 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US11059821B2 (en) 2014-04-23 2021-07-13 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US10472358B2 (en) 2014-04-23 2019-11-12 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US11702416B2 (en) 2014-04-23 2023-07-18 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US9540368B2 (en) 2014-04-23 2017-01-10 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US9822124B2 (en) 2014-07-14 2017-11-21 Incyte Corporation Bicyclic heteroaromatic carboxamide compounds useful as Pim kinase inhibitors
US9890162B2 (en) 2014-07-14 2018-02-13 Incyte Corporation Bicyclic aromatic carboxamide compounds useful as pim kinase inhibitors
US10227359B2 (en) 2014-09-15 2019-03-12 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
US9527864B2 (en) 2014-09-15 2016-12-27 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US10618910B2 (en) 2014-09-15 2020-04-14 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US9834565B2 (en) 2014-09-15 2017-12-05 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
WO2016044130A1 (en) * 2014-09-15 2016-03-24 Incyte Corporation Tricyclic heterocycles for use as bet protein inhibitors
WO2016061144A1 (en) 2014-10-14 2016-04-21 The Regents Of The University Of California Use of cdk9 and brd4 inhibitors to inhibit inflammation
CN105985282B (en) * 2015-01-28 2020-12-08 中国科学院广州生物医药与健康研究院 2-oxo-1, 2-dihydrobenzo [ cd ] indole compound and application thereof
CN105985282A (en) * 2015-01-28 2016-10-05 中国科学院广州生物医药与健康研究院 2-oxo-1,2-dihydrobenzo[cd]indole compound and application thereof
WO2016146755A1 (en) 2015-03-19 2016-09-22 Glaxosmithkline Intellectual Property Development Limited Covalent conjugates of bet inhibitors and alpha amino acid esters
US9540347B2 (en) 2015-05-29 2017-01-10 Incyte Corporation Pyridineamine compounds useful as Pim kinase inhibitors
US9802918B2 (en) 2015-05-29 2017-10-31 Incyte Corporation Pyridineamine compounds useful as Pim kinase inhibitors
CN108349996A (en) * 2015-09-08 2018-07-31 豪夫迈·罗氏有限公司 Tricyclic PI3K inhibitor compounds and its application method
US9862705B2 (en) 2015-09-09 2018-01-09 Incyte Corporation Salts of a pim kinase inhibitor
US10336728B2 (en) 2015-09-09 2019-07-02 Incyte Corporation Salts of a Pim kinase inhibitor
US11505540B2 (en) 2015-09-09 2022-11-22 Incyte Corporation Salts of a Pim kinase inhibitor
US11066387B2 (en) 2015-09-09 2021-07-20 Incyte Corporation Salts of a Pim kinase inhibitor
US11053215B2 (en) 2015-10-02 2021-07-06 Incyte Corporation Heterocyclic compounds useful as Pim kinase inhibitors
US9920032B2 (en) 2015-10-02 2018-03-20 Incyte Corporation Heterocyclic compounds useful as pim kinase inhibitors
US10450296B2 (en) 2015-10-02 2019-10-22 Incyte Corporation Heterocyclic compounds useful as Pim kinase inhibitors
US10329305B2 (en) 2015-10-29 2019-06-25 Incyte Corporation Amorphous solid form of a BET protein inhibitor
US20210079016A1 (en) * 2015-10-29 2021-03-18 Incyte Corporation Amorphous solid form of a bet protein inhibitor
US10858372B2 (en) 2015-10-29 2020-12-08 Incyte Corporation Amorphous solid form of a BET protein inhibitor
US11091480B2 (en) 2016-06-20 2021-08-17 Incyte Corporation Crystalline solid forms of a BET inhibitor
US11377446B2 (en) 2016-06-20 2022-07-05 Incyte Corporation Crystalline solid forms of a BET inhibitor
US10189832B2 (en) 2016-06-20 2019-01-29 Incyte Corporation Crystalline solid forms of a BET inhibitor
US10626114B2 (en) 2016-06-20 2020-04-21 Incyte Corporation Crystalline solid forms of a BET inhibitor
US11278541B2 (en) 2017-12-08 2022-03-22 Incyte Corporation Low dose combination therapy for treatment of myeloproliferative neoplasms
US10596161B2 (en) 2017-12-08 2020-03-24 Incyte Corporation Low dose combination therapy for treatment of myeloproliferative neoplasms
EP3873896A4 (en) * 2018-12-14 2022-08-31 Jiangsu Hengrui Medicine Co., Ltd. Tricyclic compounds as sting agonists, and preparation methods and medicinal uses thereof
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms

Also Published As

Publication number Publication date
EA201992712A2 (en) 2020-03-31
IL267609B (en) 2020-07-30
US20170210754A1 (en) 2017-07-27
US20180346481A1 (en) 2018-12-06
NZ712453A (en) 2020-06-26
CN105164131A (en) 2015-12-16
MX2015013149A (en) 2016-01-08
PH12019502318A1 (en) 2020-12-07
US20160046650A1 (en) 2016-02-18
IL241158A0 (en) 2015-11-30
CA2903881C (en) 2021-05-18
JP6529546B2 (en) 2019-06-12
US10919912B2 (en) 2021-02-16
ES2909778T3 (en) 2022-05-10
US20200131195A1 (en) 2020-04-30
UA119848C2 (en) 2019-08-27
SG10201707487VA (en) 2017-10-30
JP2018008958A (en) 2018-01-18
AR095326A1 (en) 2015-10-07
ES2755827T3 (en) 2020-04-23
CN105164131B (en) 2018-12-28
EP2970282A1 (en) 2016-01-20
ZA202001242B (en) 2021-08-25
KR102216288B1 (en) 2021-02-18
US10464947B2 (en) 2019-11-05
IL267609A (en) 2019-08-29
EP3581576A1 (en) 2019-12-18
EA035469B1 (en) 2020-06-22
US9938294B2 (en) 2018-04-10
CR20150513A (en) 2016-01-04
EP3581576B1 (en) 2022-01-26
EA201591785A1 (en) 2015-12-30
US9624241B2 (en) 2017-04-18
BR112015022942B1 (en) 2022-02-22
US11498926B2 (en) 2022-11-15
JP2016513716A (en) 2016-05-16
AU2014228175A1 (en) 2015-10-08
EA201992712A3 (en) 2020-05-31
PE20151990A1 (en) 2016-01-13
CA2903881A1 (en) 2014-09-18
CN109593096A (en) 2019-04-09
CN109593096B (en) 2022-01-14
TW201930303A (en) 2019-08-01
IL241158B (en) 2019-07-31
AU2014228175B2 (en) 2018-05-31
CL2015002734A1 (en) 2016-03-28
JP6712344B2 (en) 2020-06-17
JP6243003B2 (en) 2017-12-06
MX366703B (en) 2019-07-22
TW201512198A (en) 2015-04-01
JP2019142973A (en) 2019-08-29
SG11201506924YA (en) 2015-09-29
KR20150136497A (en) 2015-12-07
EA038494B1 (en) 2021-09-07
BR112015022942A2 (en) 2017-07-18
MX2019008521A (en) 2019-10-30
EP2970282B1 (en) 2019-08-21
ZA201507255B (en) 2023-03-29
US20140275030A1 (en) 2014-09-18
TWI719464B (en) 2021-02-21
KR20210021090A (en) 2021-02-24
US9227985B2 (en) 2016-01-05
US20210188872A1 (en) 2021-06-24
PH12015502157A1 (en) 2016-01-25
TWI667238B (en) 2019-08-01
KR102355670B1 (en) 2022-02-08
ECSP15043772A (en) 2017-08-31
HK1218650A1 (en) 2017-03-03

Similar Documents

Publication Publication Date Title
US11498926B2 (en) Tricyclic heterocycles as BET protein inhibitors
EP3134403B1 (en) 1h-pyrrolo[2,3-c]pyridin-7(6h)-ones and pyrazolo[3,4-c]pyridin-7(6h)-ones as inhibitors of bet proteins
EP3019502B1 (en) Tricyclic heterocycles as bet protein inhibitors
WO2015081246A1 (en) Bicyclic heterocycles as bet protein inhibitors

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201480025137.0

Country of ref document: CN

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

Ref document number: 14721642

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2903881

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 241158

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2016502650

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 002021-2015

Country of ref document: PE

Ref document number: 12015502157

Country of ref document: PH

Ref document number: MX/A/2015/013149

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 15227987

Country of ref document: CO

Ref document number: 2014721642

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: CR2015-000513

Country of ref document: CR

ENP Entry into the national phase

Ref document number: 2014228175

Country of ref document: AU

Date of ref document: 20140314

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 201591785

Country of ref document: EA

ENP Entry into the national phase

Ref document number: 20157029800

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: A201510087

Country of ref document: UA

Ref document number: IDP00201506648

Country of ref document: ID

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112015022942

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112015022942

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20150912