WO2023159155A1 - Inhibiteurs de phosphoinositide 3-kinase (pi3k) et leurs utilisations - Google Patents

Inhibiteurs de phosphoinositide 3-kinase (pi3k) et leurs utilisations Download PDF

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WO2023159155A1
WO2023159155A1 PCT/US2023/062781 US2023062781W WO2023159155A1 WO 2023159155 A1 WO2023159155 A1 WO 2023159155A1 US 2023062781 W US2023062781 W US 2023062781W WO 2023159155 A1 WO2023159155 A1 WO 2023159155A1
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alkyl
phenyl
cyano
heterocyclyl
heteroaryl
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Victor J. Cee
Andrew S. Tasker
Mary Walton
Tom Nguyen
Miles Douglas KUBOTA
Peter BUCHOWIECKI
Dora TOLEDO WARSHAVIAK
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Pivalent Therapeutics, Inc.
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds and compositions capable of acting as inhibitors of phosphoinositide 3-kinase (PI3K). More specifically, invention relates to compounds and compositions capable of acting as inhibitors of PI3K mutants, such as H1047R. The compounds and compositions may be used in the treatment of cancer.
  • PI3K phosphoinositide 3-kinase
  • the present disclosure is directed to allosteric inhibitors of phosphoinositide 3-kinase (PI3K) useful in the treatment of diseases or disorders associated with PI3K modulation.
  • the disclosure is directed toward compounds and compositions which inhibit PI3K, methods of treating a disease or disorder associated with PI3K (e.g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer), and methods of using PI3K inhibitors in combination with one or more additional disorder or cancer therapy.
  • a disease or disorder associated with PI3K e.g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS)
  • breast cancer e.g.,
  • the activity of cells can be regulated by external signals that stimulate or inhibit intracellular events.
  • the process by which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response is referred to as signal transduction.
  • cascades of signal transduction events have been elucidated and found to play a central role in a variety of biological responses. Defects in various components of signal transduction pathways have been found to account for a vast number of diseases, including numerous forms of cancer, inflammatory disorders, metabolic disorders, vascular and neuronal diseases (Gaestel et al. Current Medicinal Chemistry (2007) 14:2214-2234).
  • PI3Ks are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3’-OH group on phosphatidylinositols or phosphoinositides.
  • the PI3K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation (Katso et al., 2001).
  • the class I PI3Ks (p110 ⁇ , p110 ⁇ , p110 ⁇ , and p110 ⁇ ) are typically activated by tyrosine kinases or G-protein coupled receptors to generate PIP3, which engages downstream effectors such as those in the pathways of Akt/PDKl, mTOR, the Tec family kinases, and the Rho family GTPases.
  • the class II and III PI3-Ks play a key role in intracellular trafficking through the synthesis of PI(3)P and PI(3,4)P 2.
  • the PI3K isoforms have been implicated, for example, in a variety of human cancers and disorders.
  • Mutations in the gene coding for PI3K isoforms or mutations which lead to upregulation of a PI3K isoform are believed to occur in many human cancers. Mutations in the gene coding for a PI3K isoform are point mutations clustered within several hotspots in helical and kinase domains. [007] Currently PI3K ⁇ inhibitors are nearly equipotent to wild-type and mutant PI3K ⁇ . Mutant selective inhibitors have been elusive due to the PI3K ⁇ mutations’ location far from the active site. As such, inhibitors which target a second, peripheral binding pocket near a known mutation (e.g., H1047R) may provide a route to selective PI3K ⁇ inhibition.
  • a known mutation e.g., H1047R
  • One embodiment relates to compounds of Formula 1A, 1B, 1C or 1D, or a pharmaceutically acceptable salt thereof: wherein: X 1 , X 2 , and X 3 is each independently -CR 5 - or -N-; X 5 is a carbon atom when a double bond is attached or is -CR 5 - or -N- when a single bond is attached; R is oxo or -OR x ; R x is H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; or R together with R 2 and the carbon and nitrogen to which they are attached forms a 5-6 membered heteroaryl ring; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C
  • One embodiment relates to compounds of Formula 1A, 1B or 1C, or a pharmaceutically acceptable salt thereof: wherein: X 1 , X 2 and X 3 is each independently -CR 5 - or -N-; R is oxo or -OR x ; R x is H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; or R together with R 2 and the carbon and nitrogen to which they are attached forms a 5-membered heteroaryl ring; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, -OR 1a , - SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a ,
  • R 4 is -COOH.
  • R 6 is independently selected from H, oxo, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -N(R 7 ) 2 , -(CH 2 ) n -C(O)R 7 , -(CH 2 ) n -C (O)N(R 7 ) 2 , -(CH 2 ) n -SO 2 R 7 , C 3 - C 10 cycloalkyl, 5-10 membered heterocyclyl, -(CH 2 ) n -aryl, or 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally
  • R 6 is independently selected from oxo, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -N(R 7 ) 2 , -(CH 2 ) n -C(O)R 7 , -(CH 2 ) n -C (O)N(R 7 ) 2 , -(CH 2 ) n -SO 2 R 7 , C 3 - C 10 cycloalkyl, 5-10 membered heterocyclyl, -(CH 2 ) n -aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted
  • R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, hydroxymethyl, methoxymethyl, methylamino, dimethylamino, methylaminomethyl, dimethylaminomethyl, methylaminocarbonyl, aminocarbonyl, methylsulfonyl, methoxy and cyclopropyl, and p is 1.
  • R 6 is selected from fluoro, chloro, cyano, methyl, trifluoromethyl, hydroxymethyl, methoxymethyl, methylamino, dimethylamino, methylaminomethyl, dimethylaminomethyl, methylaminocarbonyl, aminocarbonyl, methylsulfonyl, and cyclopropyl; and p is 1.
  • each R 2 , R 3 and R 5 is independently selected from H, halo, cyano, C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -C(O)R 7 , phenyl- C 1 -C 6 alkyl, 5-6 membered heteroaryl-C 1 -C 6 alkyl, 5-6 membered heterocyclyl- C 1 -C 6 alkyl, C 5 -C 6 cycloalkyl- C 1 -C 6 alkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, C 5 -C 6 cycloalkyl, C 5 -C 6 cycl
  • R 2 is selected from H, cyano, fluoro, chloro, C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -C(O)R 7 , C 3 -C 10 cycloalkyl, phenyl and 5-6 membered heteroaryl; R 7 is selected from methyl, ethyl, cyclohexyl, and phenyl; and n is 0 or 1.
  • R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy, benzyl, phenyl, and cyclopropyl.
  • R 2 is H, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, benzyl, phenyl, or cyclopropyl.
  • R 3 is H, cyano, fluoro, chloro, C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -C(O)R 7 , C 3 -C 6 cycloalkyl, phenyl and 5-6 membered heteroaryl; R 7 is selected from methyl, ethyl, cyclohexyl, and phenyl; and n is 0 or 1.
  • R 3 is selected from H, fluoro, chloro, cyano, methylsulfonyl, hydroxymethyl, methoxy, methyl, trifluoromethyl and cyclopropyl. [024] In one embodiment, R 3 is H, fluoro, chloro, methyl or trifluoromethyl. [025] In one embodiment, R 5 is H, cyano, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl.
  • R 5 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methoxy and cyclopropyl. [027] In one embodiment, R 5 is H, fluoro, chloro, methyl or trifluoromethyl. [028] In one embodiment, R 5 is H. [029] In one embodiment, R together with R 2 and the carbon and nitrogen to which they are attached forms a triazolyl ring. [030] In one embodiment, R is oxo. [031] In one embodiment, R is selected from hydroxy, methoxy, ethoxy, -OCH 2 CF 3 , OCH 2 CF 2 H, OCH 2 CFH 2 and OCF 3 .
  • R 1 is selected from 5-10 membered nitrogen containing heteroaryl, 4-10 membered nitrogen containing heterocyclyl, 4-10 membered oxygen containing heterocyclyl, 6-10 membered aryl, C 4 -C 6 cycloalkenyl and C 3 -C 6 cycloalkyl; wherein the nitrogen containing heteroaryl, nitrogen containing heterocyclyl, aryl, cycloalkenyl or cycloalkyl is substituted with 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, hydroxy, phenyl, aralkyl, C 3-6 -cycloalkyl and C 1 -C 3 hydroxyalkyl.
  • R 1 is selected from 5-10 membered nitrogen containing heteroaryl, 5-10 membered nitrogen containing heterocyclyl, 6-10 membered aryl, C 4 -C 6 cycloalkenyl and C 3 -C 6 cycloalkyl; wherein the nitrogen containing heteroaryl, nitrogen containing heterocyclyl, aryl, cycloalkenyl or cycloalkyl is substituted with 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 - C 4 alkoxy, hydroxy, phenyl, aralkyl, C 3 - 6 -cycloalkyl and C 1 -C 3 hydroxyalkyl.
  • R 1 is selected from 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2- tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1- imidazolinyl, 1-imidazolidinyl, 2-tetrahydronaphthyridinyl, 2-isoindolinyl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, and 1-azeti
  • R 1 is selected from 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2- tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1- imidazolinyl, 1-imidazolidinyl, and 1-azetidinyl; wherein R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, benzyl, phenyl, and cyclopropyl.
  • R 1 is selected from pyridyl, pyrimidinyl, pyrazolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, quinolinyl, 2-isoindolyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, phenyl and naphthyl, cyclohexenyl, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring has one, two or three substituents independently selected from halo, cyano, C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, hydroxy, phenyl, aralkyl, C 3-6 -cycloalkyl and hydroxy-C 1 -C 3 alkyl
  • R 1 is selected from pyridyl, pyrimidinyl, pyrazolyl, thienyl, oxazolyl, imidazolyl, quinolinyl, phenyl and naphthyl, cyclohexenyl and cyclohexyl; wherein the ring has one, two or three substituents independently selected from halo, cyano, C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 - C 4 alkoxy, hydroxy, phenyl, aralkyl, C 3 - 6 -cycloalkyl and hydroxy-C 1 -C 3 alkyl.
  • R 1 is selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , - NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , -NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, and pyridylmethyl; each R 1a is independently selected from C 1 -C 4
  • R 1 is selected from C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, and C 1 -C 3 haloalkyl.
  • R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl.
  • R 7 is selected from methyl, ethyl and phenyl.
  • L is -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-; wherein each alkylene group is substituted with 0-4 substituents independently selected from halo, cyano and C 1 -C 2 alkoxy.
  • L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or -NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy.
  • L is C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl or 5-6 membered heterocyclyl.
  • A is a ring selected from 5-6 membered heterocyclyl and C 3 -C 6 cycloalkyl.
  • A is 5-10 membered heteroaryl or phenyl.
  • A is selected from phenyl, pyridyl, benzimidazolyl, benzothienyl, pyrazinyl and pyrimidinyl.
  • A is selected from phenyl, pyridyl, benzothienyl, pyrazinyl and pyrimidinyl. [049] In one embodiment, A is selected from phenyl, 3-pyridyl and 2-pyridyl. [050] In one embodiment, X 1 and X 2 are each -CR 5 - and X 3 is N. [051] In one embodiment, X 1 and X 2 are each -N- and X 3 is N. [052] In one embodiment, X 1 is -CR 5 - , X 2 is -N- and X 3 is N.
  • X 1 is -N-
  • X 2 is -CR 5 - and X 3 is N.
  • X 1 and X 2 are each -CR 5 - and X 3 is -CR 5 - .
  • X 1 and X 2 are each -N- and X 3 is -CR 5 -.
  • X 1 is -CR 5 -
  • X 2 is -N- and X 3 is -CR 5 -.
  • X 1 is -N-
  • X 2 is -CR 5 - and X 3 is -CR 5 -.
  • R is oxo; wherein: R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1
  • R is oxo or methoxy;
  • R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2- hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl- 2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl,
  • R is oxo or methoxy
  • R 1 is selected from methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1- pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein
  • R 4 is -COOH.
  • R is oxo
  • A is benzotriazolyl and R 4 is H.
  • R is oxo wherein: R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a ,
  • R is -OR x ;
  • R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ;
  • R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , - SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , - S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1
  • R is oxo or methoxy;
  • R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2- hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl- 2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl,
  • R 4 is -COOH.
  • R is oxo wherein: R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(
  • R is -OR x ;
  • R x is selected from H, methyl, ethyl, CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ;
  • R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , - S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b ,
  • R is oxo or methoxy;
  • R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2- hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl- 2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl,
  • R is oxo or methoxy
  • R 1 is selected from methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1- pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein
  • R is -OR x ;
  • R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ;
  • R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2
  • R is -OR x ;
  • R x is selected from H, methyl, ethyl, CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ;
  • R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , - S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b ,
  • R is oxo or methoxy;
  • R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2- hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl- 2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl,
  • R is oxo or methoxy; methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2- pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein the ring substituent
  • One aspect of the invention relates to compounds having a structure of Formula 6a, 6b or 6c, or a pharmaceutically acceptable salt thereof: wherein: X 1 , X 2 , X 3 and X 4 is each independently -CR 5 - or -N-; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b , -NR 1a C(O)NR 1
  • One aspect of the invention relates to compounds having a structure of Formula 6a or 6b, or a pharmaceutically acceptable salt thereof: wherein: X 1 , X 2 , X 3 and X 4 is each independently -CR 5 - or -N-; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , - S(O) 2 NR 1b R 1b , NR 1a S(O) 2
  • R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1- dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1- piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, be
  • R 1 is selected from methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2- pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein the ring substituent in R 1 is substituted
  • R 4 is -COOH.
  • One aspect of the invention relates to compounds having a structure of Formula 7, or a pharmaceutically acceptable salt thereof: wherein: X 1 and X 2 is each independently -CR 5 - or -N-; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R
  • X 1 and X 2 is each independently -CR 5 - or -N-;
  • R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , - S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R
  • R is oxo or methoxy;
  • R 1 is selected methyl, ethyl, isopropyl, 1,1-dimethyl-2- hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl- 2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, in
  • R 1 is selected from methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2- pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein the ring substituent in R 1 is
  • R 4 is -COOH.
  • R is oxo; wherein: R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)
  • R is -OR x ;
  • R x is selected from H, methyl, ethyl, CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3;
  • R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , - SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1a R 1a , -NR 1a C(O)NR 1a R 1a , - S(O) 2 NR 1a R 1a , NR 1a S(O) 2 NR 1a R 1a ,
  • R is oxo or methoxy;
  • R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2- hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl- 2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl,
  • R is oxo or methoxy
  • R 1 is selected from methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1- pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein
  • R 4 is carboxy.
  • R is oxo or -OR x ;
  • R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ;
  • R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R
  • R is oxo or -OR x ;
  • R x is selected from H, methylr ethyl, CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3;
  • R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , --C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , - S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1
  • R is oxo or methoxy;
  • R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2- hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl- 2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl,
  • R is oxo or methoxy
  • R 1 is selected from methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1- pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein
  • R 4 is carboxy.
  • One aspect of the invention relates to compounds of Formula 10a, 10b, and 10c, or a pharmaceutically acceptable salt thereof: wherein: X 1 , X 2 , X 3 , and X 6 is each independently -CR 5 - or -N-; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b
  • R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1- dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1- piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, be
  • R 4 is -COOH.
  • R 4 -A- is selected from wherein R 6 is selected from halo, C 1 -C 3 alkyl, C 1 - C 3 haloalkyl, C 1 -C 3 alkoxy, and C 3 -C 5 cycloalkyl; wherein R 6 is a substituent on either or both rings; and p is 0, 1, or 2.
  • R 4 -A- is ; wherein 6 R is fluoro, chloro, bromo or trifluoromethyl; and p is 0 or 1.
  • R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1- dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, and dimethylaminocarbonyl.
  • A is selected from phenyl, benzothienyl, pyrazinyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl.
  • L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , wherein the ethylenyl, or -NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy.
  • the compound is selected from 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydrothieno[3,2-d]pyrimidin-7-yl)ethyl)amino)benzoic acid ; 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid ; 2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-8- yl)ethyl)amino)benzoic acid ; 6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydrothieno[3,2-d
  • the present disclosure generally relates to methods for treating cancer. These methods comprise administering to a subject in need thereof, a therapeutically effective amount of a PI3K inhibitor (e.g., PI3K ⁇ inhibitor or PI3K ⁇ H1047R mutant inhibitor).
  • a PI3K inhibitor e.g., PI3K ⁇ inhibitor or PI3K ⁇ H1047R mutant inhibitor
  • the PI3K inhibitor is a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in the Schemes).
  • a pharmaceutical composition comprising a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in the Examples).
  • the present disclosure provides a method of modulating PI3K (e.g., PI3K ⁇ ) activity (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof.
  • PI3K ⁇ sequence correlates with NCBI Reference Sequence: NP 006209.2.
  • the PI3K ⁇ sequence correlates with NCBI Reference Sequence: NP_006210.1.
  • an amino acid sequence encoding PI3K ⁇ comprises or consists of an amino acid sequence: [0115] In some aspects, an amino acid sequence encoding PI3K ⁇ with a H1047R mutation comprises or consists of an amino acid sequence: [0116] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof, for use in modulating PI3K ⁇ ) activity (e.g., in vitro or in vivo).
  • the present disclosure provides a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof, for use in greater inhibition for mutant PI3K ⁇ over wild-type PI3K ⁇ .
  • the present disclosure provides a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of Formulas 1-10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating P13K (e.g., PI3K ⁇ ) activity (e.g., in vitro or in vivo).
  • P13K e.g., PI3K ⁇
  • the present disclosure provides use of a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.
  • the present disclosure provides a method of preparing a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof. [0124] In another aspect, the present disclosure provides a method of preparing a compound of any one of Formulas 1-10, comprising one or more steps described herein.
  • PI3Ks phosphoinositide 3 -kinases
  • alpha (a) isoform of PI3K has been implicated, for example, in a variety of human cancers.
  • Angiogenesis has been shown to selectively require the ⁇ isoform of PI3K in the control of endothelial cell migration. (Graupera et al, Nature 2008; 453; 662-6).
  • Mutations in the gene coding for PI3K ⁇ or mutations which lead to upregulation of PI3K ⁇ are believed to occur in many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers.
  • Mutations in the gene coding for PI3K ⁇ are point mutations clustered within several hotspots in helical and kinase domains, such as E542K, E545K, N345K, H1047L and H1047R. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Because of the high rate of PI3K ⁇ mutations, targeting of this pathway may provide valuable therapeutic opportunities.
  • PI3K ⁇ While other PI3K isoforms such as PI3K ⁇ or PI3K ⁇ are expressed primarily in hematopoietic cells, PI3K ⁇ , along with PI3K ⁇ , is expressed constitutively. Due to the central role of PI3K ⁇ in regulating organismal glucose homeostasis, PI3K inhibition in patients often gives rise to hyperglycemia and/or hyperinsulinemia (Busaidy NL, et al., Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt- mTOR pathway. J Clin Oncol 2012;30:2919-28).
  • the present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder in which PI3K plays a role by administering to a patient in need thereof a therapeutically effective amount of a PI3K inhibitor.
  • the methods of the present disclosure can be used in the treatment of a variety of PI3K- dependent diseases and disorders.
  • the disease of disorder is a cancer (e.g., breast cancer, brain cancers, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, and head and neck cancer).
  • the disease or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous-cell cancer, cervical squamous- cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small-cell lung cancer, esophagogastric cancer, nerve-sheath tumor, head and neck squamous-cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft-tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorec
  • the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary, cardiac (heart) tumors, atypical teratoid/rhabdoid tumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, mycosis fungoides, Sezary syndrome,
  • ALL acute lymphoblastic
  • the cancer is endometrial cancer, breast cancer, esophageal squamous-cell cancer, cervical squamous-cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, nerve- sheath tumor, head and neck squamous-cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft- tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear-cell carcinoma, renal clear-cell carcinoma, germ-cell carcinoma, thymic tumor
  • the cancer is a breast cancer, a prostate cancer, or a brain cancer.
  • the cancer is a breast cancer.
  • the cancer is a prostate cancer.
  • the cancer is a brain cancer.
  • the breast cancer is metastatic breast cancer.
  • the breast cancer is ductal carcinoma in situ (DCIS).
  • the breast cancer is invasive ductal carcinoma.
  • the breast cancer is triple negative breast cancer.
  • the breast cancer is medullary carcinoma.
  • the breast cancer is tubular carcinoma.
  • the breast cancer is mucinous carcinoma.
  • the breast cancer is Paget disease of the breast or nipple. In some embodiments, the breast cancer is inflammatory breast cancer (IBC).
  • IBC inflammatory breast cancer
  • the prostate cancer is an adenocarcinoma. In some embodiments, the prostate cancer is a small cell carcinoma. In some embodiments, the prostate cancer is a neuroendocrine tumor. In some embodiments, the prostate cancer is a transitional cell carcinoma. In some embodiments, the prostate cancer is a sarcoma.
  • the brain cancer is an acoustic neuroma. In some embodiments, the brain cancer is an astrocytoma. In some embodiments, the brain cancer is a brain metastasis.
  • the brain cancer is choroid plexus carcinoma. In some embodiments, the brain cancer is craniopharyngioma. In some embodiments, the brain cancer is an embryonal tumor. In some embodiments, the brain cancer is an ependymoma. In some embodiments, the brain cancer is a glioblastoma. In some embodiments, the brain cancer is a glioma. In some embodiments, the brain cancer is a medulloblastoma. In some embodiments, the brain cancer is a meningioma. In some embodiments, the brain cancer is an oligodendroglioma. In some embodiments, the brain cancer is a pediatric brain tumor.
  • the brain cancer is a pineoblastoma. In some embodiments, the brain cancer is a pituitary tumor.
  • the disease or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome (congenial lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.
  • CLOVES syndrome congenial lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome
  • PROS PIK3CA-related overgrowth syndrome
  • the diseases or disorder associated with PI3K is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome).
  • CLOVES syndrome congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome.
  • the disease or disorder associated with PI3K is PIK3CA-related overgrowth syndrome (PROS).
  • the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.
  • the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.
  • the disease or disorder associated with PI3K is leukemia, lymphoma, or sarcoma.
  • the cancer is endometrial cancer, head and neck cancer, or a sarcoma.
  • the cancer is endometrial cancer. In some embodiments the cancer is head and neck cancer. In some embodiments, the cancer is a sarcoma.
  • the sarcoma is soft tissue sarcoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, hemangioendothelioma, angiosarcoma, fibrosarcoma, myofibrosarcoma, chordoma, adamantinoma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, or malignant solitary fibrous tumor.
  • the sarcoma is soft tissue sarcoma.
  • the soft tissue sarcoma is liposarcoma, atypical lipomatous tumor, dermatofibrosarcoma protuberans, malignant solitary fibrous tumor, inflammatory myofibroblastic tumor, low-grade myofibroblastic sarcoma, fibrosarcoma, myxofibrosarcoma, low-grade fibromyxoid sarcoma, giant cell tumor of soft tissues, leiomyosarcoma, malignant glomus tumor, rhabdomyosarcoma, hemangioendothelioma, angiosarcoma of soft tissue, extraskeletal osteosarcoma, gastrointestinal stromal tumor, malignant gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath tumor, malignant Triton tumor, malignant granular cell tumor, malignant ossifying fibromyxoid tumor, stromal sarcoma, myoepithelial carcinoma, malignant phosphaturic mesenchy
  • the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating or preventing a breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating or preventing a prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating or preventing a brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in modulating PI3K (e.g., PI3K ⁇ ) activity (e.g., in vitro or in vivo).
  • PI3K e.g., PI3K ⁇
  • the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.
  • the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating or preventing a cancer in a subject in need thereof.
  • the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating a cancer in a subject in need thereof.
  • the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating or preventing a breast cancer in a subject in need thereof.
  • the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating a breast cancer in a subject in need thereof.
  • the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating or preventing a prostate cancer in a subject in need thereof.
  • the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating a prostate cancer in a subject in need thereof.
  • the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating or preventing a brain cancer in a subject in need thereof.
  • the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating a brain cancer in a subject in need thereof.
  • the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3K (e.g., PI3K ⁇ ) activity (e.g., in vitro or in vivo).
  • the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein. [0169] In some aspects, the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a cancer in a subject in need thereof. [0170] In some aspects, the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cancer in a subject in need thereof.
  • the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a breast cancer in a subject in need thereof.
  • the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a breast cancer in a subject in need thereof.
  • the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a prostate cancer in a subject in need thereof.
  • the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a prostate cancer in a subject in need thereof.
  • the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a brain cancer in a subject in need thereof.
  • the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a brain cancer in a subject in need thereof.
  • the present disclosure provides compounds that function as modulators of PI3K activity.
  • the present disclosure therefore provides a method of modulating PI3K activity in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.
  • PI3K modulation is inhibition of PI3K.
  • the PI3K inhibitor is a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof.
  • the PI3K inhibitor is a PI3K ⁇ inhibitor.
  • the PI3K inhibitor is a PI3K ⁇ H1047R mutant inhibitor.
  • the PI3K inhibitor is ⁇ ⁇ ⁇ non-selective. In some embodiments, the PI3K inhibitor is alpha selective. In some embodiments, the PI3K inhibitor is beta selective. [0180] Effectiveness of compounds of the disclosure can be determined by industry-accepted assays/disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge. [0181] The present disclosure also provides a method of treating a disease or disorder in which PI3K activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.
  • the disclosure provides a method of modulating the activity of the PI3K ⁇ allosteric active site, wherein the modulation is induced through peripheral site targeting.
  • the peripheral site is targeted with an agent selected from a small molecule, a peptide, a peptidomimetic, a protein, a protein mimetic, a nucleic acid, an antibody, an antibody- drug conjugate, a nucleoprotein complex, an immunotherapy, or a combination thereof.
  • Routes of Administration [0183]
  • the compounds of Formulas 1-10 or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular,
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals, having the number of carbon atoms designated (i.e., C 1 -C 10 means one to ten carbons).
  • Alkyl is an uncyclized chain.
  • Preferred alkyl substituents are C 1 -C 6 alkyl.
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH 2 CH 2 CH 2 CH 2 -.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds referred to as “alkenyl” or “alkynyl” groups, respectively.
  • Preferred alkenyl substituents are C 2 -C 6 alkenyl and preferred alkynyl substituents are C 2 -C 6 alkynyl.
  • alkenyl or alkynyl groups include, but are not limited to, ethenyl, vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- propynyl, 3-propynyl, and 3-butynyl.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, S, B, As, or Si), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) e.g., O, N, P, S, B, As, or Si
  • Heteroalkyl is an uncyclized chain.
  • heteroalkyl also includes terms such as alkoxy, and alkylamino.
  • An “alkoxy” is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).
  • Preferred alkoxy substituents include C 1-4 alkoxy. Examples of alkoxy groups include, but are not limited to methoxy, ethoxy, and propoxy.
  • Preferred alkylamino substituents include mono substituted C 1-4 alkylamino and disubstituted alkylamino.
  • alkylamino groups include, but are not limited to methylamino, dimethylamino, and diethylamino.
  • Anther subgroup of heteroalkyl includes “alkoxyalkyl” where an alkyl group is substituted with an alkoxy group, as defined above.
  • Preferred alkoxyalkyl substituents include C 1-4 alkoxy- C 1-4 alkyl.
  • alkoxyalkyl groups include, but are not limited to methoxymethyl, ethoxymethyl, and methoxyethyl.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as , alkyl-NR'R'', alkyl-OR', alkyl-SR', and/or alkyl-SO 2 R'.
  • An “aralkyl” is an alkyl substituent substituted with an aryl moiety. Preferred aralkyl substituents include unsubstituted or substituted phenyl-C 1-4 alkyl. Examples of aralkyl groups include benzyl or phenethyl.
  • heteroarylalkyl alkyl groups substituted with heteroaryl, heterocyclyl and cycloalkyl moieties, respectively.
  • cycloalkyl by itself or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl”. Cycloalkyl are not fully aromatic rings. Preferred cycloalkyl substituents include C 3 -C 6 cycloalkyl.
  • a “cycloalkylene” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl.
  • a cycloalkyl group having 3 to 8 ring members may be referred to as a (C 3 - C 8 )cycloalkyl
  • a cycloalkyl group having 3 to 7 ring members may be referred to as a (C 3 -C 7 )cycloalkyl
  • a cycloalkyl group having 4 to 7 ring members may be referred to as a (C 4 -C 7 )cycloalkyl.
  • the cycloalkyl group can be a (C 3 -C 10 )cycloalkyl, a (C 3 -C 8 )cycloalkyl, a (C 3 -C 7 )cycloalkyl, a (C 3 -C 6 )cycloalkyl, or a (C 4 -C 7 )cycloalkyl group and these may be referred to as C 3 -C 10 cycloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkyl, C 3 - C 6 cycloalkyl, or C 4 -C 7 cycloalkyl groups.
  • cycloalkenyl by itself or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkenyl”. Cycloalkenyl are not fully aromatic rings. Preferred cycloalkenyl substituents include C 4 -C 6 cycloalkenyl.
  • a cycloalkenyl group having 4 to 8 ring members may be referred to as a (C 4 - C 8 )cycloalkenyl
  • a cycloalkenyl group having 3 to 7 ring members may be referred to as a (C 3 -C 7 )cycloalkenyl
  • a cycloalkenyl group having 4 to 6 ring members may be referred to as a (C 4 -C 6 )cycloalkenyl.
  • Heterocycloalkyl is also referred by the term heterocyclyl.
  • Preferred heterocyclyl substituents include C 3 -C 7 oxygen or nitrogen containing rings, or both nitrogen and oxygen atoms. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from heterocycloalkyl.
  • Heterocyclyl refers to a cyclic group that includes at least one saturated, partially unsaturated, but non- aromatic, cyclic ring. Heterocyclyl groups include at least one heteroatom as a ring member.
  • Typical heteroatoms include O, S, and N and are independently chosen.
  • Heterocyclyl groups include monocyclic ring systems and bicyclic ring systems.
  • Bicyclic heterocyclyl groups include at least one non-aromatic ring with at least one heteroatom ring member that may be fused to a cycloalkyl ring or may be fused to an aromatic ring where the aromatic ring may be carbocyclic or may include one or more heteroatoms.
  • the point of attachment of a bicyclic heterocyclyl group may be at the non-aromatic cyclic ring that includes at least one heteroatom or at another ring of the heterocyclyl group.
  • a heterocyclyl group derived by removal of a hydrogen atom from one of the 9-membered heterocyclic compounds shown below may be attached to the rest of the molecule at the 5- membered ring or at the 6-membered ring.
  • a heterocyclyl group includes 5 to 10 ring members of which 1, 2, 3 or 4 or 1, 2, or 3 are heteroatoms independently selected from O, S, or N.
  • a heterocyclyl group includes 3 to 7 ring members of which 1, 2, or 3 heteroatom are independently selected from O, S, or N.
  • a heterocyclyl group includes 3 or 4 ring members of which 1 is a heteroatom selected from O, S, or N. In other embodiments, a heterocyclyl group includes 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from O, S, or N.
  • Typical heterocyclyl groups include, but are not limited to, groups derived from epoxides, aziridine, azetidine, imidazolidine, morpholine, piperazine, piperidine, hexahydropyrimidine, 1,4,5,6-tetrahydropyrimidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, benzimidazolone, pyridinone, and the like.
  • Heterocyclyl groups may be fully saturated, but may also include one or more double bonds.
  • heterocyclyl groups include, but are not limited to, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 2,5-dihydro-1H-pyrolyl, 2,3-dihydro- 1H-pyrolyl, 1H-azirinyl, 1,2-dihydroazetenyl, and the like.
  • heterocyclyl also includes spiro rings and bridged rings.
  • halo or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • hydroido or “H” is a hydrogen radical.
  • haloalkyl is meant to include monohaloalkyl and polyhaloalkyl.
  • C 1 -C 3 - haloalkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3- bromopropyl, and the like.
  • acyl means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • heteroaryl refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Heteroaryl refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
  • Heteroaryl groups typically include 5- to 14-membered, but more typically include 5- to 10-membered aromatic, monocyclic, bicyclic, and tricyclic rings containing one or more, for example, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3, heteroatoms chosen from O, S, or N, with the remaining ring atoms being carbon.
  • monocyclic heteroaryl groups the single ring is aromatic and includes at least one heteroatom.
  • a monocyclic heteroaryl group may include 5 or 6 ring members and may include 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom where the heteroatom(s) are independently selected from O, S, or N.
  • both rings are aromatic.
  • bicyclic heteroaryl groups at least one of the rings must include a heteroatom, but it is not necessary that both rings include a heteroatom although it is permitted for them to do so.
  • heteroaryl includes a 5- to 7- membered heteroaromatic ring fused to a carbocyclic aromatic ring or fused to another heteroaromatic ring.
  • tricyclic aromatic rings all three of the rings are aromatic and at least one of the rings includes at least one heteroatom.
  • the point of attachment may be at the ring including at least one heteroatom or at a carbocyclic ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another.
  • the total number of S and O atoms in the heteroaryl group is not more than 2.
  • the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H- benzo[d][1,2,3]triazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazo
  • the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example, a 5 to 14 membered or 5 to 10 membered heteroaryl.
  • heteroaryl groups can be those derived from thiophene, pyrrole, benzothiophene, 2H-benzo[d][1,2,3]triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.
  • cyano refers to the radical -CN.
  • amino refers to the radical -NH 2 .
  • aminocarbonyl refers to the radical -CO-NH 2 . Aminocarbonyl radicals may be substituted with one or two alkyl groups to form “alkylaminocarbonyl” groups.
  • alkylcarbonyl refers to the radical alkyl-CO-.
  • hydroxyl and “hydroxy” refers to the radical -OH.
  • oxo means an oxygen that is double bonded to a carbon atom.
  • a “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and each substituted or unsubstituted heteroaryl is
  • each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group.
  • each substituted or unsubstituted alkyl may be a substituted or unsubstituted C 1 -C 20 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted or unsubstituted
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 20 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 8 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 8 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 7 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
  • the compound is a chemical species set forth in the Examples section, figures, or tables below.
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted cycloalkyl, substituted
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alky
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one substituent group wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one size-limited substituent group wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different.
  • each size-limited substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each lower substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each substituent group, size-limited substituent group, and/or lower substituent group is different.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention.
  • the compounds of the present invention do not include those that are known in art to be too unstable to synthesize and/or isolate.
  • the present invention is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • R Optically active
  • S S
  • D dibenzyl- and (L)-isomers
  • the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • the term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • stereoisomer or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound.
  • a stereomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound.
  • a stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.
  • a bond drawn with a wavy line indicates that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule.
  • this invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention.
  • isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium [D] or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this is selected from invention.
  • a or “an,” as used in herein means one or more.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C 1 -C 20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C 1 -C 20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • the present invention provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • Prodrugs of the compounds described herein may be converted in vivo after administration.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention.
  • compositions of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents,
  • Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture.
  • the term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme.
  • contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway.
  • the terms “disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein.
  • the disease may be a cancer.
  • cancer refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin’s lymphomas (e.g., Burkitt’s, Small Cell, and Large Cell lymphomas), Hodgkin’s lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma.
  • cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc. including solid and lymphoid cancers, kidney, breast, lung, bladder, colon,
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemia, carcinomas, and sarcomas.
  • leukemia refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow.
  • sarcoma generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
  • melanoma is taken to mean a tumor arising from the melanocytic system of the skin and other organs.
  • carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
  • carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma
  • treating refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
  • the term "treating” and conjugations thereof, may include prevention of an injury, pathology, condition, or disease.
  • treating is preventing. In embodiments, treating does not include preventing.
  • “Patient” or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human.
  • An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g.
  • an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.”
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist.
  • a “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). [0246] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays.
  • Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
  • therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
  • Dosages may be varied depending upon the requirements of the patient and the compound being employed.
  • the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
  • administering means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
  • Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) compatible with the preparation.
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • "Co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies.
  • the compounds of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • the preparations can also be combined, when desired, with other active substances (e.g.
  • compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • a “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA.
  • a cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring.
  • Control or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).
  • modulator refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule.
  • modulate is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.
  • signaling pathway refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propogated to other signaling pathway components.
  • extra-cellular components e.g. proteins, nucleic acids, small molecules, ions, lipids
  • Chlorination such as with POCl 3 , yields the 4- chloro bicyclic dihydro-pyrimidines. Conversion of the chloro derivatives to the hydrazines and the resulting cyclization yields the bromo tricyclic compounds.
  • Preparation of the desired compounds of Formula 6 where L is alkyl involves conversion of the bromo compounds to the corresponding ketones/aldehydes, alcohols, alkyl halides.
  • SCHEME II [0260]
  • the 1,3,5-triazanaphthalen-4-ones of the invention can be synthesized according to Scheme II from corresponding amino pyridyl carboxylic acids. The aryl acids are converted to amides, such as by coupling substituted amines and HATU.
  • 5,7- Dichloro 1-thia-4,6-diazaindenes are oxidized, such as with NaOH in THF, to yield the 5-chloro-1-thia-4,6- diazainden-7-ones.
  • the 5-chloro-1-thia-4,6-diazainden-7-ones are converted to the R 2 substituted compounds, such as with treatment with sodium hydride and the iodo reagents. Bromination of the R 2 substituted compounds, such as with NBS, yields the corresponding 3-bromo-5-chloro-1-thia-4,6-diazainden-7-ones.
  • the 3- bromo-5-chloro-1-thia-4,6-diazainden-7-ones are converted to the disubstituted compounds (where R 1 is an amine or nitrogen-containing heterocyclyl or heteroaryl ring), such as by coupling with substituted amines and base.
  • R 1 is an amine or nitrogen-containing heterocyclyl or heteroaryl ring
  • Alkylation of the bromo compounds, such as with Pd(OAc) 2 and butyl vinyl ether yields the 3-ketones.
  • Reduction of the ketone such as with NaBH 4 , yields the alcohols.
  • Preparation of the desired compounds of Formula 7 involves treatment with PBr 3 or MsCl, coupling with the 2-aminobenzoic ester, and deprotection/hydrolysis.
  • 1,4a-diaza-4-naphthalenones of the invention can be synthesized according to Scheme VI from corresponding 8-methylketones in Scheme V.
  • Treatment of the of the ketone with tertbutyl-sulfinylamine yields the protected amino alkyl compounds.
  • Deprotection and coupling with the 3-fluoro-pyridyl ester, and ester hydrolysis yields the desired compounds.
  • the 3-amino-4-carboxylic acids can be treated with methylamine to form the corresponding amide.
  • Cyclization with CDI or triphosgene then chlorination with POCl 3 yields the 2-chloro-1,3,7- triazanapthalen-4-ones intermediates.
  • SCHEME VIII [0266] Methods of preparing 1,4a-diaza-4-naphthalenone intermediates (where R 2 and R 3 are methyl), can be synthesized according to Scheme VIII from corresponding 2,4,6-trichlorphenol. Treatment of the phenols with the diacid provides the diester. Treatment of a 2-aminopyridine with the diester yields the 2-hydroxy-11,4a- diaza-4-naphthalenone intermediates.
  • Removal of the sulfinamide group such as with treatment with acid, more particularly 1M HCl, provides the primary amines, which can be coupled with substituted rings A, such as fluoropyridines, to provide the compounds 11 (where R 1 is H).
  • substituted rings A such as fluoropyridines
  • Providing 4-oxo-3,4- dihydroquinazolines (where R 1 is not H) is accomplished by Pd/Cu arylation, such as by treatment of the compounds 11 with Pd(OAc) 2 , CuI, 4,4'-dimethoxy-2,2'-bipyridine, and LiOtBu-.
  • SCHEME XIV [ 0272] Methods of preparing 4-oxo-3,4-dihydroquinazolines (where R 4 are amides), can be synthesized according to Scheme XIV from corresponding acids. The acids can be converted to the amides by standard amidation chemistry, such as coupling with primary amines with HATU.
  • SCHEME XV [0273] Methods of preparing BOC-protected 4-oxo-3,4-dihydroquinazolines (where R 1 is substituted aryl or heteraryl substituentsamides), can be synthesized according to Scheme XV from corresponding halo substituted compounds 11 using Suzuki coupling chemistry.
  • halo substituted compounds 11 made by methods similar to that described previously, can be converted to the substituted ring compounds by standard Suzuki coupling chemistry, such as coupling with Pd(dppf)Cl 2 and K 2 CO 3 . Conversion to the free acid can be achieved such as by treatment with TFA.
  • SCHEME XVI [0274] Methods of preparing 4-oxo-3,4-dihydroquinazoline acids, can be synthesized according to Scheme XVI from corresponding esters using ether cleavage chemistry. The esters, made by methods similar to that described previously, can be converted to the acids with treatment with BBr 3 . At a temperature between about 0 °C and RT.
  • Preparative methods CP Preparative Pre-HPLC Method A: Mobile Phase: A: Water (10mM NH 4 HCO 3 ) B:ACN Gradient: 25% - 55% B within 9 min, stop at 17min Flow Rate: 30 ml/min Column: Xtimate Prep C1810 ⁇ m 21.2 ⁇ 250mm Column Temperature: 40C Detection: UV (214 nm, 254 nm) Method B: Mobile Phase: A: Water (0.2% FA ) B:ACN Gradient: 25% - 55% B within 9 min, stop at 17min Flow Rate: 30 ml/min Column: Boston Prep C1810 ⁇ m 21.2 ⁇ 250mm Column Temperature: 40 °C Detection: UV (214 nm, 254 nm) LCMS experiments: [0277] All CP LCMS experiments were run on Agilent 1200, with a column temperature of 40 °C, monitoring UV absorption at 214 nm and scanning a mass range from 100-1000.
  • LCMS CP Method A (014): Column: Xbridge SB-C184.6*50MM, 3.5um; Mobile Phase: A: Water (0.1%TFA), B: ACN (0.1%TFA); Gradient: 5% B increase to 95% B over 1.8 min, stop at 3 min. Flow Rate: 1.8 mL/min
  • LCMS CP Method B (026): Column: XBridge C18, 4.6*50mm, 3.5um; Mobile Phase: A: Water (0.05%TFA), B: ACN (0.05%TFA); Gradient: 5% B increase to 95% B over 1.7min, stop at 3 min.
  • LCMS CP Method C (025): Column: XBridge C1850*4.6mm, 3.5um; Mobile Phase: A: H 2 O (10mM NH 4 HCO 3 ), B: MeCN; Gradient: 5%-95% B in 1.3min, 95%B for 2.95min, back to 5%B within 0.05 min; Flow Rate: 2.0 mL/min [0281] LCMS CP Method D (028): Column: X-Bridge C18, 4.6*50mm, 3.5um; Mobile phase: A 10mM NH 4 HCO 3 in water B ACN; Gradient: 5% increase to 95%B within 1.4min, 95%B for 1.6min; Flow Rate: 2.0 ml/min [0282] LCMS CP Method E (008): Column: XBridge SB-C18, 4.6*50mm, 3.5um; Mobile Phase: A: Water (10mM NH 4 HCO 3 ), B: ACN; Gradient: 5%-95% B in 1.3min, 95%B
  • LCMS CP Method T (024): Column: Agilent Poroshell, 30* 3.0 mm, 2.7 um; Mobile Phase: A: water (0.01%TFA) B: ACN (0.01%TFA); Gradient: 5% increase to 95%B within 1.0 min, 95%B for 1.0 min; Flow Rate: 1.6 ml/min [0298] Preparation 1: THF (50 mL) was cooled to -78°C.
  • N-methoxy- N-methylpropanamide (395 ⁇ L, 1.2 eq., 3.24 mmol) was added to the mixture and stirred at -78 °C for 30 min. The mixture was warmed to r.t. for 1 h. The reaction was quenched with sat. aqueous NH 4 Cl solution (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 X 10 mL). The organic layers were combined, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex).
  • Step 1 A mixture of 2-amino-3-bromo-5-methylbenzoic acid (2.29 g, 10 mmol), methanamine hydrochloride (1.0 g, 15 mmol), HATU (5.15 g, 15 mmol) and DIPEA (3.87 g, 30 mmol) in DCM (50 ml) was stirred at RT overnight. Water (50 ml) was added and the mixture was extracted with DCM (50 ml*3).
  • Step 2 To a solution of 2-amino-3-bromo-5-methylbenzamide (2.2 g, 9.09 mmol) in dioxane (40 ml) was added thiophosgene (2.07 g, 18.18 mmol) dropwise. The mixture was stirred at RT for 1 h and then stirred at 105 °C for 1 h.
  • Step 4 A mixture of 8-bromo-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (1.0 g, 3.0 mmol), Pd(PPh 3 ) 2 Cl 2 (210 mg, 0.3 mmol) and tributyl(1-ethoxyvinyl)stannane (1.31 g, 3.6 mmol) in dioxane (25 ml) was stirred at 95 °C under N 2 overnight.
  • Step 5 A solution of 8-acetyl-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (500 mg, 1.67 mmol) in MeOH (20 ml) was added NaBH 4 (127 mg, 3.34 mmol) in portions at 0 °C and the mixture was stirred at RT for 1 h. The mixture was diluted with water (20 ml) and extracted with DCM (30 ml*3).
  • Step 6 To a solution of 8-(1-hydroxyethyl)-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (500 mg, 1.66 mmol) in DCM (30 ml) was added PBr 3 (900 mg, 3.32 mmol) dropwise at 0 °C and the mixture was stirred at RT for 1 h. The mixture was cooled to 0 °C and the pH was adjusted to 8 with saturated aqueous NaHCO 3 solution. The mixture was extracted with DCM (40 ml*3).
  • Step 7 A mixture of 8-(1-bromoethyl)-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (450 mg, 1.24 mmol) and methyl 2-aminobenzoate (280 mg, 1.86 mmol) in DMF (10 ml) was stirred at 80 °C overnight. After cooled to RT, water (50 ml) was added and the mixture was extracted with EtOAc (40 ml*3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated.
  • Step 8 A mixture of methyl 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoate (170 mg, 0.39 mmol) and LiOH (46 mg, 1.95 mmol) in MeOH (5 ml) and H 2 O (1 ml) was stirred at 50 °C for 8 h. The mixture was concentrated and the pH was adjusted to 4-5 with 1 N HCl.
  • Example 2 3,6-Dimethyl-8-(1-(phenylamino)ethyl)-2-(piperidin-1-yl)quinazolin-4(3H)-one [0312] A mixture of 8-acetyl-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (180 mg, 0.6 mmol), aniline (111.6 mg, 1.2 mmol) and HOAc (72 mg, 1.2 mmol) in MeOH (5 mL) was stirred at RT for 6 h, then NaBH 3 CN (75.6 mg, 1.2 mmol) was added and the mixture was stirred at RT overnight.
  • aniline 111.6 mg, 1.2 mmol
  • HOAc 72 mg, 1.2 mmol
  • Step 1 A mixture of 2-amino-3-bromo-5-methylbenzoic acid (2.00 g, 8.67 mmol), methanamine hydrochloride (0.874 mg, 13.0 mmol), HATU (4.95 g, 13.0 mmol) and DIPEA (2.24 g, 17.4 mmol) in DCM (50 mL) was stirred at RT overnight.
  • Step 2 To a solution of 2-amino-3-bromo-5-methylbenzamide (2.2 g, 9.09 mmol) in dioxane (40 mL) was added thiophosgene (2.07 g, 18.18 mmol) dropwise. The mixture was stirred at RT for 1 h and at 105 °C for additional 1 h. The mixture was concentrated to afford the crude 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)- one (2.59 g, purity: 70% (254 nm)) as a yellow solid which was used directly in the next step reaction without further purification.
  • Step 3 To a solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (1.00 g, mmol) in DCM (50 mL) were added 4,4-dimethylpiperidine hydrogen chloride (0.593 mg, 5.24 mmol) and DIPEA (0.902 mg, 6.99 mmol). The resulting mixture was stirred at 40 °C overnight. Water (50 mL) was added and the mixture was extracted with DCM (50 mL*3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated.
  • Step 4 A mixture of 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (1.0 g, 2.754 mmol), Pd(PPh 3 ) 2 Cl 2 (0.996 mg, 1.378 mmol) and tributyl(1-ethoxyvinyl)stannane (1.31 g, 3.6 mmol) in dioxane (25 mL) was heated to 95 °C and stirred at the same temperature overnight under N 2 . HCl aqueous solution (1.5 mL, 2 M) was added into the mixture and the mixture stirred at 50 °C for 0.5 h.
  • Step 5 To a solution of 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (200 mg, 0.612 mmol) in MeOH (20 mL) was added NaBH 4 (46.48 mg, 1.223 mmol) in portions at 0 °C and the resulting mixture was stirred at RT for 1 h. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL*3).
  • Step 6 To a solution of 2-(4,4-dimethylpiperidin-1-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4(3H)- one (210 mg, 0.638 mmol) in DCM (30 mL) was added PBr 3 (346 mg, 1.276 mmol) dropwise at 0 °C and the resulting mixture was stirred at RT for 1 h. The mixture was cooled 0 °C and the pH value was adjusted to 8 with saturated aqueous solution of NaHCO 3 . The mixture was extracted with DCM (40 ml*3).
  • Step 7 A solution of 8-(1-bromoethyl)-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (200 mg, 0.512 mmol) and methyl 2-aminobenzoate (154.5 mg, 1.023 mmol) in DMF (10 mL) was stirred at 80 °C for 3 hours. After cooled to RT, water (50 ml) was added and the mixture was extracted with ethyl acetate (40 ml*3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated.
  • Step 8 A mixture of methyl 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (150 mg, 0.325 mmol), LiOH (68.1mg, 1.623 mmol), MeOH (5 mL) and H 2 O (1 mL) was stirred at 50 °C for 16 h. Then the mixture was concentrated and the pH value was adjusted to 4-5 with 1 N HCl aqueous solution.
  • Step 1 To a solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (600 mg, 2.10 mmol) in DCM (50 ml) was added isoindoline (499.3 mg, 4.195 mmol) and the mixture was stirred at 40 °C overnight. Water (50 mL) was added and the mixture was extracted with DCM (50 mL*3).
  • Step 2 A mixture of 8-bromo-2-(isoindolin-2-yl)-3,6-dimethylquinazolin-4(3H)-one (500 mg, 1.35 mmol), Pd(PPh 3 ) 2 Cl 2 (285 mg, 0.406 mmol) and tributyl(1-ethoxyvinyl)stannane (1.36 g, 3.78 mmol) and dioxane (25 mL) was stirred at 95 °C overnight under N 2 . After cooled to RT, HCl (1.5 mL, 2 M) was added into the mixture and stirred at 50 °C for 0.5 h.
  • HCl 1.5 mL, 2 M
  • Step 3 To a solution of 8-acetyl-2-(isoindolin-2-yl)-3,6-dimethylquinazolin-4(3H)-one (350 mg, 1.05 mmol) in MeOH (20 mL) was added NaBH 4 (79.8 mg, 2.10 mmol) in portions at 0 °C and the mixture was stirred at RT for 1 h. Then the mixture was diluted with water (20 mL) and extracted with DCM (30 mL*3).
  • Step 4 To a solution of 8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-3,6-dimethylquinazolin-4(3H)-one (300 mg, 0.896 mmol) in DCM (30 mL) was added PBr 3 (432 mg, 1.79 mmol) dropwise at 0 °C and the mixture was stirred at RT for 1 h. Then the mixture was cooled 0 °C and the pH value was adjusted to 8 with saturated aqueous solution of NaHCO 3 . The mixture was extracted with DCM (40 ml*3).
  • Step 5 A solution of 8-(1-bromoethyl)-2-(isoindolin-2-yl)-3,6-dimethylquinazolin-4(3H)-one (280 mg, 0.705 mmol) and methyl 2-aminobenzoate (213 mg, 1.41 mmol) in DMF (10 mL) was stirred at 80 °C overnight. After cooled to RT, water (50 mL) was added and the mixture was extracted with ethyl acetate (40 mL*3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated.
  • Step 6 A mixture of methyl 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoate (100 mg, 0.39 mmol) and LiOH (44.8 mg, 1.068 mmol), MeOH (5 mL) and H 2 O (1 mL) was stirred at 50 °C for 8 h. Then the mixture was concentrated and the pH value was adjusted to 5 with 1 N HCl aqueous solution.
  • Step 1 A mixture of 2-amino-3-bromo-5-methylbenzoic acid (2.29 g, 10 mmol), methanamine hydrochloride (1.0 g, 15 mmol), HATU (5.15 g, 15 mmol) and DIPEA (3.87 g, 30 mmol) in DCM (50 ml) was stirred at RT overnight. Water (50 ml) was added and the separated aqueous layer was extracted with DCM (50 ml*3).
  • Step 3 To a solution of 8-bromo-3,6-dimethyl-2-phenylquinazolin-4(3H)-one (500 mg, 1.52 mmol, Step 2) in dioxane (25 ml) were added ethyl tributylstannane carboxylate (1.1 g, 3.04 mmol) and Pd(PPh 3 ) 2 Cl 2 (213 mg, 0.304 mmol) and the resulting mixture was stirred overnight at 95 °C under N 2 . HCl (1.5 ml, 2 M) was added into the mixture and stirred at 50 °C for 0.5 h.
  • Step 4 To a solution of 8-acetyl-3,6-dimethyl-2-phenylquinazolin-4(3H)-one (230 mg, 0.79 mmol, Step 3) in MeOH (20 ml) was added NaBH 4 (60 mg, 1.58 mmol) in portions at 0 °C. The mixture was stirred at RT for 1 h. The mixture was diluted with water (20 ml) and extracted with DCM (30 ml*3).
  • Step 5 To a solution of 8-(1-hydroxyethyl)-3,6-dimethyl-2-phenylquinazolin-4(3H)-one (230 mg, 0.78 mmol, Step 4) in DCM (20 ml) was added PBr 3 (422 mg, 1.56 mmol) dropwise at 0 °C. The mixture was stirred at RT for 1 h. The mixture was cooled 0 °C and the pH was adjusted to 8 with saturated aqueous solution of NaHCO 3 .
  • Step 6 To a solution of 8-(1-bromoethyl)-3,6-dimethyl-2-phenylquinazolin-4(3H)-one (200 mg, 0.56 mmol, Step 5) in DMF (10 ml) was added methyl 2-aminobenzoate (169 mmol, 1.12 mmol) and the mixture was heated to 80 °C and stirred overnight. After cooling to RT, water (50 ml) was added and the mixture was extracted with EtOAc (40 ml*3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated.
  • Step 7 To a solution of methyl 2-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoate (110 mg, 0.26 mmol, Step 6) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (31 mg, 1.3 mmol) and the mixture was stirred at 50 °C overnight. The mixture was concentrated to remove MeOH and the pH was adjusted to 4-5 with 1 N HCl.
  • Example 6 2-((1-(3,6-Dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzamide [0334] To a solution of 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (90 mg, 0.21 mmol, Ex.1) in DMF (5 ml) were added NH 4 Cl (22 mg, 0.42 mmol), EDCI (48 mg, 0.25 mmol) and DMAP (13 mg, 0.11 mmol).
  • Step 1 To a solution of 8-(1-bromoethyl)-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (300 mg, 0.83 mmol) in DMF (10 ml) was methyl 3-amino-6-chloropicolinate (308 mg, 1.66 mmol) and the mixture was heated to 80 °C and stirred overnight.
  • Step 2 To a solution of methyl 6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (150 mg, 0.32 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (38 mg, 1.6 mmol) and the mixture was stirred at 50 °C overnight. The mixture was concentrated to remove MeOH and the pH value was adjusted to 4-5 with 1 N HCl.
  • Example 8 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydrothieno[3,2-d]pyrimidin-7-yl)ethyl)amino)benzoic acid [0337]
  • Step 1 2-chlorothieno[3,2-d]pyrimidin-4(3H)-one.
  • a mixture of 2,4-dichlorothieno[3,2-d]pyrimidine (5 g, 24.38 mmol, 1 eq) and 5N NaOH (10 mL, 2 eq) in THF (30 mL) was heated at 80 °C for 16 h.
  • Step 4 7-bromo-3-methyl-2-(piperidin-1-yl)thieno[3,2-d]pyrimidin-4(3H)-one.
  • a mixture of 7- bromo-2-chloro-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (0.85 g, 3.05 mmol, 1 eq), DIEA (1.6 mL, 9.16 mmol, 3 eq), and piperidine (0.39 g, 4.58 mmol, 1.5 eq) in DMSO (10 mL) was heated at 80 °C for 16 h. water was added, and the mixture was extracted with EtOAc (3x).
  • Step 8 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydrothieno[3,2-d]pyrimidin-7- yl)ethyl)amino)benzoic acid.
  • methyl 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydrothieno[3,2-d]pyrimidin-7-yl)ethyl)amino)benzoate 16.5 mg, 0.0387 mmol, 1equiv) in MeOH (1 mL) was added 2N LiOH (0.2 mL, 0.194 mmol, 5 equiv).
  • Step 1 A solution of 3-bromo-5-methylpyridin-2-amine (2.00 g, 10.6 mmol, 1.00 eq) in acetone (14 mL) was heated at 56 °C, then bis(2,4,6-trichlorophenyl) malonate (5.00 g, 10.8 mmol, 1.02 eq) was added portionwise. After stirring at reflux for 2 h, the mixture was concentrated in vacuo to ⁇ 5 mL in volume.
  • Step 2 A 0 °C solution of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.1 g, 8.2 mmol, 1.0 eq) and Et3N (2.3 mL, 17 mmol, 2.0 equiv) in DCE (27 mL) was treated dropwise with methanesulfonyl chloride (890 ⁇ L, 12 mmol, 1.4 equiv). After the addition was completed, the resulting mixture warmed to RTand stirred vigorously for 30 min. Piperidine (2.4 mL, 25 mmol, 3.0 equiv) was added and the resulting mixture stirred vigorously at 70 °C for 18 h.
  • methanesulfonyl chloride 890 ⁇ L, 12 mmol, 1.4 equiv
  • Step 3 A mixture of 9-bromo-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (2.0 g, 6.2 mmol, 1.0 equiv), butyl vinyl ether (970 ⁇ L, 7.5 mmol, 1.2 equiv) and BINAP (390 mg, 0.62 mmol, 0.10 equiv) in DMF (52 mL) was deoxygenated with bubbling argon gas for 10 min, then Pd(OAc) 2 (70 mg, 0.31 mmol, 0.050 equiv) was added. The resulting mixture stirred vigorously at 120 °C for 18 h.
  • Step 4 4 N HCl (13 mL) was added to a stirring solution of 9-(1-butoxyvinyl)-7-methyl-2-(piperidin-1-yl)- 4H-pyrido[1,2-a]pyrimidin-4-one (250 mg, 0.74 mmol) in AcOH (3.7 mL). After stirring for 1 h at room temp, the mixture was neutralized to pH 7 ⁇ 8 with 10 N NaOH. The resulting precipitates were collected by filtrated to afford 9-acetyl-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (160 mg, 78% yield) as a tan solid.
  • Steps 5 and 6 A 0 °C solution of 9-acetyl-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (160 mg, 0.56 mmol, 1.0 equiv) in MeOH (6.7 mL) was treated portionwise with NaBH 4 (42 mg, 1.1 mmol, 2.0 equiv). After the addition was completed, the mixture was warmed to RT and stirred for 2.5 h. The reaction was quenched at 0 °C with water (10 mL) and extracted with DCM (3 ⁇ 10 mL).
  • Step 7 A mixture of 9-(1-bromoethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (150 mg, 0.44 mmol, 1.0 equiv) and methyl 2-aminobenzoate (99 mg, 0.65 mmol, 1.5 equiv) in DMF (3.5 mL) was heated at 80 °C for 18 h. The reaction was diluted with EtOAc (30 mL) and sequentially washed with LiCl solution (3 ⁇ 30 mL) and brine (1 ⁇ 30 mL). The organic phase was dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo.
  • Step 8 A 0 °C solution of 9-(1-hydroxyethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (96 mg, 0.33 mmol, 1.0 equiv) and DIPEA (120 ⁇ L, 0.67 mmol, 2.0 equiv) in DCM (1.5 mL) was treated dropwise with methanesulfonyl chloride (36 ⁇ L, 0.47 mmol, 1.4 equiv). After the addition was completed, the mixture was warmed to RTand stirred for 18 h.
  • Step 9 A solution of 9-(1-chloroethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (100 mg, 0.33 mmol, 1.0 equiv) in DMF (1.6 mL) was treated with methyl 2-aminobenzoate (76 mg, 0.50 mmol, 1.5 equiv) and heated at 80 °C for 18 h. Additional 2-aminobenzoate (76 mg, 0.50 mmol, 1.5 equiv) was added, then the mixture heated at 120 °C for 5.5 h.
  • Step 10 A solution of methyl 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (120 mg, 0.28 mmol, 1.0 equiv) in MeOH (3.5 mL) was treated with an aqueous solution of LiOH (2 N, 700 ⁇ L, 5.0 equiv). The resulting mixture stirred at 50 °C for 18 h. The mixture was concentrated in vacuo, then dissolved in H 2 O (30 mL) and extracted with MTBE (3 ⁇ 30 mL).
  • Step 3 8-bromo-6-chloro-3-methylpyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione.
  • 3-amino-4-bromo-6-chloro-N-methylpicolinamide (0.75 g, 2.83 mmol, 1 equiv) and DIEA (1.5 mL, 8.51 mmol, 3 equiv) in DCM (15 mL) at 0 °C
  • triphosgene 1. g, 4.54 mmol, 1.5 equiv
  • Step 7 6-chloro-2-(4,4-difluoropiperidin-1-yl)-8-(1-hydroxyethyl)-3-methylpyrido[3,2-d]pyrimidin- 4(3H)-one.
  • 8-acetyl-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylpyrido[3,2- d]pyrimidin-4(3H)-one (0.35 g, 0.98 mmol, 1 equiv) in MeOH (10 mL) at 0 °C was added NaBH 4 (0.06 g, 1.46 mmol, 1.5 equiv).
  • Step 8 8-(1-bromoethyl)-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylpyrido[3,2-d]pyrimidin- 4(3H)-one.
  • 6-chloro-2-(4,4-difluoropiperidin-1-yl)-8-(1-hydroxyethyl)-3-methylpyrido[3,2- d]pyrimidin-4(3H)-one 0.1 g, 0.3 mmol, 1 equiv
  • PBr 3 0.3 mL, 1.1 mmol, 4 equiv.
  • Step 9 methyl 2-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4-dihydropyrido[3,2- d]pyrimidin-8-yl)ethyl)amino)benzoate.
  • Example 18 (R)-6-chloro-3-((1-(2-(1-methoxycyclopropyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0365]
  • Step 1 T3P 50% in PhMe (0.75 g, 2.37 mmol) was added to 1-methoxycyclopropane-1-carboxylic acid (0.25 g, 2.15 mmol) and 2-amino-3-bromo-N,5-dimethylbenzamide (0.58 g, 2.37 mmol) suspended in PhMe (20 mL) and heated to reflux for 16 h.
  • Step 2 8-Bromo-2-(1-methoxycyclopropyl)-3,6-dimethylquinazolin-4(3H)-one (0.52 g, 1.62 mmol), Pd(PPh 3 ) 2 Cl 2 (114 mg, 1.62 mmol), and tributyl(1-ethoxyvinyl)tin (0.66 mL, 1.95 mmol) were suspended in dioxane (16 mL), purged with Ar, and stirred at 100 °C for 3 h.2 N HCl (5 mL) was added to the mixture and stirred at 50 °C for 20 min. The mixture was dried over MgSO 4 , filtered over Celite, and concentrated in vacuo.
  • Step 3 8-Acetyl-2-(1-methoxycyclopropyl)-3,6-dimethylquinazolin-4(3H)-one (0.44 g, 1.52 mmol), (R)-2- methylpropane-2-sulfinamide (0.32 g, 3.05 mmol), Ti(O-iPr) 4 (1.35 mL, 4.57 mmol), was heated to reflux in THF (15 mL) for 36 h. The mixture was cooled to r.t., filtered, and concentrated in vacuo. The crude product was purified by ISCO silica column chromatography (0-100% EtOAc/Hex).
  • Step 4 NaBH 3 CN (84.0 mg, 0.13 mmol) was added to a mixture of (R,Z)-N-(1-(2-(1- methoxycyclopropyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfinamide (173 mg, 0.44 mmol), AcOH (0.20 mL, 3.55 mmol), DCM:MeOH (1:1, 4 mL) at 0 °C and stirred for 30 min. The mixture was diluted with DCM (10 mL) washed with sat. aq.
  • Step 5 1 M HCl in MeOH (1.2 mL) was added to a mixture of (R)-N-((R)-1-(2-(1-methoxycyclopropyl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (160 mg, 0.41 mmol) in MeOH (1 mL) at r.t. and stirred for 20 min.
  • Step 6 (R)-8-(1-aminoethyl)-2-(1-methoxycyclopropyl)-3,6-dimethylquinazolin-4(3H)-one hydrochloride (0.04 g, 0.124 mmol), methyl 6-chloro-3-fluoropicolinate (35.0 mg, 0.15 mmol), DIPEA (0.06 mL, 0.37 mmol) was dissolved in DMF (1 mL) and heated to 100 °C for 16 h. The mixture was cooled to r.t., diluted with EtOAc (5 mL), washed with sat. aq. NH 4 Cl solution (5 mL), separated, washed with aq.
  • Step 2 HCl (245 mg, 9 eq., 6.71 mmol), was added to a solution of (R)-N-[(1R)-1- ⁇ 5-ethyl-2-methoxy-9- methylbenzo[c]2,7-naphthyridin-7-yl ⁇ ethyl]-2-methylpropane-2-sulfinamide (298 mg, 746 ⁇ mol) in MeOH (3 mL) and stirred at r.t. for 2 h. The mixture was concentrated in vacuo and used in the next reaction without further purification.
  • Step 3 Methyl 6-chloro-3-fluoropyridine-2-carboxylate (170 mg, 1.2 eq., 895 ⁇ mol), ethylbis(propan-2- yl)amine (531 ⁇ L, 4 eq., 2.98 mmol), 1,4-dioxane (7.46 mL, 87.4 mmol) were added to the vial and heated to 110 °C and stirred for 16 h. The mixture was cooled to r.t., diluted with EtOAc (10 mL), then washed with sat.
  • Step 4 LiOH (20.9 mg, 5 eq., 871 ⁇ mol) was added to a solution of methyl 6-chloro-3- ⁇ [(1R)-1- ⁇ 5-ethyl- 2-methoxy-9-methylbenzo[c]2,7-naphthyridin-7-yl ⁇ ethyl]amino ⁇ pyridine-2-carboxylate (81 mg, 174 ⁇ mol) in THF (1.74 mL, 21.4 mmol) and stirred at r.t. for 5 h.2 N HCl (2 mL) was added the mixture. The mixture was extracted with DCM (3 X 5 mL) and separated.
  • the compound was dissolved in DCM:MeOH (1:1, 90 mL) and cooled to 0 °C. AcOH (4.07 mL, 73.3 mmol) and NaBH 3 CN (1.73 g, 27.5 mmol) was added to the mixture and stirred for 30 min. The reaction was quenched with sat. aq. NaHCO 3 solution (50 mL) and the organic layer was separated. The aqueous layer was extracted with DCM (3 X 50 mL), the organic layers were combined, dried over MgSO 4 , filtered, and concentrated in vacuo.
  • Step 5 3 M HCl in MeOH (6 mL) was added to a solution of (R)-N-((R)-1-(3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (0.50 g, 1.56 mmol in MeOH (6 mL) and stirred at r.t. for 1 h. The mixture was concentrated in vacuo and used in the next reaction without further purification. [0381] Step 6.
  • Methyl 6-chloro-3-fluoropicolinate (0.32 g, 1.71 mmol), DIPEA (1.1 mL, 6.22 mmol), and DMF (6 mL) were added to the vial and the mixture was heated to 100 °C for 6 h. The mixture was cooled to r.t., diluted with EtOAc (10 mL) washed with sat. aq. NH 4 Cl solution (10 mL) and separated. The organic layer was washed with aq. LiCl solution (3 X 10 mL), separated, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO column chromatography (0-100% EtOAc/Hex).
  • Step 2 LiOH (3.31 mg, 3 eq., 138 ⁇ mol) was added to a solution of methyl 3- ⁇ [(1R)-1-(3,6-dimethyl-4- oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl]amino ⁇ -6-methylpyridine-2-carboxylate (20.4 mg, 46.1 ⁇ mol) in THF (461 ⁇ L, 5.66 mmol) and stirred at r.t. for 16 h. The mixture was diluted with DCM (5 mL), acidified with 2 N HCl (2 mL), and separated. The aqueous layer was extracted with DCM (3 X 5 mL).
  • Step 5.3 M HCl in MeOH (2 mL) was added to a mixture of (R)-N-((R)-1-(2-(6-iodopyridin-3-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (0.18 g, 0.34 mmol) in MeOH (3 mL) and stirred at r.t. for 3 h. The mixture was concentrated in vacuo and used in the next reaction without further purification. [0393] Step 6.
  • tert-butyl 6-chloro-3-fluoropicolinate (0.12 g, 0.52 mmol) and DIPEA (0.25 mL, 1.37 mmol) were added to the crude product from step 6 and dissolved in DMF (3 mL). The mixture was heated to 100 °C and stirred for 24 h. The mixture was cooled to r.t., diluted with EtOAc (5 mL), and washed with sat. aq. NH 4 Cl solution (5 mL). The organic layer was separated, washed with aq. LiCl solution (3 X 5 mL), separated, dried over MgSO 4 , filtered, and concentrated in vacuo.
  • Step 1 A heterogeneous mixture of 6-chloro-3-fluoropicolinic acid (3.3 g, 19 mmol) and DMAP (2.7 g, 22 mmol) in DCM (30 mL) was treated dropwise with Boc 2 O (5.1 mL, 22 mmol) at room temp. After 16 h, the mixture was concentrated in vacuo.
  • Step 2 A solution of crude (R)-8-(1-aminoethyl)-2-(difluoromethyl)-3,6-dimethylquinazolin-4(3H)-one (1.5 mmol), in DMF (7 mL) was treated with tert-butyl 6-chloro-3-fluoropicolinate (690 mg, 3.0 mmol) and DIPEA (1.3 mL, 7.4 mmol).
  • Step 3 A solution of tert-butyl (R)-6-chloro-3-((1-(2-(difluoromethyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate in DCM (6 mL) at RT was treated with TFA (4 mL).
  • Example 28 (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-6-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0400]
  • Step 1 HATU (6.49 g, 17.1 mmol) was added to a mixture of 2-amino-3-bromo-5-fluorobenzoic acid (2.00 g, 8.54 mmol), methylamine hydrochloride (1.07 g, 17.1 mmol), DIPEA (5.95 mL, 34.2 mmol), in DCM (85 mL) and stirred at r.t.
  • Step 8 1 M HCl in EtOAc (6.4 mL, 6.37 mmol) was added to (R)-N-((R)-1-(2-(4,4-difluoropiperidin-1-yl)- 6-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (283 mg, 0.64 mmol) dissolved in EtOAc (6 mL) and stirred for 2 h at r.t. The mixture was concentrated in vacuo and used in the next reaction without further purification. [0408] Step 9.
  • Example 29 6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6,7-trimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0410]
  • 2-Amino-4,5-dimethylbenzoic acid (1.00 g, 6.05 mmol) and NBS (1.19 g, 6.66 mmol) was stirred in DMF (20 mL) at r.t. for 16 h. Additional NBS (0.60 g) was added to the mixture and stirred for 1 h at r.t. H 2 O (20 mL was added to the mixture and filtered.
  • Step 2 The compound from Step 1 was added to a flask containing methylamine hydrochloride (0.76 g, 12.1 mmol), HATU (4.60 g, 12.1 mmol), DIPEA (4.2 mL, 24.2 mmol) and DCM (61 mL). The mixture was stirred at r.t. for 2 h. The mixture was washed with sat.
  • Step 7 The mixture from Step 7 was added to a vial containing PBr 3 (0.1 mL, 1.03 mmol) in DCM (10 mL) and stirred at r.t. for 1 h. The mixture was concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give 8-(1-bromoethyl)-2-(4,4-difluoropiperidin-1-yl)-3,6,7-trimethylquinazolin-4(3H)-one (70.0 mg, 16% over 2 steps) as a colorless oil. [0418] Step 9.
  • Example 30 6-chloro-3- ⁇ [(1R)-1- ⁇ 2,6,6-trimethyl-11-oxo-6H,7H,8H,9H,11H-pyrido[2,1-b]quinazolin-4- yl ⁇ ethyl]amino ⁇ pyridine-2-carboxylic acid [0420] Step 1. A solution of 2-amino-3-bromo-5-methylbenzoic acid (1 g, 1.1 eq., 4.35 mmol) and sulfuryl dichloride (10 mL, 35 eq., 138 mmol) in toluene (10 mL, 84.5 mmol) was stirred at 105 °C for 16 h.
  • Step 5 To a stirred solution of (R)-2-methyl-N-[(1R)-1- ⁇ 2,6,6-trimethyl-11-oxo-6H,7H,8H,9H,11H- pyrido[2,1-b]quinazolin-4-yl ⁇ ethyl]propane-2-sulfinamide (150 mg, 0.385 mmol) in DCM (1 mL, 15.6 mmol) was added 4M HCl in dioxane (2 mL) at 0 °C. The resulting mixture was stirred at RT for 1 h.
  • Step 2 To a stirred solution of 8-bromo-6-methyl-2-phenyl-4H-3,1-benzoxazin-4-one (1.7 g, 5.38 mmol) in Aq. ammonia (40 mL) at RT under N 2 atmosphere, resulting mixture was stirred at 100 °C for 1 hours. After completion the reaction was quenched with water (30 mL) and resulting residue was filtered. The obtained solid was dried under reduced vacuum to afford crude 8-bromo-6-methyl-2-phenyl-3,4-dihydroquinazolin-4-one (1.4 g, 82%) as white solid, which was as such taken for next step.
  • Step 3 To a solution of 8-bromo-6-methyl-2-phenyl-3,4-dihydroquinazolin-4-one (1.4 g, 4.44 mmol) dissolved in POCl 3 (3.74 mL, 40 mmol) under N 2 . The resulting mixture was stirred at reflux (105 °C) for 4 hours. After completion of the reaction, the reaction was quenched with ice water and obtained solid was filtered, dried under reduced pressure to result in crude 8-bromo-4-chloro-6-methyl-2-phenylquinazoline (1.46 g, 98%) as off white solid, which was as such taken for next step. LCMS: 333.0 (M+H) + . [0430] Step 4.
  • Step 5 To a solution of 8-bromo-4-hydrazinyl-6-methyl-2-phenylquinazoline (1.3 g, 3.95 mmol) dissolved in (diethoxymethoxy)ethane (3.27 mL, 19.7 mmol) under argon. The resulting mixture was stirred at 130 °C for 16 hours. After completion of the reaction, the reaction was quenched with water and resulting residue was filtered, dried under reduced pressure to result in crude 7-bromo-9-methyl-5-phenyl-[1,2,4]triazolo[4,3- c]quinazoline (1.32 g, 98%) which was as such taken for next step.
  • Step 10 To a solution of (1R)-1- ⁇ 9-methyl-5-phenyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl ⁇ ethan-1-amine (0.1 g, 0.33 mmol) and methyl 6-chloro-3-fluoropyridine-2-carboxylate (0.093 g, 0.49 mmol) dissolved in DMF (1 mL) was added DIPEA (0.115 mL, 0.65 mmol) under argon. The resulting mixture was stirred at 100 °C for 4 hours.
  • Step 7 To a stirred solution of 1- ⁇ 5-ethyl-2,9-dimethylimidazo[1,2-c] quinazolin-7-yl ⁇ ethan-1-one (1.2 g, 4.49 mmol) in THF (7.5 mL, 92.2 mmol) was added (R)-2-methylpropane-2-sulfinamide (1.36 g, 11.2 mmol) followed by addition of titanium(IV) isopropoxide (13.3 mL, 44.9 mmol) and stirred at 100 °C for 1 h in microwave.
  • Step 8 To a stirred solution of (R)-N-[(1Z)-1- ⁇ 5-ethyl-2,9-dimethylimidazo[1,2-c]quinazolin-7- yl ⁇ ethylidene]-2-methylpropane-2-sulfinamide (0.4 g, 1.08 mmol) in THF (2 mL, 24.6 mmol) was added borane THF (464 mg, 5.4 mmol) at -78°C and stirred at same temperature for 1 h. After 1 h reaction was quenched with water (25 mL) and extracted with EtOAc (3*50 mL) then organic layer was dried over sodium sulphate, filtered and concentrated to afford crude.
  • Step 10 To a solution of (1R)-1- ⁇ 5-ethyl-9-methylimidazo[1,2-c]quinazolin-7-yl ⁇ ethan-1-amine (0.055 g, 0.216 mmol) and methyl 6-chloro-3-fluoropyridine-2-carboxylate (0.06 g, 0.236 mmol) dissolved in dimethyl sulfoxide (0.602 mL) was added DIPEA (0.082 mL, 0.472 mmol) under N 2 . The resulting mixture was stirred at 80 °C for 4 hours.
  • Step 2 To a solution of 2-amino-3-bromo-5-methylbenzamide (2.0 g, 8.8 mmol) in dioxane (40 ml) was added thiophosgene (2.02 g, 17.6 mmol) dropwise.
  • Step 3 To a solution of crude 8-bromo-2-chloro-6-methylquinazolin-4(3H)-one (2.39 g, 8.8 mmol) in DCM (50 ml) was added piperidine (3.19 g, 26.4 mmol), the mixture was stirred at 40 °C for 5 days.
  • Step 5 To a solution of 8-bromo-4-chloro-2-(4,4-difluoropiperidin-1-yl)-6-methylquinazoline (940 mg, 90%) as a yellow solid.
  • LCMS: (M + H) + 376.0
  • Step 5 To a solution of 8-bromo-4-chloro-2-(4,4-difluoropiperidin-1-yl)-6-methylquinazoline (940 mg, 2.5 mmol) in EtOH (20 ml) at RT was added N 2 H 4 .H 2 O (625 mg, 12.5 mmol). The mixture was stirred at RT overnight.
  • Step 7 To a mixture of 7-bromo-5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazoline (700 mg, 1.84 mmol) and ethyl tributylstannanecarboxylate (1.33 g, 3.68 mmol) in dioxane (15 ml) was added Pd(PPh 3 ) 2 Cl 2 (129 mg, 0.184 mmol). The mixture was stirred at 95 °C under N 2 for 16 hours.
  • Step 8 To a mixture of 1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7- yl)ethan-1-one (300 mg, 0.87 mmol) and (R)-2-methylpropane-2-sulfinamide (210 mg, 1.74 mmol) in THF (20 ml) at RT was added Ti(i-PrO) 4 (1.24 g, 4.35 mmol). The mixture was stirred at 75 °C for 48 hours. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour.
  • Step 9 To a mixture of crude (R,Z)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[4,3- c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfinamide (390 mg, 0.87 mmol) and HOAc (164 mg, 6.96 mmol) in DCM (10 ml) and MeOH (10 ml) was added NaBH 3 CN (127 mg, 2.61 mmol) in portions at 0 °C, the mixture was stirred for 1 hour.
  • Step 10 A mixture of (R)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7- yl)ethyl)-2-methylpropane-2-sulfinamide (150 mg, 0.33mmol) in a solution of HCl in MeOH (3 ml, 4 M) was stirred at RT for 10 min.
  • Step 11 To a mixture of (R)-1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7- yl)ethan-1-amine (100 mg, 0.29 mmol) and methyl 6-chloro-3-fluoropicolinate (82 mg, 0.435 mmol) in DMSO (5 ml) was added DIPEA (112 mg, 0.87 mmol), the mixture was heated to 95 °C and stirred for 16 hours.
  • Step 12 To a mixture of methyl (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl- [1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)picolinate (120 mg, 0.23 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (55 mg, 2.3 mmol). The mixture was stirred at 50 °C for 1 hour.
  • Step 1 To a mixture of methyl (R)-3-((1-(2-bromo-5-ethyl-9-methylimidazo[1,2-c]quinazolin-7- yl)ethyl)amino)-6-chloropicolinate (110 mg, 0.219 mmol), tripropyl(vinyl)stannane (72.7 mg, 0.263 mmol), CuCl (4.35 mg, 0.0439 mmol) and LiCl (1.84 mg, 0.0439 mmol) in DMF (5 mL) was added Pd(PPh 3 ) 4 (50.72 mg, 0.0439 mmol).
  • Step 2 To a mixture of methyl (R)-6-chloro-3-((1-(5-ethyl-9-methyl-2-vinylimidazo[1,2-c]quinazolin-7- yl)ethyl)amino)picolinate (24 mg, 0.0534 mmol) in THF (5 mL) was added PtO 2 (20%, 4.8 mg) at RT. The mixture was stirred at RT for 2 hours.
  • Step3 To a solution of methyl (R)-6-chloro-3-((1-(2,5-diethyl-9-methylimidazo[1,2-c]quinazolin-7- yl)ethyl)amino)picolinate (20 mg, 0.0443 mmol) in THF (5 mL) and H 2 O (1 mL) was added LiOH (9.31 mg, 0.222 mmol). The mixture was stirred at 50 °C for 3 hours.
  • Step 2 To a solution of (R)-methyl 6-chloro-3-(1-(5-ethyl-9-methyl-2-(1-methyl-1H-pyrazol-3- yl)imidazo[1,2-c]quinazolin-7-yl)ethylamino)picolinate (90 mg, 0.18 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (21.6 mg, 0.90 mmol). The mixture was stirred at 50 °C for 1 hour.
  • Step 1 To a mixture of (R)-methyl 3-(1-(2-bromo-5-ethyl-9-methylimidazo[1,2-c]quinazolin-7- yl)ethylamino)-6-chloropicolinate (160 mg, 0.32 mmol), propyne (1mol/L in DMF) (3.2 ml, 3.2 mmol), CuI (12 mg, 0.064 mmol) and TEA (97 mg, 0.96 mmol) in 1.4-dioxane (3 ml) was added Pd(PPh 3 ) 2 Cl 2 (45 mg, 0.064 mmol).
  • Step 2 To a solution of (R)-methyl 6-chloro-3-(1-(5-ethyl-9-methyl-2-(prop-1-ynyl)imidazo[1,2- c]quinazolin-7-yl)ethylamino)picolinate (60 mg, 0.13 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (16 mg, 0.65 mmol). The mixture was stirred at 50 °C for 1 hour.
  • Step 1 tert-butyl 4-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate.
  • Step 2 tert-butyl 4-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate.
  • Step 3 tert-butyl 4- ⁇ 3,6-dimethyl-8-[(1E)-1- ⁇ [(R)-2-methylpropane-2-sulfinyl]imino ⁇ ethyl]-4-oxo-3,4- dihydroquinazolin-2-yl ⁇ piperidine-1-carboxylate.
  • Step 4 tert-butyl 4- ⁇ 3,6-dimethyl-8-[(1R)-1- ⁇ [(R)-2-methylpropane-2-sulfinyl]amino ⁇ ethyl]-4-oxo-3,4-dihydroquinazolin-2-yl ⁇ piperidine- 1-carboxylate.
  • Step 5 tert-butyl 4- ⁇ 8-[(1R)-1-aminoethyl]-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl ⁇ piperidine-1- carboxylate.
  • Step 6 methyl 3- ⁇ [(1R)-1-(2- ⁇ 1-[(tert-butoxy)carbonyl]piperidin-4-yl ⁇ -3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl]amino ⁇ -6-chloropyridine-2-carboxylate.
  • Step 7 methyl 6-chloro-3- ⁇ [(1R)-1-[3,6-dimethyl-4-oxo-2-(piperidin-4-yl)-3,4-dihydroquinazolin-8- yl]ethyl]amino ⁇ pyridine-2-carboxylate.
  • Step 8 methyl 3-[(R)-1- ⁇ 2-[1-(5-methoxy-4-pyrimidinyl)-4-piperidyl]-3-methyl-6-methyl-4-oxo-8- quinazolinyl ⁇ ethylamino]-6-chloro-2-pyridinecarboxylate.
  • Step 9 3-[(R)-1- ⁇ 2-[1-(5-methoxy-4-pyrimidinyl)-4-piperidyl]-3-methyl-6-methyl-4-oxo-8- quinazolinyl ⁇ ethylamino]-6-chloro-2-pyridinecarboxylic acid.
  • Example 42 3-[(R)-1- ⁇ 2-[1-(6-chloro-2-cyano-3-pyridyl)-4-piperidyl]-3-methyl-6-methyl-4-oxo-8- quinazolinyl ⁇ ethylamino]-6-chloro-2-pyridinecarboxylic acid. [0499] The title compound (23 mg, 46%) was prepared in the same method as described in Example 40.
  • Example 43 6-chloro-3- ⁇ [(1R)-1- ⁇ 3,6-dimethyl-4-oxo-2-[1-(pyridin-3-yl)piperidin-4-yl]-3,4-dihydroquinazolin-8- yl ⁇ ethyl]amino ⁇ pyridine-2-carboxylic acid [0500] Step 1. methyl 6-chloro-3- ⁇ [(1R)-1- ⁇ 3,6-dimethyl-4-oxo-2-[1-(pyridin-3-yl)piperidin-4-yl]-3,4- dihydroquinazolin-8-yl ⁇ ethyl]amino ⁇ pyridine-2-carboxylate.
  • Step 2 6-chloro-3- ⁇ [(1R)-1- ⁇ 3,6-dimethyl-4-oxo-2-[1-(pyridin-3-yl)piperidin-4-yl]-3,4- dihydroquinazolin-8-yl ⁇ ethyl]amino ⁇ pyridine-2-carboxylic acid.
  • Step 2 3-amino-4-bromo-6-chloro-N-methylpicolinamide.
  • NBS 4.3 g, 24.18 mmol, 1.2 eq.
  • Step 7 (R,E)-N-(1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4-dihydropyrido[3,2- d]pyrimidin-8-yl)ethylidene)-2-methylpropane-2-sulfinamide.
  • Step 8 (R)-N-((R)-1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4-dihydropyrido[3,2- d]pyrimidin-8-yl)ethyl)-2-methylpropane-2-sulfinamide.
  • Step 9 (R)-8-(1-aminoethyl)-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylpyrido[3,2- d]pyrimidin-4(3H)-one hydrochloride.
  • Step 10 methyl (R)-6-chloro-3-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4- dihydropyrido[3,2-d]pyrimidin-8-yl)ethyl)amino)picolinate.
  • Example 45 (R)-6-chloro-3-((1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4-dihydropyrido[3,4-d]pyrimidin-8- yl)ethyl)amino)picolinic acid
  • Step 1 5-amino-2-chloro-N-methylisonicotinamide.
  • the title compound (4.7 g, 88%) was prepared in the same method as described in Example 44. (MS (m/z): 185.2 (M+H). ).
  • Step 2 3-amino-2-bromo-6-chloro-N-methylisonicotinamide.
  • Step 5 (R,E)-N-(1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4-dihydropyrido[3,4-d]pyrimidin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide.
  • the title compound (290 mg, 63%) was prepared in the same method as described in Example 40. MS (m/z): 417.1 (M+H).
  • Step 6 (R)-N-((R)-1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4-dihydropyrido[3,4-d]pyrimidin-8- yl)ethyl)-2-methylpropane-2-sulfinamide.
  • the title compound (87 mg, 31%) was prepared in the same method as described in Example 40. MS (m/z): 419.1 (M+H).
  • Step 7 (R)-8-(1-aminoethyl)-6-chloro-3-methyl-2-phenylpyrido[3,4-d]pyrimidin-4(3H)-one hydrochloride.
  • Step 8 tert-butyl (R)-6-chloro-3-((1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4-dihydropyrido[3,4- d]pyrimidin-8-yl)ethyl)amino)picolinate.
  • the title compound (41.6 mg, 38%) was prepared in the same method as described in Example 40 (tert butyl ester was used instead of methyl ester).
  • Step 9 (R)-6-chloro-3-((1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4-dihydropyrido[3,4-d]pyrimidin-8- yl)ethyl)amino)picolinic acid (ONCV-000118).
  • Step 2 (R)-8-(1-aminoethyl)-3,6-dimethyl-2-phenylpyrido[3,4-d]pyrimidin-4(3H)-one hydrochloride.
  • the title compound (31.5 mg, 100%) was prepared in the same methods as described in Example 40.
  • Step 3 methyl (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydropyrido[3,4-d]pyrimidin- 8-yl)ethyl)amino)picolinate.
  • Step 4 (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydropyrido[3,4-d]pyrimidin-8- yl)ethyl)amino)picolinic acid.
  • the title compound 12.6 mg, 42%) was prepared in the same method as described in Example 40 Step 10.
  • Example 47 (R)-6-Chloro-3-((1-(2-(3-cyanophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid. [0525] The title compound 16.8 mg, 39%) was prepared in the same method as described in Example 48.
  • Example 48 (R)-6-Chloro-3-((1-(2-(5-cyanopyridin-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid. [0526] The title compound (20.4 mg, 51%) was prepared in the same method as described in Example 48.
  • Example 49 (R)-6-chloro-3-((1-(2-(3-cyano-5-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid. [0527] The title compound (10.6 mg, 34%) was prepared in the same method as described in Example 48.
  • Example 50 (R)-6-chloro-3-((1-(2-(2,6-difluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid. [0528] The title compound (54.5 mg, 85%) was prepared in the same method as described in Example 48.
  • Example 51 6-chloro-3-(((R)-1-(2-((1s,3S)-3-hydroxycyclobutyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid. [0529] The title compound was prepared in the same method as described in Example 14.
  • Step 2 8-bromo-3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-3,4-dihydro-4-quinazolinone.
  • 8-bromo-3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-1,2,3,4-tetrahydro-4-quinazolinone (1.43 g, 4.12 mmol) in chloroform (14.3 mL, 179 mmol) at RT was added 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene- 1,2-dicarbonitrile (935 mg, 4.12 mmol).
  • Step 4 8-[1-(tert-butylsulfinylimino)ethyl]-3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-4(3H)- quinazolinone.
  • Step 7 methyl 3- ⁇ (R)-1-[3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-4-oxo-8- quinazolinyl]ethylamino ⁇ -6-chloro-2-pyridinecarboxylate.
  • Step 8 3- ⁇ (R)-1-[3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-4-oxo-8-quinazolinyl]ethylamino ⁇ - 6-chloro-2-pyridinecarboxylic acid.
  • Step 4 (R,E)-N-(1-(3,6-dimethyl-2-(5-methylpyrimidin-2-yl)-4-oxo-3,4-dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide.
  • Step 5 (R)-N-((R)-1-(3,6-dimethyl-2-(5-methylpyrimidin-2-yl)-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide.
  • Step 7 methyl 3- ⁇ (R)-1-[3-methyl-6-methyl-2-(5-methyl-2-pyrimidinyl)-4-oxo-8- quinazolinyl]ethylamino ⁇ -6-chloro-2-pyridinecarboxylate.
  • Step 8 3- ⁇ (R)-1-[3-methyl-6-methyl-2-(5-methyl-2-pyrimidinyl)-4-oxo-8-quinazolinyl]ethylamino ⁇ - 6-chloro-2-pyridinecarboxylic acid.
  • Example 54 6-chloro-3- ⁇ [(1S)-1-(2-ethyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)-2- hydroxyethyl]amino ⁇ pyridine-2-carboxylic acid [0546] Step 1: 8-bromo-2-ethyl-3,6-dimethylquinazolin-4(3H)-one.
  • Step 2 2-ethyl-3,6-dimethyl-8-vinylquinazolin-4(3H)-one.
  • Step 7 (R)-N-[(1R)-2-[(tert-butyldimethylsilyl)oxy]-1-(2-ethyl-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl]-2-methylpropane-2-sulfinamide.
  • Step 8 8-[(1S)-1-amino-2-hydroxyethyl]-2-ethyl-3,6-dimethyl-3,4-dihydroquinazolin-4-one hydrochloride.
  • (R)-N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-(2-ethyl-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl]-2-methylpropane-2-sulfinamide 118 mg, 246 ⁇ mol
  • MeOH 4 mL
  • HCl 0.6 mL, 10 eq., 2.46 mmol
  • Step 9 methyl 6-chloro-3- ⁇ [(1S)-1-(2-ethyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)-2- hydroxyethyl]amino ⁇ pyridine-2-carboxylate.
  • Step 10 6-chloro-3- ⁇ [(1S)-1-(2-ethyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)-2- hydroxyethyl]amino ⁇ pyridine-2-carboxylic acid.
  • Step 4 8-[(1R)-1-( ⁇ 6-chloro-2-[4-(oxan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl ⁇ amino)ethyl]-3,6- dimethyl-2-phenyl-3,4-dihydroquinazolin-4-one.
  • Step 5 8-[(1R)-1- ⁇ [6-chloro-2-(4H-1,2,4-triazol-3-yl)pyridin-3-yl]amino ⁇ ethyl]-3,6-dimethyl-2- phenyl-3,4-dihydroquinazolin-4-one.
  • Example 58 3-[(R)-1- ⁇ 3-methyl-6-methyl-4-oxo-2-[1-(1,3,6-triaza-5-naphthyl)-4-piperidyl]-8-quinazolinyl ⁇ ethylamino]-6- chloro-2-pyridinecarboxylic acid. [0563] The title compound (23 mg, 46%) was prepared in the same method as described in Example 40.
  • Example 59 3-[(R)-1- ⁇ 2-[1-(5-chloro-1-thia-4,6-diaza-7-indenyl)-4-piperidyl]-3-methyl-6-methyl-4-oxo-8- quinazolinyl ⁇ ethylamino]-6-chloro-2-pyridinecarboxylic acid. [0564] The title compound (23 mg, 44%) was prepared in the same method as described in Example 40.
  • Step 2 To a stirred solution of crude methyl 3-amino-2-bromo-6-methylisonicotinate in MeOH (20 mL) as added 5 N NaOH (3 equiv) and the mixture stirred at Rtovernight. The mixture was concentrated to dryness, cooled to 0 °C in an ice-water bath, then acidified with 6 N HCl to pH 5-6.
  • Step 3 From 3-amino-2-bromo-6-methylisonicotinic acid, (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1- yl)-3,6-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)ethyl)amino)picolinic acid was synthesized in a method analogous to the synthesis of (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-6-fluoro-3-methyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid as an off-white solid, LCMS [
  • Step 2 A mixture of crude 3-amino-6-chloro-2-iodoisonicotinic acid (2.5 g, 8.3 mmol), DIPEA (4.3 mL, 25 mmol), HATU (4.7 g, 12 mmol), and methylamine hydrochloride (840 mg, 12 mmol) in DCM (20 mL) stirred at Rtfor 16 h. The mixture was diluted with DCM (100 mL) and sequentially washed with sat. aq. NH 4 Cl (100 mL), water (100 mL), and brine (100 mL); then dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo.
  • DIPEA 4.3 mL, 25 mmol
  • HATU 4.7 g, 12 mmol
  • methylamine hydrochloride 840 mg, 12 mmol
  • Step 3 From 3-amino-6-chloro-2-iodo-N-methylisonicotinamide, (R)-6-chloro-3-((1-(6-chloro-3-methyl- 2-(1-methylcyclopropyl)-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)ethyl)amino)picolinic acid was synthesized analogously to Example 45.
  • Step 2 A solution of 8-bromo-3-ethyl-6-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (2.6 g, 8.7 mmol) in chloroform (45 mL) was treated with sulfuryl chloride (700 ⁇ L, 8.7 mmol). The resulting solution heated at reflux for 5 h. After cooling to room temp, the mixture was diluted with DCM (200 mL) and sequentially washed with sat. aq. NaHCO 3 (2 ⁇ 200 mL) and brine (1 ⁇ 150 mL).
  • Step 3 A mixture of crude 8-bromo-2-chloro-3-ethyl-6-methylquinazolin-4(3H)-one (2.6 g, 8.7 mmol), 4,4-difluoropiperidine hydrochloride (1.4 g, 8.7 mmol), and DIPEA (3.8 mL, 22 mmol) in DCM (25 mL) were heated at 45 °C overnight.
  • Step 4 A mixture of 8-bromo-2-(4,4-difluoropiperidin-1-yl)-3-ethyl-6-methylquinazolin-4(3H)-one (240 mg, 0.63 mmol), cesium fluoride (380 mg, 2.5 mmol), and TMS-acetal (180 ⁇ L, 1.3 mmol) in DCE (3.0 mL) was deoxygenated with bubbling argon gas for 10 min, then tetrakis(triphenylphosphine)palladium(0) (73 mg, 0.063 mmol) was added. The resulting heterogeneous mixture stirred vigorously at 75 °C overnight.
  • Step 5 From 8-acetyl-2-(4,4-difluoropiperidin-1-yl)-3-ethyl-6-methylquinazolin-4(3H)-one, (R)-6-chloro- 3-((1-(2-(4,4-difluoropiperidin-1-yl)-3-ethyl-6-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid was synthesized analogously to Example 18.
  • Step 2 To a mixture of 3-bromo-2-iodo-5-methylbenzoic acid (3 g, 8.82 mmol) and methylamine hydrochloride (900 mg, 13.23 mmol) in DMF (50 ml) were added DIPEA (2.28 g, 17.64 mmol) and HATU (4.02 g, 10.58 mmol). The mixture was stirred at RT for 2 h. Water (250 ml) was added and the mixture was extracted with EtOAc (100 ml * 3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated.
  • Step 3 To a mixture of 3-bromo-2-iodo-N,5-dimethylbenzamide (1.6 g, 4.53 mmol) and acetophenone (1.1 g, 9.06 mmol) in DMSO (15 ml) were added Cs 2 CO 3 (3.0 g, 9.06 mmol) and CuBr (65 mg, 0.45 mmol). The mixture was stirred 80 °C for 16 h.
  • Step 4 To a mixture of 5-bromo-2,7-dimethyl-3-phenylisoquinolin-1(2H)-one (750 mg, 2.29 mmol) and tributyl(1-ethoxyvinyl)stannane (1.66 g, 4.58 mmol) in 1.4-dioxane (15 ml) was added Pd(PPh 3 ) 2 Cl 2 (161 mg, 0.229 mmol). The mixture was stirred at 100 °C under N 2 for 16 h.
  • Step 5 To a mixture of 5-acetyl-2,7-dimethyl-3-phenylisoquinolin-1(2H)-one (540 mg, 1.86 mmol) and (R)-2-methylpropane-2-sulfinamide (450 mg, 3.72 mmol) and THF (15 ml) was added Ti(Oi-Pr) 4 (15 ml). The mixture was stirred at 75 °C under N 2 for 16 h. The mixture was diluted with EtOAc (30ml) and 30 ml brine was added, the mixture was stirred at RT for 0.5 hour.
  • Step 6 To a mixture of crude (R,Z)-N-(1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinolin-5- yl)ethylidene)-2-methylpropane-2-sulfinamide (620 mg, 1.57 mmol) and AcOH (754 mg, 12.56 mmol) in DCM/MeOH (1: 1) (15 ml) was added NaBH 3 CN (297 mg, 4.71 mmol) 0 °C. The mixture was stirred at 0 °C for 2 h.
  • Step 7 A mixture of (R)-N-((R)-1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinolin-5-yl)ethyl)-2- methylpropane-2-sulfinamide (210 mg, 0.53 mmol) in HCl (3 M in MeOH) (5 ml) was stirred at RT for 0.5 hour.
  • Step 8 To a mixture of (R)-5-(1-aminoethyl)-2,7-dimethyl-3-phenylisoquinolin-1(2H)-one (90 mg, 0.31 mmol) and methyl 6-chloro-3-fluoropicolinate (88 mg, 0.47 mmol) in DMSO (5 ml) was added DIPEA (120 mg, 0.93 mmol). The mixture was stirred at 100 °C for 16 h.
  • Step 9 To a solution of (R)-methyl 6-chloro-3-(1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinolin-5- yl)ethylamino)picolinate (90 mg, 0.2 mmol) in MeOH/H 2 O (5: 1) (5 ml) was added LiOH (24 mg, 1.0 mmol). The mixture was stirred at 50 °C for 1 hour.
  • Step 2 To a solution of bis(2,4,6-trichlorophenyl) 2-methylmalonate (15.3 g, 0.192 mmol,) in acetone (500 mL) was added 3-bromo-5-methylpyridin-2-amine (5 g, 26.7 mmol). The mixture was stirred at 60 °C for 12 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL ⁇ 3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated.
  • Step 3 To a solution of 9-bromo-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.5 g, 13.3 mmol) in POCl 3 (50 mL) was added PCl 5 (276.9 mg, 1.33 mmol). The mixture was stirred at 100 °C for 5 h.
  • Step 4 To a solution of 9-bromo-2-chloro-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.2 g, 7.65 mmol) in DCM(20 mL) were added 4,4-difluoropiperidine (1.85 g, 15.3 mmol) and DIEA (2.97 g, 22.95 mmol). The mixture was stirred at 40 °C for 2 h. Water (50 ml) was added and the mixture was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated.
  • Step 5 To a mixture of 9-bromo-2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4- one (2.2 g, 5.91 mmol) and tributyl(1-ethoxyvinyl)stannane (2.56 g, 0.709 mmol) in dioxane (25 ml) was added Pd(PPh 3 ) 2 Cl 2 (414 mg, 0.591 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h.
  • Step 6 To a mixture of 9-acetyl-2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4- one (1.8 g, 5.36 mmol) and (R)-2-methylpropane-2-sulfinamide (1.3 g, 10.72 mmol) in THF (20 ml) at RT was added Ti(i-PrO) 4 (20 ml). The mixture was stirred at 75 °C for 12 h. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour.
  • Step 7 To a solution of (R,Z)-N-(1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.5 g, 3.42 mmol) in DCM (20 mL) and MeOH(20 mL) were added NaBH 3 CN (322 mg,5.13 mmol) and HOAc (0.2 mL) at 0 °C. The mixture was stirred for 1 hour.
  • Step 8 To a solution of (R)-N-(1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (1.0 g, 2.27 mmol) in MeOH (4 mL) was added a solution of HCl in MeOH (10 ml, 4 M). The mixture was stirred at RT for 5 min.
  • Step 9 To a solution of (R)-9-(1-aminoethyl)-2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one (100 mg, 0.297 mmol) in DMSO (5 mL) were added 6-chloro-3-fluoropicolinic acid (78 mg, 0.446 mmol) and DIEA (115 mg, 0.891 mmol). The mixture was stirred at 100 °C for 5 h.
  • Step 2 To a solution of methyl (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl) amino)benzoate (90 mg, 0.191 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (46 mg, 1.91 mmol). The mixture was stirred at 50 °C for 1 hour.
  • Step 2 To a mixture of 8-bromo-2-cyclohexyl-3,6-dimethylquinazolin-4(3H)-one (230 mg, 0.686 mmol) and tributyl(1-ethoxyvinyl)stannane (294 g, 0.823 mmol) in dioxane (15 ml) was added Pd(PPh 3 ) 2 Cl 2 (48 mg, 0.069 mmol). The mixture was stirred at 95 °C under N 2 for 16 h.
  • Step 3 To a solution of 8-acetyl-2-cyclohexyl-3,6-dimethylquinazolin-4(3H)-one (200 mg, 0.67 mmol) in MeOH (15 mL) was added NaBH 4 (50.7 mg, 1.34 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with Ammonium chloride solution (40 mL) and extracted with EtOAc (40 mL ⁇ 3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated.
  • Step 2 To a solution of 2-((1-(3,6-dimethyl-4-oxo-2-(piperidine-1-yl)-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzonitrile (75 mg, 0.186 mmol) in toluene (10 mL) were added TMSCN (28 mg, 0.28 mmol) and DBTO (45 mg, 0.224 mmol). The mixture was stirred under N 2 at 105 °C for 2 h.
  • Step 2 To a solution of methyl (R)-2-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (150 mg, 0.31 mmol) in THF (3mL) and MeOH (3 mL) were added LiOH (30 mg, 1.22 mmol) and H 2 O (3 mL) at RT, The resulting mixture was stirred at RT for 1 hour.
  • Step 2 To a solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (2.9 g, 4.41mmol) in DCM (50 ml) were added DIPEA (3.64 g, 28.23 mmol) and 4,4-difluoropiperidine (2.28 g, 8.82 mmol), the mixture was stirred at 40 °C for 16 h. Water (50 ml) was added and the mixture was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated.
  • Step 3 To a mixture of 8-bromo-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylquinazolin-4(3H)-one (3.4 g, 8.67 mmol) and tributyl(1-ethoxyvinyl)stannane (6.26 g, 17.34 mmol) in dioxane (25 ml) was added Pd(PPh 3 ) 2 Cl 2 (609 mg, 0.867 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h.
  • Step 4 To a mixture of 8-acetyl-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylquinazolin-4(3H)-one (2.1 g, 5.90 mmol) and (R)-2-methylpropane-2-sulfinamide (1.43 g, 11.80 mmol) in THF (20 ml) at RT was added Ti(i- PrO) 4 (20 ml). The mixture was stirred at 75 °C for 12 h. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour.
  • Step 5 To a solution of (R,Z)-N-(1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfinamide (2.0 g, 4.36 mmol) in DCM (20 mL) and MeOH(20 mL) were added NaBH 3 CN (548 mg, 8.72 mmol) and HOAc (0.2 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h.
  • Step 6 To a solution of (R)-N-(1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (1.8 g, 3.90 mmol) in MeOH (4 mL) was added a solution of HCl in MeOH (10 ml, 4 M). The mixture was stirred at RT for 5 min.
  • Step 8 To a solution of methyl (R)-6-chloro-3-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (160 mg, 0.30 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (73 mg, 3.04 mmol). The mixture was stirred at 50 °C for 3 h.
  • Step 2 To a solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (1.0 g, 3.48 mmol) in DCM (50 ml) were added DIPEA (1.35 g, 10.44 mmol) and 3,3-difluoroazetidine (647 mg, 6.96 mmol), the mixture was stirred at 40 °C overnight.
  • Step 3 To a mixture of 8-bromo-2-(3,3-difluoroazetidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (1.1 g, 3.2 mmol) and tributyl(1-ethoxyvinyl)stannane (2.31 g, 6.4 mmol) in dioxane (25 ml) was added Pd(PPh 3 ) 2 Cl 2 (225 mg, 0.32 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h.
  • Step 4 To a mixture of 8-acetyl-2-(3,3-difluoroazetidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (800 mg, 2.6 mmol) and (R)-2-methylpropane-2-sulfinamide (629 mg, 5.2 mmol) in THF (20 ml) at RT was added Ti(i- PrO) 4 (20 ml). The mixture was stirred at 75 °C for 12 h. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour.
  • Step 5 To a solution of (R,Z)-N-(1-(2-(3,3-difluoroazetidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfinamide (900 mg, 2.17 mmol) in DCM (20 mL) and MeOH(20 mL) were added NaBH 3 CN (273 mg, 4.34 mmol) and HOAc (0.2 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h.
  • Step 6 To a solution of (R)-N-(1-(2-(3,3-difluoroazetidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (750 mg, 1.82 mmol) in MeOH (4 mL) was added a solution of HCl in MeOH (10 ml, 4 M). The mixture was stirred at RT for 5 min.
  • Step 7 To a solution of (R)-8-(1-aminoethyl)-2-(3,3-difluoroazetidin-1-yl)-3,6-dimethylquinazolin-4(3H)- one (100 mg, 0.32 mmol) in DMSO (5 mL) were added methyl 6-chloro-3-fluoropicolinate (91 mg, 0.48 mmol) and DIEA (124 mg, 0.96 mmol). The mixture was stirred at 100 °C for 2 h.
  • Step 8 To a solution of methyl (R)-6-chloro-3-((1-(2-(3,3-difluoroazetidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (75 mg, 0.15 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (36 mg, 1.5 mmol). The mixture was stirred at 50 °C for 1 hour.
  • Step 2 To a solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (1.3 g, 4.53 mmol) in DCM (50 ml) were added DIPEA (1.75 g, 13.59 mmol) and 3,3-difluoropyrrolidine (969 mg, 9.06 mmol), the mixture was stirred at 40 °C overnight. Water (100 ml) was added and the mixture was extracted with DCM (80 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated.
  • Step 3 To a mixture of 8-bromo-2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (1.1 g, 3.07 mmol) and tributyl(1-ethoxyvinyl)stannane (2.22 g, 6.14 mmol) in dioxane (25 ml) was added Pd(PPh 3 ) 2 Cl 2 (215 mg, 0.307 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h.
  • Step 4 To a mixture of 8-acetyl-2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (700 mg, 2.18 mmol) and (R)-2-methylpropane-2-sulfinamide (649 mg, 5.36 mmol) in THF (20 ml) at RT was added Ti(i-PrO) 4 (20 ml). The mixture was stirred at 75 °C for 12 h. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour.
  • Step 5 To a solution of (R,Z)-N-(1-(2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfinamide (850 mg, 2.00mmol) in DCM (20 mL) and MeOH (20 mL) were added NaBH 3 CN (251 mg, 4.00 mmol) and HOAc (0.2 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h.
  • Step 6 To a solution of (R)-N-(1-(2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (700 mg, 1.64 mmol) in MeOH (4 mL) was added a solution of HCl in MeOH (10 ml, 4 M). The mixture was stirred at RT for 10 min.
  • Step 7 To a solution of (R)-8-(1-aminoethyl)-2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethylquinazolin-4(3H)- one (80 mg, 0.248 mmol) in DMSO (5 mL) were added methyl methyl 6-chloro-3-fluoropicolinate (71 mg, 0.372 mmol) and DIEA (96 mg, 0.744 mmol). The mixture was stirred at 100 °C for 2 h.
  • Step 8 To a solution of methyl (R)-6-chloro-3-((1-(2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (70 mg, 0.14 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (34 mg, 1.4 mmol). The mixture was stirred at 50 °C for 1 hour.
  • Step 2 To a solution of methyl (R)-2-((1-(2-(3,3-difluoroazetidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (100 mg, 0.23 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (55 mg, 2.3 mmol). The mixture was stirred at 50 °C for 1 hour.
  • Step 2 To a solution of methyl (R)-2-((1-(2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (80 mg, 0.175 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (42 mg, 1.75 mmol). The mixture was stirred at 50 °C for 1 hour.
  • Step 2 To a mixture of methyl (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-6- (trifluoromethyl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (80 mg, 0.14 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (17 mg, 0.7 mmol). The mixture was stirred at 50 °C for 3 h.
  • Step 1 To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-phenylquinazolin-4(3H)-one (200 mg, 0.68 mmol), methyl 2-iodobenzoate (267 mg, 1.02 mmol), Cs 2 CO 3 (443 mg, 1.36 mmol) in 1.4-dioxane (5 ml) were added Xant-Phos (157 mg, 0.272 mmol) and Pd 2 (dba) 3 (125 mg, 0.136 mmol).
  • Step 2 To a solution of (R)-methyl 2-(1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8- yl)ethylamino)benzoate (190 mg, 0.4 mmol) in MeOH/H 2 O (5: 1) (5 ml) was added LiOH (48 mg, 2.0 mmol). The mixture was stirred at 50 °C for 16 h.
  • Step 2 To a solution of 2-amino-3-bromo-N-methyl-5-(trifluoromethyl)benzamide (2.0 g, 6.8 mmol) in dioxane (30 ml) was added Thiophosgene (1.56 g, 13.6 mmol), the mixture was stirred at RT for 1 hour, then heated to 105 °C and stirred for 1 hour. The resulting mixture was concentrated, the residue was dissolved with DCM (30 ml), 4,4-difluoropiperidine (1.65 g, 13.6 mmol) and DIPEA (1.75 g, 13.6 mmol) were added, the mixture was stirred at 50 °C overnight.
  • Step 3 To a mixture of 8-bromo-2-(4,4-difluoropiperidin-1-yl)-3-methyl-6-(trifluoromethyl)quinazolin- 4(3H)-one (910 mg, 2.14 mmol) and ethyl tributylstannanecarboxylate (1.55 g, 4.28 mmol) in dioxane (20 ml) was added Pd(PPh 3 ) 2 Cl 2 (300 mg, 0.43 mmol). The mixture was stirred at 95 °C under N 2 for 16 h.
  • Step 4 To a mixture of 8-acetyl-2-(4,4-difluoropiperidin-1-yl)-3-methyl-6-(trifluoromethyl)quinazolin- 4(3H)-one (800 mg 2.06 mmol) and (R)-2-methylpropane-2-sulfinamide (499 mg, 4.12 mmol) in THF (30 ml) at RT was added Ti(i-PrO) 4 (2.93 g, 10.3 mmol). The mixture was stirred at 75 °C for 24 h.
  • Step 5 To a mixture To a mixture (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (1.0 g, 2 mmol) and HOAc (960 mg, 16 mmol) in DCM (10 ml) and MeOH (10 ml) at 0 °C was added NaBH 3 CN (186 mg, 6 mmol) slowly, the mixture was stirred for 1 hour.
  • Step 6 A mixture of (R)-N-(1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (400 mg, 0.81 mmol) in a solution of HCl in MeOH (15 ml, 4 M) was stirred at RT for 0.5 hour.
  • Step 7 To a mixture of (R)-8-(1-aminoethyl)-2-(4,4-difluoropiperidin-1-yl)-3-methyl-6- (trifluoromethyl)quinazolin-4(3H)-one (120 mg, 0.31 mmol), methyl 2-iodobenzoate (162 mg, 0.62 mmol), Pd2(dba)3 (53 mg, 0.062 mmol)and xantphos (71 mg, 0.124 mmol) in dioxane (5 ml) was added Cs 2 CO 3 (202 mg, 0.62 mmol), the mixture was stirred at 100 °C for 24 h.
  • Step 8 To a mixture of methyl (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-6-(trifluoromethyl)- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (120 mg, 0.23 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (28 mg, 1.15 mmol). The mixture was stirred at 50 °C for 3 h.
  • Step 2 To a mixture of 8-bromo-2-(3-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (800 mg, 2.3 mmol) and tributyl(1-ethoxyvinyl)stannane (1.67 g, 4.6 mmol) in 1.4-dioxane (30 ml) was added Pd(PPh 3 ) 2 Cl 2 (161 mg, 0.23 mmol). The mixture was heated to 100 °C and stirred under N 2 for 6 h.
  • Step 3 To a mixture of 8-acetyl-2-(3-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (650 mg, 2.1 mmol) and (R)-2-methylpropane-2-sulfinamide (508 mg, 4.2 mmol) in THF (15 ml) was added Ti(i-PrO) 4 (15 ml). the mixture was stirred at 75 °C under N 2 for 16 h. The mixture was diluted with EtOAc (50 ml) and a saturated solution of NaCl (50 ml) was added, the mixture was stirred at RT for 0.5 hour.
  • EtOAc 50 ml
  • NaCl 50 ml
  • Step 4 To a mixture of crude (R,Z)-N-(1-(2-(3-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (867 mg, 2.1 mmol) and HOAc (1.01 g, 16.8 mmol) in DCM (10 ml) and MeOH (10 ml) at 0°C was added NaBH 3 CN (397 mg, 6.3 mmol) slowly. The mixture was stirred at RT for 1 hour.
  • Step 5 A mixture of (R)-N-((R)-1-(2-(3-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 0.48 mmol) in a solution of HCl in MeOH (5 ml, 4 M) was stirred at RT for 10 min.
  • Step 6 To a mixture of (R)-8-(1-aminoethyl)-2-(3-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (80 mg, 0.26 mmol) and methyl 6-chloro-3-fluoropicolinate (74 mg, 0.39 mmol) in DMSO (4 ml) was added DIPEA (101 mg, 0.78 mmol), the mixture was heated to 90 °C overnight. Cooling to RT, water (20 ml) was added and the mixture was extracted with EtOAc (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated.
  • Step 7 To a mixture of methyl (R)-6-chloro-3-((1-(2-(3-fluorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (85 mg, 0.18 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (22 mg, 0.9 mmol). The mixture was stirred at 50 °C for 16 h.
  • Step 2 To a solution of methyl (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (70 mg, 0.14 mmol) in MeOH (5 ml) was added Pd (15 mg, 20%). The mixture was stirred at RT under H 2 balloon overnight.
  • Step 3 To a mixture of methyl (R)-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (60 mg, 0.13 mmol) in MeOH (4 ml) and H 2 O (1 ml) was added LiOH (16 mg, 0.65 mmol). The mixture was stirred at 50 °C for 4 h.
  • Step 2 To a mixture of 8-bromo-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (2.3 g, 6.63 mmol mmol) and tributyl(1-ethoxyvinyl)stannane (4.79 g, 13.26 mmol) in dioxane (25 ml) was added Pd(PPh 3 ) 2 Cl 2 (465 mg, 0.66 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h.
  • Step 3 To a mixture of 8-acetyl-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (1.8 g, 5.81 mmol) and (R)-2-methylpropane-2-sulfinamide (1.41 g, 11.62 mmol) in THF (20 ml) at RT was added Ti(i-PrO) 4 (20 ml). The mixture was stirred at 75 °C for 12 h. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour.
  • Step 4 To a solution of (R,Z)-N-(1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (2.0 g, 4.84 mmol) in EtOH (20 mL) was added a solution of LiBH 4 (4.84 ml, 4.84 mmol, 1 M) at -20 °C. The mixture was stirred at RT for 2 h.
  • Step 5 To a solution of (R)-N-((R)-1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (330 mg, 0.79 mmol) in MeOH (4 mL) was added a solution of HCl in MeOH (10 ml, 4 M). The mixture was stirred at RT for 5 min.
  • Step 6 To a solution of methyl (R)-8-(1-aminoethyl)-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)- one (110 mg, 0.36 mmol) in DMSO (5 mL) were added methyl 6-chloro-3-fluoropicolinate (137 mg, 0.72 mmol) and DIEA (139 mg, 1.08 mmol). The mixture was stirred at 100 °C for 2 h.
  • Step 7 To a solution of methyl (R)-6-chloro-3-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (130 mg, 0.27 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (65 mg, 2.70 mmol). The mixture was stirred at 50 °C for 1 hour.
  • Step 2 To a mixture of 8-bromo-2-(2-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (1.0 g, 2.9 mmol) and tributyl(1-ethoxyvinyl)stannane (2.1 g, 5.8 mmol) in 1.4-dioxane (30 ml) was added Pd(PPh 3 ) 2 Cl 2 (204 mg, 0.29 mmol). The mixture was heated to 100 °C and stirred under N 2 for 6 h.
  • Step 3 To a mixture of 8-acetyl-2-(2-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (800 mg, 2.58 mmol) and (R)-2-methylpropane-2-sulfinamide (624 mg, 5.16 mmol) in THF (15 ml) was added Ti(i-PrO) 4 (15 ml). the mixture was stirred at 75 °C under N 2 for 16 h. The mixture was diluted with EtOAc (50 ml) and a saturated solution of NaCl (50 ml) was added, the mixture was stirred at RT for 0.5 hour.
  • Step 4 To a solution of (R,Z)-N-(1-(2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (900 mg, 2.18 mmol) in THF (20 ml) at 0°C was added a solution of LiBH 4 in THF (2.18 ml, 2.18 mmol, 1 M) slowly. The mixture was stirred at 0°C for 0.5 hour.
  • Step 5 A mixture of (R)-N-((R)-1-(2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 0.6 mmol) in a solution of HCl in MeOH (5 ml, 4 M) was stirred at RT for 10 min.
  • Step 2 To a mixture of 8-bromo-3,6-dimethyl-2-(pyridin-3-yl)quinazolin-4(3H)-one (1.5 g, 4.56 mmol), and tributyl(1-ethoxyvinyl)stannane (3.31 g, 9.12 mmol) in 1.4-dioxane (100 ml) was added Bis(tri-tert- butylphosphine)palladium(0) (234 mg, 0.456 mmol). The mixture was heated to 100 °C and stirred under N 2 for 4 h.
  • Step 3 To a mixture of 8-acetyl-3,6-dimethyl-2-(pyridin-3-yl)quinazolin-4(3H)-one (900 mg, 3.07 mmol) and (R)-2-methylpropane-2-sulfinamide (743 mg, 6.14 mmol) in THF (20 ml) was added Ti(i-PrO) 4 (30 ml). the mixture was stirred at 75 °C under N 2 for 16 h. The mixture was diluted with EtOAc (50 ml) and a saturated solution of NaCl (50 ml) was added, the mixture was stirred at RT for 0.5 hour.
  • Step 4 To a solution of crude (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-(pyridin-3-yl)-3,4-dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (987 mg, 2.49 mmol) in THF (20 ml) at 0°C was added a solution of LiBH 4 in THF (2.5 ml, 2.5 mmol, 1 M) slowly. The mixture was stirred at 0°C for 1 hour.
  • Step 5 A mixture of (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(pyridin-3-yl)-3,4-dihydroquinazolin-8-yl)ethyl)- 2-methylpropane-2-sulfinamide (140 mg, 0.35 mmol) in a solution of HCl in MeOH (5 ml, 4 M) was stirred at RT for 10 min.
  • Step 6 To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-3-yl)quinazolin-4(3H)-one (100 mg, 0.34 mmol) and methyl 6-chloro-3-fluoropicolinate (96 mg, 0.51 mmol) in DMSO (5 ml) was added DIPEA (88 mg, 0.68 mmol), the mixture was heated to 90 °C overnight. Cooling to RT, water (30 ml) was added and the mixture was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated.
  • Step 7 To a mixture of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(pyridin-3-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (100 mg, 0.22 mmol) in THF (2 ml), MeOH (2 ml) and H 2 O (2 ml) was added LiOH (26 mg, 1.1 mmol). The mixture was stirred at RT for 3 h.
  • Step 2 To a solution of tert-butyl (R)-(1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)carbamate (300 mg, 0.657 mmol) in DMF (5 mL) were added Ruphos G4 (56 mg, 0.066 mmol) and Zn(CN) 2 (154 mg, 1.314 mmol). The mixture was stirred in a microwave under N 2 at 100 °C for 1 hour.

Abstract

La divulgation concerne des composés de formules 1A, 1B, 1C et 1D, (1A), (1B), (1C) et (1D) et des procédés de fabrication et des procédés d'utilisation de ceux-ci.
PCT/US2023/062781 2022-02-18 2023-02-17 Inhibiteurs de phosphoinositide 3-kinase (pi3k) et leurs utilisations WO2023159155A1 (fr)

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WO2024044769A1 (fr) * 2022-08-26 2024-02-29 Mirati Therapeutics, Inc. Pyridopyrimidinones substituées
WO2024054469A1 (fr) 2022-09-08 2024-03-14 Onkure, Inc. Isoquinolones utilisés en tant qu'inhibiteurs de pi3k
WO2024051778A1 (fr) * 2022-09-09 2024-03-14 InventisBio Co., Ltd. Composés, leurs procédés de préparation et leurs utilisations
WO2024064024A1 (fr) 2022-09-19 2024-03-28 Onkure, Inc. Dérivés de ((4-oxo-3,4-dihydroquinazolin-8-yl)méthyl)amine utilisés en tant qu'inhibiteurs de p13k pour le traitement du cancer
WO2024081345A1 (fr) 2022-10-14 2024-04-18 Onkure, Inc. Benzopyrimidin-4(3h)-ones utilisées en tant qu'inhibiteurs de pi3k

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WO2024026424A1 (fr) * 2022-07-27 2024-02-01 Black Diamond Therapeutics, Inc. Dérivés de quinazolinone et utilisations associées
WO2024044769A1 (fr) * 2022-08-26 2024-02-29 Mirati Therapeutics, Inc. Pyridopyrimidinones substituées
WO2024054469A1 (fr) 2022-09-08 2024-03-14 Onkure, Inc. Isoquinolones utilisés en tant qu'inhibiteurs de pi3k
WO2024051778A1 (fr) * 2022-09-09 2024-03-14 InventisBio Co., Ltd. Composés, leurs procédés de préparation et leurs utilisations
WO2024064024A1 (fr) 2022-09-19 2024-03-28 Onkure, Inc. Dérivés de ((4-oxo-3,4-dihydroquinazolin-8-yl)méthyl)amine utilisés en tant qu'inhibiteurs de p13k pour le traitement du cancer
WO2024081345A1 (fr) 2022-10-14 2024-04-18 Onkure, Inc. Benzopyrimidin-4(3h)-ones utilisées en tant qu'inhibiteurs de pi3k

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