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  • 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
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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  • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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  • 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
  • C07D401/10—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 carbon chain containing aromatic rings
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  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D405/02—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 two hetero rings
  • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
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  • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
  • C07F9/572—Five-membered rings
  • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems

Definitions

• KIF18A is a kinesin involved in assisting the kinetochore-microtubule (kt-MT) attachment and chromosomal alignment during cell mitosis. Its cargo domain binds directly to protein phosphatase 1 (PP1) and carries it to the plus end of MT where PP1 dephosphorylates Hec1, a kinetochore complex component, further enhancing kt-MT attachment throughout metaphase and anaphase.
• PP1 protein phosphatase 1
• MT-binding motor domain has ATPase activity that powers the KIF18A translocation along MT lattice, enhanced by its C-terminal MT-binding site, and caps and depolymerizes growing microtubule at the plus end, thus dampening MT dynamics.
• This modulation of MT dynamics by KIF18A often occurs at the following (or trailing) sister chromatid, thereby providing a counterbalancing tension to the leading sister chromatid movement catalyzed by another kinesin Kif2C/MCAK.
• KIF18A Loss of KIF18A function causes defective kt-MT attachments and loss of tension within the spindle in cells of high chromosome instability (CIN), leading to hyper stable, longer and multipolar spindles, mitotic arrest, centrosome fragmentation and spindle assembly checkpoint activation or cell death.
• KIF18A is identified from DEPMAP RNAi data re-analysis as one of the top candidates essential for CIN-high cells.
• Reported synthetic lethality screens also singled out KIF18A as a potential anticancer target whose knockdown preferentially renders CIN-high (but not CIN-low), aneuploid and whole-genome doubled cells vulnerable to death.
• composition comprising a compound of Formula (I), Formula (I-1), Formula (Ia1), Formula (Ia2), Formula (I-3), Formula (Ia1), Formula (Ia2), or Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
• a method of inhibiting KIF18A comprising contacting a cell with an effective amount of a compound or a pharmaceutical composition as described herein.
• methods of treating or preventing a disease or condition in an individual comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition as described herein.
• Figures 1A-1E show graphs of tumor volume of vehicle- and compound-treated mice plotted as a function of time after start of treatment.
• Figure 1A shows Compound 22 (10 mg/kg BID, 30 mg/kg BID, 60 mg/kg BID) treatment of HCC15 implanted SCID Beige mice.
• Figure 1B shows Compound 22 (10 mg/kg QD, 30 mg/kg QD, 60 mg/kg QD) treatment of OVCAR-3 implanted Balb/C nude mice.
• Figure 1C shows Compound 134 (10 mg/kg BID, 30 mg/kg BID, 60 mg/kg BID) treatment of HCC15 implanted SCID Beige mice.
• Figure 1D shows Compound 134 (10 mg/kg BID, 30 mg/kg BID, 60 mg/kg BID) treatment of OVCAR-3 implanted Balb/C nude mice.
• Figure 1E shows Compound 134 (30 mg/kg BID, 30 mg/kg QD, 60 mg/kg QD) treatment of OVCAR-3 implanted Balb/C nude mice.
• DETAILED DESCRIPTION [0015] The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments.
• references to a compound of Formula (I), Formula (I-1), Formula (Ia1), Formula (Ia2), Formula (I-2), Formula (I-3), Formula (Ia1), Formula (Ia2), or Formula (II)in include all subgroups defined herein, such as Formula (I-1), (Ia1), or (Ia2), including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and/or described herein.
• references to a compound of Formula (I), Formula (I-1), Formula (Ia1), Formula (Ia2), Formula (I-2), Formula (I-3), Formula (Ia1), Formula (Ia2), or Formula (II), and subgroups thereof, such as Formula (I-1), (Ia1), or (Ia2) include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and/or protected forms thereof.
• references to a compound of Formula (I), Formula (I-1), Formula (Ia1), Formula (Ia2), Formula (I-2), Formula (I-3), Formula (Ia1), Formula (Ia2), or Formula (II), and subgroups thereof, such as Formula (I-1), (Ia1), or (Ia2), include polymorphs, solvates, co-crystals, isomers, tautomers and/or oxides thereof.
• references to a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (Ia1), Formula (Ia2), or Formula (II), and subgroups thereof, such as Formula (I-1), (Ia1), or (Ia2) include polymorphs, solvates, and/or co-crystals thereof.
• references to a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (Ia1), Formula (Ia2), or Formula (II), and subgroups thereof, such as Formula (I-1), (Ia1), or (Ia2) include isomers, tautomers and/or oxides thereof.
• references to a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (Ia1), Formula (Ia2), or Formula (II), and subgroups thereof, such as Formula (I-1), (Ia1), or (Ia2), include solvates thereof.
• “Alkyl” encompasses straight and branched carbon chains having the indicated number of carbon atoms, for example, from 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 3 carbon atoms.
• C 1-6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms.
• alkyl residue having a specific number of carbons When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, “propyl” includes n- propyl and isopropyl; and “butyl” includes n-butyl, sec-butyl, isobutyl and t-butyl.
• alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec- butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
• a range of values e.g., C 1-6 alkyl
• each value within the range as well as all intervening ranges are included.
• C 1-6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 , and C 1-2 alkyl.
• Alkenyl refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond.
• Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2- yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl).
• propenyl e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2- yl
• butenyl e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-
• Alkynyl refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond.
• Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl) and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3- yn-1-yl).
• Cycloalkyl indicates a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, for example, 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged and caged ring groups (e.g., norbornane, bicyclo[2.2.2]octane).
• one ring of a polycyclic cycloalkyl group may be aromatic, provided the polycyclic cycloalkyl group is bound to the parent structure via a non-aromatic carbon.
• a 1,2,3,4-tetrahydronaphthalen-1-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group
• 1,2,3,4-tetrahydronaphthalen-5- yl is not considered a cycloalkyl group.
• Cycloalkenyl indicates a non-aromatic carbocyclic ring, containing the indicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms) and at least one carbon-carbon double bond. Cycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
• cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl, as well as bridged and caged ring groups (e.g., bicyclo[2.2.2]octene).
• one ring of a polycyclic cycloalkenyl group may be aromatic, provided the polycyclic alkenyl group is bound to the parent structure via a non-aromatic carbon atom.
• inden-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is considered a cycloalkenyl group
• inden-4-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkenyl group
• polycyclic cycloalkenyl groups consisting of a cycloalkenyl group fused to an aromatic ring are described below.
• Aryl indicates an aromatic carbocyclic ring having the indicated number of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms.
• Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
• both rings of a polycyclic aryl group are aromatic (e.g., naphthyl).
• polycyclic aryl groups may include a non-aromatic ring fused to an aromatic ring, provided the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring.
• a 1,2,3,4-tetrahydronaphthalen-5- yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group
• 1,2,3,4-tetrahydronaphthalen-1-yl is not considered an aryl group.
• aryl does not encompass or overlap with “heteroaryl,” as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some instances, aryl is phenyl or naphthyl.
• aryl is phenyl. Additional examples of aryl groups comprising an aromatic carbon ring fused to a non-aromatic ring are described below.
• “Heteroaryl” indicates an aromatic ring containing the indicated number of atoms (e.g., 5 to 12, or 5 to 10 membered heteroaryl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon. Heteroaryl groups do not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2.
• the total number of S and O atoms in the heteroaryl group is not more than 1.
• heteroaryl groups may be bound to the parent structure by a carbon or nitrogen atom, as valency permits.
• pyridyl includes 2-pyridyl, 3- pyridyl and 4-pyridyl groups
• pyrrolyl includes 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl groups.
• a heteroaryl group is monocyclic.
• Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4- oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4- thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine.
• pyrrole pyrazole
• imidazole e.g., 1,2,
• both rings of a polycyclic heteroaryl group are aromatic.
• examples include indole, isoindole, indazole, benzoimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-
• polycyclic heteroaryl groups may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring.
• a non-aromatic ring e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl
• a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group
• 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group.
• polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non- aromatic ring are described below.
• Heterocycloalkyl indicates a non-aromatic, fully saturated ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon.
• Heterocycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
• heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide.
• one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom.
• a 1,2,3,4- tetrahydroquinolin-1-yl group (wherein the moiety is bound to the parent structure via a non- aromatic nitrogen atom) is considered a heterocycloalkyl group
• 1,2,3,4- tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkyl group.
• polycyclic heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are described below.
• Heterocycloalkenyl indicates a non-aromatic ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon, and at least one double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl.
• Heterocycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
• heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3- dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4- dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1,2,3,4- tetrahydropyridinyl, 1,2,3,6
• one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkenyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom.
• a 1,2-dihydroquinolin-1-yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group
• 1,2-dihydroquinolin-8-yl group is not considered a heterocycloalkenyl group.
• polycyclic heterocycloalkenyl groups consisting of a heterocycloalkenyl group fused to an aromatic ring are described below.
• polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3- dihydr
• Halogen refers to fluoro, chloro, bromo or iodo.
• Haloalkyl refers to alkyl substituted with one or more halogen.
• a haloalkyl group may have a halogen substituent at any valence-permitted location on the alkyl and may have any number of halogen substituents ranging from one to the maximum valence- permitted number.
• haloalkyl groups have 1, 2, or 3 halogen substituents.
• haloalkyl groups include, but are not limited to, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, - CH2CHF2, -CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3.
• compounds disclosed and/or described herein include all possible enantiomers, diastereomers, meso isomers and other stereoisomeric forms, including racemic mixtures, optically pure forms and intermediate mixtures thereof.
• Enantiomers, diastereomers, meso isomers and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless specified otherwise, when the compounds disclosed and/or described herein contain olefinic double bonds or other centers of geometric asymmetry, it is intended that the compounds include both E and Z isomers. When the compounds described herein contain moieties capable of tautomerization, and unless specified otherwise, it is intended that the compounds include all possible tautomers.
• Protecting group has the meaning conventionally associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site, and such that the group can readily be removed after the selective reaction is complete.
• a variety of protecting groups are disclosed, for example, in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999).
• a “hydroxy protected form” contains at least one hydroxy group protected with a hydroxy protecting group.
• amines and other reactive groups may similarly be protected.
• pharmaceutically acceptable salt refers to a salt of any of the compounds herein which are known to be non-toxic and are commonly used in the pharmaceutical literature.
• the pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19.
• Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
• Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p- toluenesulfonic acid, stearic acid and salicylic acid.
• Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
• Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum.
• Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
• the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.
• the free base can be obtained by basifying a solution of the acid salt.
• an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19).
• bases compounds see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19.
• a “solvate” is formed by the interaction of a solvent and a compound.
• Suitable solvents include, for example, water and alcohols (e.g., ethanol).
• Solvates include hydrates having any ratio of compound to water, such as monohydrates, dihydrates and hemi-hydrates.
• the term “substituted” means that the specified group or moiety bears one or more substituents including, but not limited to, substituents such as alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl,
• unsubstituted means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system.
• a substituted group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from one another.
• a substituted group or moiety bears from one to five substituents.
• a substituted group or moiety bears one substituent.
• a substituted group or moiety bears two substituents.
• a substituted group or moiety bears three substituents.
• a substituted group or moiety bears four substituents. In some embodiments, a substituted group or moiety bears five substituents.
• “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
• “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and/or inherently unstable.
• the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.
• the compounds disclosed and/or described herein can be enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
• the compound contains at least one deuterium atom.
• deuterated forms can be made, for example, by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds may improve the efficacy and increase the duration of action of compounds disclosed and/or described herein.
• Deuterium substituted compounds can be synthesized using various methods, such as those described in: Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
• pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
• patient “individual,” and “subject” refer to an animal, such as a mammal, bird, or fish. In some embodiments, the patient or subject is a mammal.
• Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans.
• the patient, individual, or subject is a human, for example a human that has been or will be the object of treatment, observation or experiment.
• the compounds, compositions and methods described herein can be useful in both human therapy and veterinary applications.
• the term “therapeutically effective amount” or “effective amount” refers to that amount of a compound disclosed and/or described herein that is sufficient to affect treatment, as defined herein, when administered to a patient in need of such treatment.
• a therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation (e.g., inhibition) of KIF18a.
• the therapeutically effective amount will vary depending upon, for example, the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound, the dosing regimen to be followed, timing of administration, the manner of administration, all of which can readily be determined by one of ordinary skill in the art.
• the therapeutically effective amount may be ascertained experimentally, for example by assaying blood concentration of the chemical entity, or theoretically, by calculating bioavailability.
• Treatment includes one or more of: inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and/or relieving a disease or disorder (i.e., causing relief from or regression of clinical symptoms).
• the term covers both complete and partial reduction of the condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder.
• compounds described and/or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder.
• ring A is substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of -SR a21 , - C(O)R a22 , and C 1-6 alkyl substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of -OH, cyano, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl optionally substituted with one, two, three, four, five, or more halo.
• ring A is substituted with -SR a21 , -C(O)R a22 , or C 1-6 alkyl substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of -OH, cyano, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl optionally substituted with one, two, three, four, five, or more halo.
• one or more R B groups are independently C 1-6 alkyl substituted with one, two, three, four, five, or more halo.
• an R B group is C 1-6 alkyl substituted with one, two, three, four, five, or more halo.
• R C2 is -NR c14 C(O)OR c15 , wherein R c14 and R c15 are each independently hydrogen, C 3-10 cycloalkyl, or C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.
• cycloalkyl or heterocycloalkyl groups include spiro groups. In some embodiments, cycloalkyl or heterocycloalkyl groups include fused groups.
• ring A is C 6-14 aryl or 5- to 12-membered heteroaryl, each optionally substituted. In some embodiments, ring A is optionally substituted C 6-14 aryl. In some embodiments, ring A is optionally substituted phenyl. In some embodiments, ring A is optionally substituted 5- to 12-membered heteroaryl. In some embodiments, ring A is optionally substituted 6-membered heteroaryl. In some embodiments, ring A is optionally substituted 5-membered heteroaryl.
• ring A is indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each optionally substituted. In some embodiments, ring A is optionally substituted thiophenyl.
• the 3- to 10-membered heterocycloalkyl is piperidinyl. In some embodiments, the 3- to 10-membered heterocycloalkyl is .
• R a1 is hydrogen or C 1-6 alkyl. In some embodiments, R a1 is hydrogen. In some embodiments, R a2 and R a3 are each independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl. In some embodiments, R a2 and R a3 are each independently hydrogen, cyclopropyl, ethyl, or isopropyl.
• R a4 is hydrogen or C 1-6 alkyl. In some embodiments, R a4 is hydrogen.
• R a8 and R a9 are each independently methyl or cyclopentyl.
• -OR a10 is .
• R a10 is C 3-10 cycloalkyl.
• R a10 is cyclopentyl.
• -S(O)R a11 is .
• R a11 is C 3-10 cycloalkyl.
• R a11 is cyclopentyl.
• -S(O)(NR a12 )R a13 is or .
• R a12 is hydrogen or C 1-6 alkyl.
• R a12 is hydrogen or methyl.
• R a13 is C 3-10 cycloalkyl.
• R a13 is cyclopentyl.
• -S(O) 2 NR a14 R a15 is
• - S(O) 2 NR a14 R a15 is , , , , , , or .
• R a14 and R a15 are each independently hydrogen or C 1-6 alkyl. In some embodiments, R a14 is hydrogen and R a15 is butyl. In some embodiments, R a15 is tert-butyl. In some embodiments, -S(O) 2 R a16 is , , , , , , a16 , . In some embodiments, -S(O) 2 R is , , , , , , , , , , or .
• R a16 is C 3-10 cycloalkyl; or 3- to 12-membered heterocycloalkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of C 1-6 alkyl or halo.
• -(CR a17 R a18 )0-1C(O)NR a19 R a20 is -C(O)NR a19 R a20 or -(CR a17 R a18 )C(O)NR a19 R a20 .
• -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 is -C(O)NR a19 R a20 .
• - (CR a17 R a18 )0-1C(O)NR a19 R a20 is -(CR a17 R a18 )C(O)NR a19 R a20 .
• R a17 and R a18 are each independently hydrogen or C 1-6 alkyl.
• R a17 and R a18 are each hydrogen.
• R a19 and R a20 are each independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl.
• R a19 and R a20 are each independently hydrogen or cyclopropyl.
• -SR a21 is .
• R a21 is C 3-10 cycloalkyl.
• -C(O)R a22 is .
• R a22 is C 3-10 cycloalkyl.
• the optionally substituted C 1-6 alkyl is or .
• C 1-6 alkyl is optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of -OH, cyano, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl optionally substituted with one, two, three, four, five, or more halo.
• the 3- to 10-membered heterocycloalkyl is piperidinyl optionally substituted with one, two, three, four, five, or more halo.
• the 3- to 10-membered heterocycloalkyl is optionally substituted with one, two, three, four, five, or more fluoro.
• the 3- to 10-membered heterocycloalkyl is piperidinyl optionally substituted with one, two, three, four, five, or more fluoro.
• ring A is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, -OH, amino, , , , , , and .
• ring A is optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of fluoro, chloro, -OH, amino, , , , , , , , , ,
• ring B is C 5-7 cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon. In some embodiments, ring B is C 5-7 cycloalkyl. In some embodiments, ring B is cyclopentyl, cyclohexyl, or cycloheptyl.
• ring B is or , wherein * denotes the point of attachment to the rest of Formula (I), Formula (I-1), Formula (I-2), or Formula (I-3). In some embodiments, ring B is C 5-7 cycloalkenyl. In some embodiments, ring B is cyclopentenyl, cyclohexenyl, or cycloheptenyl. In some embodiments, ring B is , wherein * denotes the point of attachment to the rest of Formula (I), Formula (I-1), Formula (I-2), or Formula (I-3). In some embodiments, ring B is , wherein * denotes the point of attachment to the rest of Formula (I), Formula (I-1), Formula (I-2), or Formula (I-3).
• ring B is 5- to 7-membered heterocycloalkyl. In some embodiments, ring B is 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon. In some embodiments, ring B is tetrahydrofuranyl or 1,3- dioxanyl. In some embodiments, ring B is or , wherein * denotes the point of attachment to the rest of Formula (I), Formula (I-1), Formula (I-2), or Formula (I-3).
• ring B is substituted with m R B groups, wherein each R B group is independently halo, C 1-6 alkyl optionally substituted with one, two, three, four, five, or more halo, or C 2-6 alkenyl; or two vicinal R B groups are taken together with the carbon atoms to which they are attached to form C 3-10 cycloalkyl; or two geminal R B groups are taken together with the carbon atom to which they are attached to form C 3-10 cycloalkyl.
• an R B group is methyl or ethyl.
• two vicinal R B groups are taken together with the carbon atoms to which they are attached to form cyclopropyl.
• two geminal R B groups are taken together with the carbon atom to which they are attached to form cyclopropyl.
• m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. [0063] In some embodiments, of Formula (I), Formula (I-1), Formula (I- 2), or Formula (I-3), is , , , , , , , or wherein * denotes the point of attachment to the rest of Formula (I), Formula (I-1), Formula (I-2), or Formula (I-3).
• Y 1 is N or CR C1 ; Y 2 is N or CR C2 ; Y 3 is N or CR C3 ; and Y 4 is N or CR C4 . In some embodiments, no more than three of Y 1 , Y 2 , Y 3 , and Y 4 are N.
• Y 1 , Y 2 , Y 3 , and Y 4 are N. In some embodiments, no more than one of Y 1 , Y 2 , Y 3 , and Y 4 is N. In some embodiments, Y 1 is CR C1 ; Y 2 is CR C2 ; Y 3 is CR C3 ; and Y 4 is CR C4 . In some embodiments, Y 1 is N; Y 2 is CR C2 ; Y 3 is CR C3 ; and Y 4 is CR C4 .
• Y 1 is CR C1 ; Y 2 is N; Y 3 is CR C3 ; and Y 4 is CR C4 .
• R c1 -R c18 are each independently hydrogen, C 3-10 cycloalkyl, or C 1-6 alkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of halo and -OH.
• R c1 -R c15 are each independently hydrogen, C 3-10 cycloalkyl, or C 1-6 alkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of halo and -OH.
• R C1 is hydrogen or halo.
• R C1 is hydrogen or fluoro.
• R C3 is hydrogen.
• R C4 is hydrogen or -NH2.
• R C1 , R C3 , and R C4 are each independently hydrogen, halo, or -NH 2 .
• R C2 is cyano, -OH, -CH2OH, bromo, -NO2, , , , , or . In some embodiments, R C2 is cyano, -OH, -CH 2 OH, bromo, -NO 2 , , , , or .
• -C(O)NR c1 R c2 is .
• R c1 and R c2 are each independently hydrogen or C 1-6 alkyl.
• R c1 and R c2 are each independently hydrogen, methyl, or ethyl.
• -NR c3 R c4 is .
• R c3 and R c4 are each independently hydrogen or C 1-6 alkyl.
• R c1 and R c2 are each independently hydrogen, methyl, or ethyl.
• -NR c5 S(O) 2 R c6 is , , , or .
• R c5 is hydrogen or C 1-6 alkyl. In some embodiments, R c5 is hydrogen, methyl, or ethyl. In some embodiments, R c6 is hydrogen or C 1-6 alkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from halo and - OH. In some embodiments, R c5 is methyl or -CH 2 CH 2 OH. In some embodiments, R c5 is hydrogen. In some embodiments, R c6 is ethyl. In some embodiments, -P(O)R c7 R c8 is . In some embodiments, R c7 and R c8 are each independently C 1-6 alkyl.
• R c7 and R c8 are each methyl.
• R c9 and R c10 are each independently C 1-6 alkyl.
• R c9 and R c10 are each methyl.
• -S(O)(NR c11 )R c12 is or .
• R c11 is hydrogen or C 1-6 alkyl.
• R c11 is hydrogen or methyl.
• R c12 is C 1-6 alkyl or C 3-10 cycloalkyl. In some embodiments, R c12 is cyclopropyl.
• -S(O) 2 R c13 is .
• R c13 is C 1-6 alkyl.
• R c13 is methyl.
• NR c14 C(O)OR c15 is c .
• R 14 and R c15 are each independently hydrogen or C 1- 6 alkyl.
• R c14 is hydrogen.
• R c15 is ethyl.
• -NR c16 S(O) 2 (CH 2 ) 1- 6 NR c17 C(O)R c18 is .
• -NR c16 S(O) 2 (CH 2 ) 1- 6 NR c17 C(O)R c18 is -NR c16 S(O) 2 (CH 2 ) 1- 3 NR c17 C(O)R c18 .
• R c16 , R c17 and R c18 are each independently hydrogen or C 1-6 alkyl.
• R c16 and R c17 are hydrogen.
• R c18 is methyl.
• R C2 is -NR c5 S(O) 2 R c6 .
• R c5 is hydrogen and R c6 is C 1-6 alkyl.
• R c5 is hydrogen and R c6 is ethyl.
• R c5 is hydrogen.
• R c6 is ethyl.
• R c6 is methyl.
• R a14 is hydrogen and R a15 is C 1-6 alkyl.
• R a14 is hydrogen and R a15 is tert-butyl.
• R a14 is hydrogen.
• R a15 is tert-butyl.
• ring B is , wherein * denotes the point of attachment to the rest of Formula (Ia1).
• of Formula (Ia1) is .
• ring B is not , wherein * denotes the point of attachment to the rest of Formula (I).
• R C1 is not fluoro.
• R is not hydrogen.
• ring B is not , wherein * denotes the point of attachment to the rest of Formula (I); or R C1 is not fluoro; or R C2 is not hydrogen.
• the compound is not 4'-fluoro-1'-[3-(piperidine-1- sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; 3-cyclopropyl-1-[3-( ⁇ 4'- fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indol]-1'-yl ⁇ carbonyl)phenyl]urea; 1-[3-( ⁇ 4'- fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indol]-1'-yl ⁇ carbonyl)phenyl]-3-(propan-2- yl)urea; [4-( ⁇ 4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indol]-1'- yl ⁇
• the compound is not a salt of 4'-fluoro-1'-[3-(piperidine-1- sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; 3-cyclopropyl-1-[3-( ⁇ 4'- fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indol]-1'-yl ⁇ carbonyl)phenyl]urea; 1-[3-( ⁇ 4'- fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indol]-1'-yl ⁇ carbonyl)phenyl]-3-(propan-2- yl)urea; [4-( ⁇ 4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indol]-1'--yl]-1'-y
• Z 1 -Z 4 are independently selected from the group consisting of -SR a21 , -C(O)R a22 , and C 1-6 alkyl substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of -OH, cyano, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl optionally substituted with one, two, three, four, five, or more halo.
• ring A is substituted with -SR a21 , - C(O)R a22 , or C 1-6 alkyl substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of -OH, cyano, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl optionally substituted with one, two, three, four, five, or more halo.
• Z 4 is hydrogen and at least one of Z 1 and Z 3 is R D wherein R D is as defined elsewhere herein. In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, Z 4 is when Z 4 is R D and Z 1 is R D wherein R D is as defined elsewhere herein.
• Z 5 is C-H, N, O, S, or N-X, wherein X is H or C 1-6 alkyl. In some embodiments, X is H. In some embodiments, X is C 1-6 alkyl. In some embodiments, X is methyl.
• one or more R B groups are independently C 1-6 alkyl substituted with one, two, three, four, five, or more halo. In some embodiments, an R B group is C 1-6 alkyl substituted with one, two, three, four, five, or more halo.
• ring B is C 5-7 cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon.
• one or more R B groups are independently halo or C 1-6 alkyl optionally substituted with one or more halo.
• R C2 is -NR c14 C(O)OR c15 , wherein R c14 and R c15 are each independently hydrogen, C 3- 10 cycloalkyl, or C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.
• R C1 -R C4 are each independently -O-S(O) 2 R c19 , wherein R c19 is as defined elsewhere herein.
• ring B is unsubstituted cyclopentyl and at least one of Z 1 -Z 4 is -S(O) 2 -(3- to 10- membered heterocycloalkyl) is substituted with one or more halo.
• ring B is unsubstituted cyclohexyl, ring A is and at least one of R C1 -R C4 is R F C1 C4 , wherein R -R and R F are as as defined elsewhere herein.
• ring B is 5- to 7-membered heterocycloalkyl optionally substituted with 1-4 R B , and at least one of Z 1 -Z 4 is -S(O) 2 -(3- to 10-membered heterocycloalkyl) is optionally substituted with one or more halo, wherein R B is as defined elsewhere herein.
• cycloalkyl or heterocycloalkyl groups include spiro groups. In some embodiments, cycloalkyl or heterocycloalkyl groups include fused groups.
• ring A is C 6-14 aryl or 5- to 12-membered heteroaryl, each optionally substituted. In some embodiments, ring A is optionally substituted C 6-14 aryl. In some embodiments, ring A is optionally substituted phenyl. In some embodiments, ring A is optionally substituted 5- to 12-membered heteroaryl. In some embodiments, ring A is optionally substituted 6-membered heteroaryl.
• ring A is optionally substituted 5-membered heteroaryl.
• ring A is indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each optionally substituted.
• ring A is optionally substituted thiophenyl.
• ring A is optionally substituted phenyl.
• ring A is optionally substituted 5- to 12-membered heteroaryl.
• ring A is optionally substituted 6-membered heteroaryl. In some embodiments, ring A is optionally substituted 5- membered heteroaryl. In some embodiments, ring A is pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, or oxazolyl. In some embodiments, ring A is is or . [0088] In some embodiments of Formula (II), R a4 is hydrogen or C 1-6 alkyl. In some embodiments, R a4 is hydrogen. In some embodiments, R a5 is hydrogen or C 1-6 alkyl. In some embodiments, R a5 is tert-butyl.
• R a10 is C 3-10 cycloalkyl. In some embodiments, R a10 is cyclopentyl. In some embodiments, -S(O)R a11 is . In some embodiments, R a11 is C 3-10 cycloalkyl. In some embodiments, R a11 is cyclopentyl. In some embodiments, -S(O)(NR a12 )R a13 is or a12 . In some embodiments, R is hydrogen or C 1-6 alkyl. In some embodiments, R a12 is hydrogen or methyl. In some embodiments, R a13 is C 3-10 cycloalkyl. In some embodiments, R a13 is cyclopentyl.
• -S(O) 2 NR a14 R a15 is some embodiments, -S(O) 2 NR a14 R a15 is , , , , , , , , , , , , . In some embodiments, - S(O) 2 NR a14 R a15 is , , , or .
• R a14 and R a15 are each independently hydrogen or C 1-6 alkyl. In some embodiments, R a14 is hydrogen and R a15 is butyl. In some embodiments, R a15 is tert-butyl. In some embodiments, -S(O) 2 R a16 is , , , , , , , , , , , o , , or . In some embodiments, -S(O) 2 R a16 is , , , or . In some embodiments, - S(O) 2 R a16 is , or .
• R a16 is C 3-10 cycloalkyl; or 3- to 12-membered heterocycloalkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of C 1-6 alkyl or halo.
• -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 is -C(O)NR a19 R a20 or - (CR a17 R a18 )C(O)NR a19 R a20 .
• -(CR a17 R a18 )0-1C(O)NR a19 R a20 is - C(O)NR a19 R a20 .
• -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 is - (CR a17 R a18 )C(O)NR a19 R a20 .
• R a17 and R a18 are each independently hydrogen or C 1-6 alkyl.
• R a17 and R a18 are each hydrogen.
• R a19 and R a20 are each independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl.
• R a21 is hydrogen, C 3-10 cycloalkyl, or C 1-6 alkyl optionally substituted with one or more C 3-10 cycloalkyl.
• -SR a21 is or .
• R a22 is hydrogen, C 3-10 cycloalkyl, or C 1-6 alkyl optionally substituted with one or more C 3-10 cycloalkyl.
• -C(O)R a22 is , or .
• R a23 and R a24 are each indeendently hydrogen, C 3-10 cycloalkyl, or C 1-6 alkyl optionally substituted with one or more C 3-10 cycloalkyl.
• -P(O)(R a23 )(R a24 ) is .
• R 24 is hydrogen, C 3-10 cycloalkyl, or C 1-6 alkyl optionally substituted with one or more C 3-10 cycloalkyl.
• Z 1 -Z 4 are each independently C 1-6 alkyl substituted with one or more substituents independently selected from the group consisting of -OH, cyano, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo or C 1-3 alkyl.
• Z 1 -Z 4 are each indepednetly , , , , , , , or [0089]
• Z 6 is 3- to 10-membered heterocycloalkyl.
• Z 6 is .
• R a26 is hydrogen or C 1-6 alkyl.
• R a27 is hydrogen.
• R a27 and R a28 are each independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl.
• R a27 and R a28 are each independently hydrogen, cyclopropyl, ethyl, or isopropyl.
• R a33 is C 3-10 cycloalkyl. In some embodiments, R a33 is cyclopentyl. In some embodiments, -S(O)(NR a34 )R a35 is or . In some embodiments, R a34 is hydrogen or C 1-6 alkyl. In some embodiments, R a34 is hydrogen or methyl. In some embodiments, R a35 is C 3-10 cycloalkyl. In some embodiments, R a35 is cyclopentyl. In some embodiments, -S(O) 2 NR a34 R a35 is , , , , , , , , , .
• - S(O) 2 NR a34 R a35 is or .
• -S(O) 2 NR a34 R a35 is , HO , or .
• R a36 and R a37 are each independently hydrogen or C 1-6 alkyl.
• R a36 is hydrogen and R a37 is butyl.
• R a37 is tert-butyl.
• -S(O) 2 R a38 is , , , or .
• - S(O) 2 R a38 is , , , , , , , o .
• -S(O) 2 R a38 is , , , , , , , , , or .
• R a38 is C 3-10 cycloalkyl; or 3- to 12-membered heterocycloalkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of C 1-6 alkyl or halo.
• -SR a39 is .
• R a39 is C 3-10 cycloalkyl.
• R a40 is C 3-10 cycloalkyl.
• -C(O)R a40 is .
• Z 7 is - OH.
• Z 7 is H.
• Z 8 is C 1-6 alkyl.
• Z 8 is C 3-10 cycloalkyl optionally substituted with one ore more halo.
• Z 8 is 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo.
• -CH(Z 7 )(Z 8 ) is , , [0090]
• Z 1 , Z 2 , Z 3 , and Z 4 are each independently selected from the group consisting of fluoro, chloro, -OH, amino, -CH 2 OH, , ,
• Z 1 , Z 2 , Z 3 , and Z 4 are each independently selected from the group consisting of –CH2OH, , , , , , , , , , , and .
• ring A is bi-subsittuted phenyl. In some embodiments, ring A is selected from the group consisting of , and .
• ring B is C 5-7 cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon.
• ring B is C 5-7 cycloalkyl.
• ring B is cyclopentyl, cyclohexyl, or cycloheptyl.
• ring B is or , wherein * denotes the point of attachment to the rest of Formula (II).
• ring B is C 5-7 cycloalkenyl.
• ring B is cyclopentenyl, cyclohexenyl, or cycloheptenyl. In some embodiments, ring B is , wherein * denotes the point of attachment to the rest of Formula (II). In some embodiments, ring B is , wherein * denotes the point of attachment to the rest of Formula (II). In some embodiments, ring B is 5- to 7-membered heterocycloalkyl. In some embodiments, ring B is 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon.
• ring B is tetrahydrofuranyl or 1,3- dioxanyl. In some embodiments, ring B is or , wherein * denotes the point of attachment to the rest of Formula (II). [0092] In some embodiments of Formula (II), ring B is substituted with m R B groups, wherein each R B group is independently halo, C 1-6 alkyl optionally substituted with one, two, three, four, five, or more halo, or C 2-6 alkenyl; or two vicinal R B groups are taken together with the carbon atoms to which they are attached to form C 3-10 cycloalkyl; or two geminal R B groups are taken together with the carbon atom to which they are attached to form C 3-10 cycloalkyl.
• an R B group is methyl or ethyl.
• two vicinal R B groups are taken together with the carbon atoms to which they are attached to form cyclopropyl.
• two geminal R B groups are taken together with the carbon atom to which they are attached to form cyclopropyl.
• m is 0, 1, 2, 3, or 4.
• m is 0, 1, 2, or 3.
• m is 0, 1, or 2.
• m is 0 or 1.
• m is 0.
• m is 1. , or wherein * denotes the point of attachment to the rest of Formula (II).
• Y 1 is N or CR C1 ; Y 2 is N or CR C2 ; Y 3 is N or CR C3 ; and Y 4 is N or CR C4 . In some embodiments, no more than three of Y 1 , Y 2 , Y 3 , and Y 4 are N.
• Y 1 , Y 2 , Y 3 , and Y 4 are N. In some embodiments, no more than one of Y 1 , Y 2 , Y 3 , and Y 4 is N. In some embodiments, Y 1 is CR C1 ; Y 2 is CR C2 ; Y 3 is CR C3 ; and Y 4 is CR C4 . In some embodiments, Y 1 is N; Y 2 is CR C2 ; Y 3 is CR C3 ; and Y 4 is CR C4 .
• R C1 is hydrogen or halo. In some embodiments, R C1 is hydrogen or fluoro. In some embodiments, R C3 is hydrogen. In some embodiments, R C4 is hydrogen or -NH2. In some embodiments, R C1 , R C3 , and R C4 are each independently hydrogen, halo, or -NH2. [0098] In some embodiments of Formula (II), R C2 is cyano, -OH, -CH 2 OH, fluro, bromo, NO2, , , , , , , , , , , or , or . , , , or .
• R C2 is cyano, - OH, -CH2OH, bromo, -NO2, , , , , , or . In some embodiments, R C2 is , , , , or .
• R C2 is -O-S(O) 2 R c19 .
• -C(O)NR c1 R c2 is .
• R c1 and R c2 are each independently hydrogen or C 1-6 alkyl.
• R c1 and R c2 are each independently hydrogen, methyl, or ethyl.
• -NR c3 R c4 is .
• R c3 and R c4 are each independently hydrogen or C 1-6 alkyl.
• R c1 and R c2 are each independently hydrogen, methyl, or ethyl.
• -NR c5 S(O) 2 R c6 is , , , , or . In some embodiments, -NR c5 S(O) 2 R c6 is or . In some embodiments, R c5 is hydrogen or C 1-6 alkyl. In some embodiments, R c5 is hydrogen, methyl, or ethyl. In some embodiments, R c6 is hydrogen or C 1-6 alkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from halo, –OH, -O(C 1-6 alkyl), and –NHC(O)(C 1-6 alky).
• R c9 and R c10 are each independently C 1-6 alkyl. In some embodiments, R c9 and R c10 are each methyl. In some embodiments, -S(O)(NR c11 )R c12 is or . In some embodiments, R c11 is hydrogen or C 1-6 alkyl. In some embodiments, R c11 is hydrogen or methyl. In some embodiments, R c12 is C 1-6 alkyl or C 3-10 cycloalkyl. In some embodiments, R c12 is cyclopropyl. In some embodiments, -S(O) 2 R c13 is . In some embodiments, R c13 is C 1-6 alkyl.
• R c13 is methyl.
• NR c14 C(O)OR c15 is .
• R c14 and R c15 are each independently hydrogen or C 1-6 alkyl.
• R c14 is hydrogen.
• R c15 is ethyl.
• -NR c16 S(O) 2 (CH2)1- 6NR c17 C(O)R c18 is .
• -NR c16 S(O) 2 (CH 2 ) 1- 6 NR c17 C(O)R c18 is -NR c16 S(O) 2 (CH 2 ) 1- 3 NR c17 C(O)R c18 .
• R c16 , R c17 and R c18 are each independently hydrogen or C 1-6 alkyl.
• R c16 and R c17 are hydrogen.
• R c18 is methyl.
• any of the compounds described herein, such as a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II), or any variation thereof, or a compound of Table 1 or 2 may be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites.
• Deuterated compounds can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non- deuterated compounds. Hydrogen atoms may also be replaced with deuterium atoms using other method known in the art.
• Any formula given herein, such as Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II) is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
• compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered within the scope of the formula.
• any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio.
• certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers.
• any formula given herein is intended to refer also to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not listed explicitly.
• the solvent is water and the solvates are hydrates.
• the compounds herein are synthetic compounds prepared for administration to an individual.
• compositions are provided containing a compound in substantially pure form.
• pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
• methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
• compositions such as pharmaceutical compositions, that include a compound disclosed and/or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, carriers, excipients, and the like.
• suitable medicinal and pharmaceutical agents include those described herein.
• the pharmaceutical composition includes a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity as described herein.
• pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, and magnesium carbonate.
• compositions such as pharmaceutical compositions that contain one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
• a pharmaceutically acceptable composition comprising a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II), or a compound of Table 1 or 2, or a pharmaceutically acceptable salt thereof.
• a composition may contain a synthetic intermediate that may be used in the preparation of a compound described herein.
• the compositions described herein may contain any other suitable active or inactive agents.
• Any of the compositions described herein may be sterile or contain components that are sterile. Sterilization can be achieved by methods known in the art.
• compositions described herein may contain one or more compounds that are substantially pure.
• packaged pharmaceutical compositions comprising a pharmaceutical composition as described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.
• Methods of Use [0114]
• the compounds of the present disclosure are inhibitors of KIF18A.
• the compounds and pharmaceutical compositions herein may be used to inhibit KIF18A.
• the compounds and pharmaceutical compositions herein may be used to treat or prevent a disease or condition in an individual.
• the inhibitory activity of the compounds described herein against KIF18A may be determined and measured by methods known in the art including, but not limited to, inhibition of ATP hydrolysis in the presence of microtubules (Hackney D.D., Jiang W. (2001) Assays for Kinesin Microtubule-Stimulated ATPase Activity. In: Vernos I. (eds) Kinesin Protocols. Methods in Molecular BiologyTM, vol 164. Humana Press. https://doi.org/10.1385/1-59259-069-1:65).
• a method of inhibiting KIF18A comprising contacting a cell with an effective amount of a compound or a pharmaceutical composition as described herein.
• provided herein are methods of inhibiting KIF18A comprising contacting a cell with an effective amount of a compound of Formula (I), (I-1), (I- 2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or 2, or a pharmaceutically acceptable salt thereof.
• methods of inhibiting KIF18A comprising contacting a cell with an effective amount of a pharmaceutical composition comprising a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II)or a compound of Table 1 or 2, or a pharmaceutically acceptable salt thereof.
• the cell is contacted in vitro.
• the cell is contacted in vivo.
• the compounds and pharmaceutical compositions herein may be used to treat or prevent a disease or condition in an individual, comprising administering an effective amount of a compound or a pharmaceutical composition as described herein.
• the compounds disclosed and/or described herein may prevent a disease or disorder from developing in an individual at risk of developing the disease or disorder, or lessen the extent of a disease or disorder that may develop.
• provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition as described herein.
• provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a compound Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or 2, or a pharmaceutically acceptable salt thereof.
• methods of treating or preventing a disease or condition in an individual comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound a compound Formula (I), (I-1), (I-2), (I- 3), (Ia1), (Ia2) or (II), or a compound of Table 1 or 2, or a pharmaceutically acceptable salt thereof.
• the disease or condition is mediated by KIF18A.
• the disease or condition is cancer.
• the disease or condition is a cellular proliferation disorder, including uncontrolled cell growth, aberrant cell cycle regulation, centrosome abnormalities (structural and or numeric, fragmentation), a solid tumor, hematopoietic cancer and hyperproliferative disorder, such as thyroid hyperplasia (especially Grave's disease), and cyst (such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome).
• Solid and hematologically derived tumors may include but are not limited to cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung (including squamous cell and small cell lung cancer), pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gall-bladder, ovary, testicle, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, and skin (including squamous cell carcinoma), hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodg
• provided are methods of treating or preventing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein.
• Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or 2, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a disease in a subject.
• methods of treating cancer comprising administering to an individual in need thereof a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or 2, or a pharmaceutically acceptable salt thereof.
• methods of treating a disease or condition mediated by KIF18A in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition as described herein.
• methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition as described herein.
• the cancer is selected from the group consisting of carcinomas, cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung, pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gall-bladder, ovary, testicle, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, or skin, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, hematopoietic tumors of any lineage, myeloma, tumors of mesenchymal origin including sarcomas, tumors of the central and peripheral nervous system, tumor of neuroendocrine origin, tumor of endocrine origin, small cell tumors,
• a daily dose ranges from about 0.01 to 100 mg/kg of body weight; in some embodiments, from about 0.05 to 10.0 mg/kg of body weight, and in some embodiments, from about 0.10 to 1.4 mg/kg of body weight.
• the dosage range would be about from 0.7 to 7000 mg per day; in some embodiments, about from 3.5 to 700.0 mg per day, and in some embodiments, about from 7 to 100.0 mg per day.
• an exemplary dosage range for oral administration is from about 5 mg to about 500 mg per day
• an exemplary intravenous administration dosage is from about 5 mg to about 500 mg per day, each depending upon the compound pharmacokinetics.
• Administration of the compounds and compositions disclosed and/or described herein can be via any accepted mode of administration for therapeutic agents including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration.
• the compound or composition is administered orally or intravenously.
• the compound or composition disclosed and/or described herein is administered orally.
• Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablet, capsule, powder, liquid, suspension, suppository, and aerosol forms.
• the compounds disclosed and/or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled/sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms) for prolonged timed, and/or pulsed administration at a predetermined rate.
• the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
• the compounds disclosed and/or described herein can be administered either alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate).
• the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate).
• auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate).
• the pharmaceutical composition will contain about 0.005% to 95%, or about 0.5% to 50%, by weight of a compound disclosed and/or described herein. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
• the compositions will take the form of a pill or tablet and thus the composition may contain, along with a compounds disclosed and/or described herein, one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and/or a binder (e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives).
• a diluent e.g., lactose, sucrose, dicalcium phosphate
• a lubricant e.g., magnesium stearate
• a binder e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives.
• Other solid dosage forms include a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides)
• Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing or suspending etc. a compound disclosed and/or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension.
• a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like
• injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection.
• the percentage of the compound contained in such parenteral compositions depends, for example, on the physical nature of the compound, the activity of the compound and the needs of the subject.
• compositions of the compounds disclosed and/or described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
• the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.
• compositions can include a compound disclosed and/or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, and the like. Suitable medicinal and pharmaceutical agents include those described herein.
• Kits [0132] Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein.
• the article of manufacture may comprise a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container may hold a pharmaceutical composition provided herein.
• the label on the container may indicate that the pharmaceutical composition is used for preventing, treating or suppressing a condition described herein, and may also indicate directions for either in vivo or in vitro use.
• kits containing a compound or composition described herein and instructions for use may contain instructions for use in the treatment of any disease or condition described herein in an individual in need thereof.
• a kit may additionally contain any materials or equipment that may be used in the administration of the compound or composition, such as vials, syringes, or IV bags.
• a kit may also contain sterile packaging.
• Combinations [0134] The compounds and compositions described and/or disclosed herein may be administered alone or in combination with other therapies and/or therapeutic agents useful in the treatment of the aforementioned disorders. [0135] The compounds and compositions described and/or disclosed herein may be combined with one or more other therapies to treat the diseases or conditions described herein.
• the disease or condition is cancer.
• the disease or condition is a cellular proliferation disorder, including uncontrolled cell growth, aberrant cell cycle regulation, centrosome abnormalities (structural and or numeric, fragmentation), a solid tumor, hematopoietic cancer and hyperproliferative disorder, such as thyroid hyperplasia (especially Grave's disease), and cyst (such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome).
• Solid and hematologically derived tumors may include but are not limited to cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung (including squamous cell and small cell lung cancer), pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gall-bladder, ovary, testicle, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, and skin (including squamous cell carcinoma), hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodg
• protecting groups may be used to protect certain functional groups (amino, carboxy, or side chain groups) from reaction conditions, and that such groups are removed under standard conditions when appropriate.
• the variables are as defined above in reference to Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II).
• this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
• diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound.
• the diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered.
• a racemate may be separated using chiral High Performance Liquid Chromatography.
• a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
• Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
• Scheme 1 outlines an exemplary route to the synthesis of compound of general formula I.
• an acid scavenger such as Et3N.
• Indoline intermediates of formula B may be prepared via the Fisher Indole Synthesis as described in Scheme 2.
• Arylhydrazines of formula C (e.g., formula C-i, formula C-ii, and formula C-iii) are reacted with a Ring B-substituted carbaldehyde of formula D in the presence of acid, followed by reaction with a reducing agent such as NaBH4, Pd/C and H2 gas, or Et 3 SiH.
• Arylhydrazines of formula C-i which are para-mono-substituted, provide indolines of formula B-i
• hydrazines of formula C-ii which contain at least one meta substituent and are not substituted in the ortho positions, provide a mixture of indolines of formulae B-ii-a and B-ii-b.
• Indolines of formula B may also be prepared via an 3,3-dialkylation method described in Scheme 3.
• An indole of formula D is reacted with an optionally substituted 3-6 atom aliphatic and heteroaliphatic linear chain with two terminal leaving groups “LG” (formula E).
• LG may be Cl, Br, I, or sulfonate ester, or another suitable group displaceable by a nucleophile.
• the transformation may be mediated by a trialkylboron, such as Et 3 B, and base, such as potassium t-butoxide.
• Indolines of formula B may also be prepared via the enolate alkylation of an indolin-2-one of formula F.
• the indolin-2-one of formula F is deprotonated with a strong base, such as butyllithium, sodium hexamethylsilazide, or potassium t-butoxide, and reacted with an optionally substituted 3-6 atom aliphatic and heteroaliphatic linear chain with two terminal leaving groups “LG” (formula E).
• LG may be Cl, Br, I, or sulfonate ester, or another suitable group displaceable by a nucleophile.
• This reaction may be mediated by an additive such as tetramethyldiaminoethane or hexamethylphosphorous triamide.
• the spiroannulation reaction is followed by a reaction with a reducing agent such as LiAlH4 or borane.
• a reducing agent such as LiAlH4 or borane.
• R a1 is hydrogen or C 1-6 alkyl
• R a2 and R a3 are each independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl
• R a4 is hydrogen or C 1-6 alkyl
• R a5 is hydrogen or C 1-6 alkyl
• R a6 and R a7 are each independently hydrogen, C 1-6 alkyl, or 5- to 12-membered heteroaryl optionally substituted with C 1-6 alkyl
• R a8 and R a9 are each independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl
• R a10 is C 3-10 cycloalkyl
• R a11 is C 3-10 cycloalkyl
• R a12 is hydrogen or C 1-6 alkyl
• R a13 is C 3-10 cycloalkyl
• R a16 is C 3-10 cycloalkyl or 3- to 12-membered heterocycloal
• 21. A pharmaceutical composition comprising a compound of any one of embodiments 1- 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
• 22. A method of inhibiting KIF18A comprising contacting a cell with an effective amount of a compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 21. 23.
• a method of treating a disease or condition mediated by KIF18A in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 21.
• a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1- 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 21. 25.
• the cancer is selected from the group consisting of carcinomas, cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung, pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gall-bladder, ovary, testicle, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, or skin, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, hematopoietic tumors of any lineage, myeloma, tumors of mesenchymal origin including sarcomas, tumors of the central and peripheral nervous system, tumor of neuroendocrine origin, tumor of endocrine origin, small cell tumor
• ring A is indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each optionally substituted.
• R a1 is hydrogen or C 1-6 alkyl
• R a2 and R a3 are each independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl
• R a4 is hydrogen or C 1-6 alkyl
• R a5 is hydrogen or C 1-6 alkyl
• R a6 and R a7 are each independently hydrogen, C 1-6 alkyl, or 5- to 12- membered heteroaryl optionally substituted with C 1-6 alkyl
• R a8 and R a9 are each independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl
• R a10 is C 3-10 cycloalkyl
• R a11 is C 3-10 cycloalkyl
• R a12 is hydrogen or C 1-6 alkyl
• R a13 is C 3-10 cycloalkyl
• R a16 is C 3-10 cycloalkyl or 3- to 12-membered hetero
• 52. A pharmaceutical composition comprising a compound of any one of embodiments 26-51, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
• 53. A method of inhibiting KIF18A comprising contacting a cell with an effective amount of a compound of any one of embodiments 26-51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 52. 54.
• a method of treating a disease or condition mediated by KIF18A in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 26-51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 52.
• a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 26- 51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 52. 56.
• cancer is selected from the group consisting of carcinomas, cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung, pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gall-bladder, ovary, testicle, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, or skin, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, hematopoietic tumors of any lineage, myeloma, tumors of mesenchymal origin including sarcomas, tumors of the central and peripheral nervous system, tumor of neuroendocrine origin, tumor of endocrine origin, small cell
• R a1 is hydrogen or C 1-6 alkyl
• R a2 and R a3 are each independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl
• R a4 is hydrogen or C 1-6 alkyl
• R a5 is hydrogen or C 1-6 alkyl
• R a6 and R a7 are each independently hydrogen, C 1-6 alkyl, or 5- to 12- membered heteroaryl optionally substituted with C 1-6 alkyl
• R a8 and R a9 are each independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl
• R a10 is C 3-10 cycloalkyl
• R a11 is C 3-10 cycloalkyl
• R a12 is hydrogen or C 1-6 alkyl
• R a13 is C 3-10 cycloalkyl
• R a16 is C 3-10 cycloalkyl or 3- to 12-membered
• a pharmaceutical composition comprising a compound of any one of embodiments 57-83, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
• a method of inhibiting KIF18A comprising contacting a cell with an effective amount of a compound of any one of embodiments 57-83, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 84.
• a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 57- 83, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 84. 88.
• cancer is selected from the group consisting of carcinomas, cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung, pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gall-bladder, ovary, testicle, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, or skin, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, hematopoietic tumors of any lineage, myeloma, tumors of mesenchymal origin including sarcomas, tumors of the central and peripheral nervous system, tumor of neuroendocrine origin, tumor of endocrine origin, small
• Step 2 A mixture of methyl 3-cyclopentylsulfinylbenzoate (0.50 g, 2.0 mmol), THF (10 mL), H2O (10 mL), and LiOH (95 mg, 4.0 mmol) was stirred at 25 °C for 2 h, and then was concentrated.
• Step 2 To a 0 °C mixture of methyl 3-(cyclopentylsulfonimidoyl) benzoate (0.25 g, 0.94 mmol) and DMF (2 mL) was added NaH (60% in mineral oil, 45 mg, 1.1). The mixture was stirred at 0 °C for 0.5 h, and MeI (64 ⁇ L, 1.0 mmol) was added.
• Step 2 A degassed mixture of methyl 3-(cyclopentanecarbonyl) benzoate (0.22 g, 0.95 mmol), LiOH (0.11 g, 4.7 mmol), THF (0.9 mL), H 2 O (0.3 mL) was stirred at 25 °C for 4 h.
• Step 1 To a mixture of 3-bromobenzonitrile (2.0 g, 11 mmol) and THF (10 mL) at -50 °C was added CuI (2.1 g, 11 mmol) and bromo(cyclobutylmethyl)magnesium (1 M, 13.2 mL). The mixture was stirred at -50 °C for 5 h then at 20 °C for 1 h. The mixture was poured into H 2 O (20 mL) and extracted with EtOAc (2 x 20 mL).
• Step 3 A mixture of methyl 3-(2-cyclobutylacetyl)benzoate (0.50 g, 2.2 mmol), THF (0.6 mL), H2O (0.2 mL), and LiOH (0.16 g, 6.7 mmol) was stirred at 20 °C for 2 h.
• Step 2 To a mixture of methyl 3-(2-cyclopentyl-1,3-dithiolan-2-yl)benzoate (0.20 g, 0.65 mmol) and CH 2 Cl 2 (10 mL) was added NIS (0.29 g, 1.3 mmol) and pyridine hydrofluoride (0.33 mL, 2.6 mmol) at - 70 °C.
• Step 2 A mixture of methyl 2-(cyclopentyl(hydroxy)methyl)isonicotinate (0.18 g, 0.77 mmol), THF (2 mL), and H2O (1 mL), and LiOH•H2O (96 mg, 2.0 mmol) was stirred at 25 °C for 2 h, poured into water (30 mL), and extracted with MTBE (2 x 20 mL).
• Step 2 To a mixture of 1-bromo-3-but-3-enylsulfanyl-benzene (6.5 g, 27 mmol) and CH 2 Cl 2 (50 mL) was added mCPBA (27 g, 0.13 mol, 85% purity).
• Step 4 To a mixture of 3-(3-bromophenyl)sulfonylcyclobutanol (1.00 g, 3.4 mmol), H2O (10 mL), MeCN (5 mL), and CH2Cl2 (5 mL) at 40 °C were added RuCl3•H2O (8 mg, 34 ⁇ mol) and NaIO 4 (3.7 g, 17 mmol).
• Step 2 To a mixture of methyl 5-cyclopentylsulfanylthiophene-3- carboxylate (0.70 g, 2.9 mmol) and CH2Cl2 (20 mL) was added mCPBA (2.4 g, 12 mmol, 85% purity).
• Step 1 A mixture of methyl 3-acetylbenzoate (1.0 g, 5.6 mmol) and 4,4- difluoropiperidine hydrochloride (0.88 g, 5.6 mmol), 1,2-dichloroethane (20 mL), Ti(OiPr)4 (6.6 mL, 23 mmol) and then was stirred at 80 °C for 12 h. NaBH(OAc)3 (3.6 g, 17 mmol) was added and the mixture was stirred at 80 °C for 2 h, poured into water (20 mL), and extracted with EtOAc (2 x 20 mL).
• Step 2 A mixture of isopropyl 3-[1-(4,4-difluoro-1-piperidyl)ethyl]benzoate (1.4 g, 4.6 mmol) in THF (14 mL), MeOH (3.3 mL), and H2O (3.3 mL), and LiOH (0.33 g, 14 mmol) was stirred at 25 °C for 2 h.
• Step 2 A mixture of methyl 3-(cyclopentylamino)benzoate (0.10 g, 0.46 mmol), THF (0.9 mL), H2O (0.3 mL), and LiOH•H2O (96 mg, 2.3 mmol) was stirred at 60 °C for 6 h, poured into H 2 O (10 mL), and the pH adjusted to 5-6 with HCl (2 N).
• Step 3 A mixture methyl 3-(3,3-difluorocyclobutanecarbonyl)benzoate (0.80 g, 3.2 mmol), THF (0.6 mL), H2O (0.2 mL), and LiOH•H2O (226 mg, 9.4 mmol, 3.0 eq) The mixture was stirred at 20 °C for 2 h, concentrated, and HCl (0.5 M, 5 mL) was added.
• Step 1 To a mixture of 1-bromo-3-ethoxyphosphonoyl-benzene (1.8 g, 7.2 mmol) and DMF (20 mL) was added NaH (0.87 g, 22 mmol, 60% purity) at 0 °C. The mixture was stirred for 30 min and iodomethylcyclobutane (1.6 mL, 14 mmol) was added. The mixture was stirred at 0-20 °C for 60 min, poured into saturated NH 4 Cl (20 mL), and extracted with EtOAc (2 x 10 mL).
• Step 3 A mixture of 1-bromo-3-[cyclobutylmethyl(methyl)phosphoryl]benzene (0.49 g, 1.7 mmol), MeOH (4 mL), 1,4-dioxane (4 mL), Mo(CO)6 (0.11 g, 0.43 mmol), K3PO4 (0.36 g, 1.7 mmol), DMAP (0.10 g, 0.85 mmol), Xantphos (99 mg, 0.17 mmol), and Pd(OAc) 2 (19 mg, 85 ⁇ mol) was stirred at 120 °C for 3 h. The reaction was poured into water (20 mL) and the resulting mixture was extracted with EtOAc (2 x 15 mL).
• Step 4 A mixture of (4-fluoro-4-methyl-cyclohexyl)methanol (0.70 mg, 4.8 mmol), CH2Cl2 (20 mL), NaHCO3 (3.2 g, 38 mmol), and Dess-Martin periodinane (4.1 g, 9.6 mmol) was stirred at 25 °C for 2 hours.
• Step 1 Dispiro[cyclopropane-1,1'-cyclohexane-4',3'-indole] was prepared from phenylhydrazine and spiro[2.5]octane-6-carbaldehyde in the manner described in Step 4a of the synthesis of B-01. [0221] Step 2.
• the reaction mixture was stirred at 140 °C in a microwave reactor for 3 h.
• the reaction mixture was diluted with water 30 mL and extracted with 1:1 EtOAc / THF (15 mL x 2).
• the extracts were combined, washed with H2O (10 mL x 3) and brine (10 mL), dried over Na 2 SO 4 , filtered, concentrated, and purified by silica chromatography (0-10% [1:1 THF/EtOAc] in petroleum ether) to provide 2-[(tert- butyldimethylsilyl)oxy]-N- ⁇ 1'',2''-dihydrodispiro[cyclopropane-1,1'-cyclohexane-4',3''-indol]- 5''-yl ⁇ ethane-1-sulfonamide (70 mg).
• Step 3 A mixture of 2-[(tert-butyldimethylsilyl)oxy]-N- ⁇ 1'',2''- dihydrodispiro[cyclopropane-1,1'-cyclohexane-4',3''-indol]-5''-yl ⁇ ethane-1-sulfonamide (60 mg, 0.11 mmol), MeOH (1.0 mL), and HCl (4 M in MeOH, 1.0 mL) was stirred at 25 °C for 5 h.
• Step 1 To a mixture of 5-formylthiophene-3-carboxylic acid (0.12 mg, 0.74 mmol) and DMF (1.5 mL) was added HATU (0.42 g, 1.1 mmol), and iPr 2 NEt (0.39 mL, 2.2 mmol). After stirring for 30 min, B-14 (0.27 mg, 0.88 mmol) was added and the mixture was stirred at 80 °C for 1.5 h, diluted with H2O (4 mL), and extracted with EtOAc (10 mL x 3).
• Step 1 A mixture of 3-vinylbenzoic acid (0.13 g, 0.89 mmol), DMF (3 mL), B-14 (0.30 mg, 0.98 mmol), HOBt (0.24 mg, 1.8 mmol), EDCI (0.34 g, 1.8 mmol), Et3N (0.37 mL, 2.7 mmol) was stirred at 20 °C for 2 h then poured into water (30 mL) and extracted with EtOAc (2 x 30 mL).
• Step 1 A degassed mixture of Compound 9 (0.50 g, 0.94 mmol) and KBF3(vinyl) (0.63 g, 4.7 mmol), K2CO3 (0.65 g, 4.7 mmol), PdCl2 (0.12 g, 0.66 mmol), and DMSO (5 mL) was was stirred at 100 °C for 3 h under an N2 atmosphere.
• Step 2 A mixture of N-(1''-(3-formylbenzoyl)dispiro[cyclopropane-1,1'- cyclohexane-4',3''-indolin]-5''-yl)methanesulfonamide (0.10 g, 0.23 mmol), MeOH (1 mL), THF (1 mL), 3,3-difluoroazetidine hydrochloride (44 mg, 0.34 mmol), and HOAc (26 ⁇ L, 0.46 mmol) was stirred at 20 °C for 2 h and NaBH 3 CN (43 mg, 0.68 mmol) was added and the miixture was stirred at 20 °C for 10 h.
• NaBH 3 CN 43 mg, 0.68 mmol
• Test compounds were plated in a 3x dilution scheme in a 384-well plate.
• Assay buffer 80 mM PIPES (pH 6.9), 1 mM MgCl 2 , 75 mM KCl, 1 mM EGTA, 1 mM DTT, 0.01% BSA, 0.005% Tween-20, 1 ⁇ M Taxol in H 2 O.
• microtubule mix was added [0.2 mg/mL pre-formed microtubules, 2.0 mM ATP in assay buffer], the plate was centrifuged for 30 s and then incubated at 28 °C for 60 min.
• 5 ⁇ L of Promega® ADP-Glo Max R1 was added, the plate was centrifuged for 30s, and the mixture incubated for 4 h at room temperature.
• 10 ⁇ L of Promega® ADP-Glo Max R2 was added, the plate centrifuged for 30 s, and incubated for 60 min at room temperature.
• Luminescence was measured with an Envision plate reader, and %Inhibition was calculated for each well as: ([max – min] – [test – min])/[max – min].
• IC50 values were calculated from concentration vs. % Inhibition data via a four-parameter variable slope model. [0289] Table 9 indicates that compounds as provided herein are potent inhibitors of KIF18a. As a comparison, the data for AMG650 (2- ⁇ 6-azaspiro[2.5]octan-6-yl ⁇ -N-[2-(4,4- difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-4-(2-hydroxyethanesulfonamido)benzamide) is 17 nM.
• Binding kinetics to KIF18a-microtubule complex [0290] Compound binding kinetics parameters (k on and k off ) were determined by the method of global progress curve analysis (GPCA). KIF18A (0.25 nM) was incubated for up to 24 hr with serially diluted compound in the assay buffer containing 80mM PIPES, pH 6.9, 1 mM ATP, 0.1 mg/ml preformed microtubule from porcine brain (Cytoskeleton), 1 mM MgCl 2 , 1 ⁇ M Taxol, 75 mM KCl, 1 mM EGTA, 1 mM DTT, 0.01% BSA and 0.005% Tween- 20.
• GPCA global progress curve analysis
• HCC15 Kerean Cell Line Bank 600 cell/well, 95 ⁇ L of RPMI-1640 media supplemented with 100 units/mL penicillin, 100 units/mL streptomycin and 10% FBS; NIH:OVCAR-3 (ATCC), 1000 cell/well, 95 ⁇ L of RPMI-1640 media supplemented with 100 units/mL penicillin, 100 units/mL streptomycin, 0.01 mg/mL bovine insulin, and 20% FBS; JIMT-1 (Addexbio) 1000 cell/well, 95 ⁇ L of DMEM media supplemented with 100 units/mL penicillin, 100 units/mL streptomycin, and 10% FBS.
• Test compounds were added to cells in a 20x dilution scheme by adding 5 ⁇ L of serially diluted compound to the plate, and the treated cells were incubated for an additional 7 days in a 37 °C, 5% CO 2 incubator.
• DMSO was used as the negative control (0% effect), and wells omitting cells were used as the positive control (100% effect).
• the cells were incubated for seven days, and cell viability determined via the Promega Cell Titre-Glo® Assay kit. Luminescence units were converted to ATP concentrations via an ATP standard curve (10 point, 2-fold dilution from 5 uM).
• %Inhibition was calculated for each well as: ([max – min] – [test – min])/[max – min].
• IC50 values were calculated from concentration vs. %Inhibition data via a four-parameter variable slope model. Results from the biological assay are summarized in Table 10. [0294] Table 11 indicates that compounds as provided herein potently inhibit cell growth or induce cell killing for KIF18a-senstive cancer cell lines.
• OVCAR-3 (ATCC) tumor cells were maintained in vitro in RPMI-1640 medium supplemented with 20% fetal bovine serum, 0.01 mg/mL bovine insulin and 1% Anti-Anti at 37oC in an atmosphere of 5% CO2 in air.
• HCC15 (DSMZ) tumor cells were maintained in vitro in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% Anti-Anti at 37oC in an atmosphere of 5% CO 2 in air.
• the tumor cells were sub-cultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
• Tumor cells (10 x 10 6 ) in 0.2 mL of PBS mixed with Matrigel (50:50) were inoculated subcutaneously on the right flank of each mouse. When the average tumor volume reached 110-175 mm 3 , animals were randomized into groups of 10 and treatment started. OVCAR-3 cells were implanted in Balb/C nude mice, and HCC15 cell were implanted in SCID Beige mice. [0299] Compounds were dosed once or twice a day (12h) orally.
• TGI Tumor Growth Inhibition

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