+

WO2025007055A1 - Inhibiteurs d'aryl indol-3-yl cétone et d'aryl indazol-3-yl cétone de kif18a - Google Patents

Inhibiteurs d'aryl indol-3-yl cétone et d'aryl indazol-3-yl cétone de kif18a Download PDF

Info

Publication number
WO2025007055A1
WO2025007055A1 PCT/US2024/036249 US2024036249W WO2025007055A1 WO 2025007055 A1 WO2025007055 A1 WO 2025007055A1 US 2024036249 W US2024036249 W US 2024036249W WO 2025007055 A1 WO2025007055 A1 WO 2025007055A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
optionally substituted
group
Prior art date
Application number
PCT/US2024/036249
Other languages
English (en)
Inventor
Derek A. Cogan
Original Assignee
Volastra Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Volastra Therapeutics, Inc. filed Critical Volastra Therapeutics, Inc.
Publication of WO2025007055A1 publication Critical patent/WO2025007055A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—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
    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates generally to inhibitors of KIF18A, compositions thereof, and methods of using said compounds and compositions thereof. More specifically, the present disclosure relates to indole and indazole inhibitors of KIF18A and methods of their use for treating disease mediated by KIF18A, such as cancer.
  • 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 (PPI) and carries it to the plus end of MT where PPI dephosphorylates Heel, a kinetochore complex component, further enhancing kt- MT attachment throughout metaphase and anaphase.
  • PPI 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), 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.
  • 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.
  • the disease or condition is mediated by KIF18A.
  • the disease or condition is cancer.
  • the disease or condition is a cellular proliferation disorder.
  • references to a compound of Formula (I) includes all subgroups of Formula (I) defined herein, such as Formula (la), including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and/or described herein.
  • references to a compound of Formula (I) and subgroups thereof, such as Formula (la) 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) and subgroups thereof, such as Formula (la), include polymorphs, solvates, co-crystals, isomers, tautomers and/or oxides thereof.
  • references to a compound of Formula (I) and subgroups thereof, such as Formula (la) include polymorphs, solvates, and/or cocrystals thereof.
  • references to a compound of Formula (I) and subgroups thereof, such as Formula (la) include isomers, tautomers and/or oxides thereof.
  • references to a compound of Formula (I) and subgroups thereof, such as Formula (la) 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.
  • Ci-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, secbutyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3 -methylpentyl.
  • a range of values e.g., Ci-6 alkyl
  • each value within the range as well as all intervening ranges are included.
  • Ci-6 alkyl includes Ci, C2, C3, C4, C 5 , C 6 , C1-6, C2-6, C3-6, C4-6, C5-6, Ci-5, C2-5, C3-5, C4-5, C , C2-4, C3-4, C1-3, C2-3, and C1-2 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.
  • the group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s).
  • Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2- yl), and butenyl (e.g., but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl).
  • propenyl e.g., prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2- yl
  • butenyl e.g., but-l-en-l-y
  • 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-l-yn-l-yl, prop-2-yn-l-yl) and butynyl (e.g., but-l-yn-l-yl, but-l-yn-3-yl, but-3- yn-l-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).
  • 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-l-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group
  • l,2,3,4-tetrahydronaphthalen-5- yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group.
  • polycyclic cycloalkyl groups consisting of a cycloalkyl group fused to an aromatic ring are described below.
  • 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). Examples of 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). In some instances, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, 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 l,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-l-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) 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).
  • 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. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 1. Unless otherwise indicated, heteroaryl groups may be bound to the parent structure by a carbon or nitrogen atom, as valency permits. For example, “pyridyl” includes 2-pyridyl, 3- pyridyl and 4-pyridyl groups, and “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 pyr
  • both rings of a polycyclic heteroaryl group are aromatic.
  • examples include indole, isoindole, indazole, benzoimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, lH-pyrrolo[2,3-b]pyridine, lH-pyrazolo[3,4-b]pyridine, 3H-imidazo [4,5-b]pyridine, 3H- [ 1 ,2,3 ] triazolo [4,5-b]pyridine, 1 H-pyrrolo [3 ,2-b]pyridine, 1 H-pyrazolo [4,3-b]pyridine, 1 H-imidazo [4,5-b]pyridine, 1 H- [ 1 ,2,3] triazolo [4,5-b]pyridine, lH-pyrrolo[[3 ,2-
  • quinoline is
  • 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 heterocyclo alkyl) 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-l-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-lH-pyrrolyl, 2,5-dihydro-lH-pyrrolyl), dihydroimidazolyl (e.g., 2,3- dihydro-lH-imidazolyl, 4,5-dihydro-lH-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4- dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1, 2,3,4- tetrahydropyridinyl (
  • 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-l-yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group
  • l,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)
  • a non-aromatic ring e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl
  • indenyl 2,3-dihydro-lH-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[l,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[l,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-lH-indazolyl, 2,3-dihydro-lH-benzo[d]imid
  • each ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group is determined by the atom through which the moiety is bound to the parent structure.
  • Halogen or “halo” refers to fluoro, chloro, bromo or iodo.
  • 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.
  • 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, sulfonylamino, sulfonyl, oxo and the like.
  • substituents such as alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino
  • 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.
  • a substituted group or moiety bears five substituents.
  • 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. It will also be understood that where a group or moiety is optionally substituted, 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, n 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.
  • 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.
  • 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.
  • the terms “patient,” “individual,” and “subject” refer to an animal, such as a mammal, bird, or fish.
  • 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.
  • therapeutically 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.
  • L is a bond, CR bl R b2 , or O;
  • R bl and R b2 are each independently H or C1-3 alkyl;
  • ring B is C3-8 cycloalkyl, C5-7 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;
  • each R B group is independently halo, C1-6 alkyl optionally substituted with one 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 C3-10 cycloalkyl; or two geminal R B groups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl;
  • m is 0, 1, 2, 3, or 4;
  • Y 1 is N or CR cl ;
  • Y 2 is N or CR C2 ;
  • Y 3 is N or CR C3 ;
  • Y 4 is N or CH;
  • R C1 , R C2 , and R C3 are each independently hydrogen, halo, cyano, -OH, -OCi-6 alkyl, or Ci-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH;
  • R cl -R c15 are each independently hydrogen, C3-10 cycloalkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.
  • ring A is Ce-14 aryl or 5- to 12-membered heteroaryl, each optionally substituted. In some embodiments, ring A is optionally substituted Ce-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 5- to 10- 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.
  • ring A is furanyl or pyridyl, each optionally substituted.
  • ring A is Ce-14 aryl.
  • ring A is phenyl.
  • ring A is 5- to 12-membered heteroaryl.
  • ring A is 5- to 10-membered heteroaryl.
  • ring A is 6-membered heteroaryl.
  • ring A is 5-membered heteroaryl. In some embodiments, ring A is indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl. In some embodiments, ring A is furanyl or pyridyl.
  • ring A is optionally substituted with one or two substituents independently selected from the group consisting of -S(O)2NR al4 R a15 , -S(O)2R a16 , Ci-6 alkyl optionally substituted with one or more substituents T 1 , and 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T 2 .
  • ring A is substituted with one or two substituents independently selected from the group consisting of -S(O)2NR al4 R a15 , -S(O)2R a16 , Ci-6 alkyl substituted with one or more substituents T 1 , and 3- to 10-membered heterocycloalkyl substituted with one or more substituents T 2 .
  • each T 1 is independently selected from the group consisting of C3-10 cycloalkyl and -OH.
  • each T 2 is independently halo.
  • each T 1 is independently selected from the group consisting of -OH and cyclopentyl.
  • each T 2 is fluoro.
  • ring A is substituted with one or more substituents selected from the group consisting of - S(O)2NR al4 R a15 , -S(O)2R a16 , C1-6 alkyl optionally substituted with one or more substituents T 1 , and 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T 2 ; wherein each T 1 is independently selected from the group consisting of C3-10 cycloalkyl and -OH; and each T 2 is independently halo.
  • ring A is substituted with one or more substituents selected from the group consisting of - S(O)2NR al4 R a15 , -S(O)2R a16 , piperidinyl optionally substituted with one or more fluoro, and alkyl optionally substituted with one or more substituents selected from the group consisting of -OH and cyclopentyl.
  • the 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T 2 is piperidinyl. In some embodiments, the 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T 2 is
  • R al is hydrogen or Ci-6 alkyl. In some embodiments, R al is hydrogen. In some embodiments, R a2 and R a3 are each independently hydrogen, Ci-6 alkyl, or C3-10 cycloalkyl. In some embodiments, R a2 and R a3 are each independently hydrogen, cyclopropyl, ethyl, or isopropyl. In some embodiments, R a4 is hydrogen or C1-6 alkyl. In some embodiments, R a4 is hydrogen. In some embodiments, R a5 is hydrogen or C1-6 alkyl.
  • R 35 is tert-butyl.
  • R a6 and R a7 are each independently hydrogen, C1-6 alkyl, or 5- to 12- membered heteroaryl optionally substituted with C1-6 alkyl.
  • R a6 and R a7 are each independently hydrogen, imidazolyl, methylimidazolyl, or pyrimidinyl.
  • R a8 and R a9 are each independently hydrogen, C1-6 alkyl, or C3-10 cycloalkyl.
  • R a8 and R a9 are each independently methyl or cyclopentyl.
  • -OR al ° is .
  • R al ° is C3-10 cycloalkyl. In some embodiments, R al ° is cyclopentyl. In some embodiments, -S(O)R a11 is . In some embodiments, R al1 is C3-10 cycloalkyl.
  • R al1 is cyclopentyl.
  • -S(O)(NR al2 )R a13 is 17 some embodiments, R is hydrogen or C1-6 alkyl.
  • R al2 is hydrogen or methyl.
  • R al3 is C3-10 cycloalkyl. In some embodiments, R al3 is cyclopentyl.
  • R al6 is C3-10 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 Ci- 6 alkyl and halo. In some embodiments, R al6 is C3-10 cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C1-6 alkyl and halo.
  • -(CR al7 R al8 )o-iC(0)NR al9 R a2 ° is -C(O)NR al9 R a20 or - (CR al7 R al8 )C(O)NR al9 R a20 .
  • -(CR al7 R al8 )o-iC(0)NR al9 R a2 ° is - C(O)NR al9 R a20 .
  • -(CR al7 R al8 )o-iC(0)NR al9 R a2 ° is - (CR al7 R al8 )C(O)NR al9 R a20 .
  • R al7 and R al8 are each independently hydrogen or Ci-6 alkyl. In some embodiments, R al7 and R al8 are each hydrogen. In some embodiments, R al9 and R a20 are each independently hydrogen, Ci-6 alkyl, or C3-10 cycloalkyl. In some embodiments, R al9 and R a20 are each independently hydrogen or cyclopropyl. In some embodiments, -SR 2121 is . In some embodiments, R a21 is C3-10 cycloalkyl. In some embodiments, -C(O)R a22 is . In some embodiments, R a22 is C3-10 cycloalkyl.
  • R al4 is hydrogen; R 15 is tert-butyl; and R 16 is azetidine optionally substituted with one or more halo.
  • ring A is optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting substituent with one or two substituents independently selected from the group consisting of [0045] In some embodiments, ring A is substituted with one, two, three, four, five, or more substituents independently selected from the group consisting some embodiments, ring A is substituent with one or two substituents independently selected from the group consisting
  • L is a bond, CR bl R b2 , or O.
  • L is a bond.
  • L is CR bl R b2 .
  • R bl and R b2 are each independently H or C1-3 alkyl.
  • R bl and R b2 are each independently H.
  • L is O.
  • ring B is C3-8 cycloalkyl, C5-7 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 C3-8 cycloalkyl.
  • ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • ring B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • ring B is
  • ring B is C3-8 cycloalkenyl. 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 substituted with m R B groups, wherein each R B group is independently halo, Ci-6 alkyl, or C2-6 alkenyl; or two vicinal R B groups are taken together with the carbon atoms to which they are attached to form C3-10 cycloalkyl; or two geminal R B groups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl. In some embodiments, two geminal R B groups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl. In some embodiments, an R B group is methyl or ethyl. In some embodiments, an R B group is fluoro.
  • two vicinal R B groups are taken together with the carbon atoms to which they are attached to form cyclopropyl. In some embodiments, two geminal R B groups are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl. In some embodiments, two geminal R B groups are taken together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments, two geminal R B groups are taken together with the carbon atom to which they are attached to form cyclobutyl.
  • 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. In some embodiments, m is 2. wherein * denotes the point of attachment to the rest of Formula (I).
  • 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 CH.
  • no more than three of Y 1 , Y 2 , Y 3 , and Y 4 are N.
  • no more than two of Y 1 , Y 2 , Y 3 , and Y 4 are N.
  • no more than one of Y 1 , Y 2 , Y 3 , and Y 4 is N.
  • R C1 , R C2 , and R C3 are each independently hydrogen, halo, cyano, -OH, -OCi-6 alkyl, or Ci-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.
  • R C1 , R C2 , and R C3 are each independently hydrogen.
  • R c is NR C5 S(O)2R C6 .
  • R cl -R c15 are each independently hydrogen, C3-10 cycloalkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH. In some embodiments, R cl -R c15 are each independently hydrogen or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.
  • C(O)NR cl R c2 is O .
  • R c2 are each independently hydrogen or C1-6 alkyl. In some embodiments, R cl and R c2 are
  • /"M 7 each independently hydrogen, methyl, or ethyl.
  • -NR c3 R c4 is H
  • R c3 and R c4 are each independently hydrogen or C1-6 alkyl. In some embodiments, R cl and R c2 are each independently hydrogen, methyl, or ethyl. [0056] In some embodiments,
  • -NR c5 S(O)2R c6 is H .
  • R c5 is hydrogen or C1-6 alkyl.
  • R c5 is hydrogen, methyl, or ethyl.
  • R c5 is hydrogen.
  • R c6 is hydrogen or C1-6 alkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from halo and - OH.
  • R c5 is methyl or -CH2CH 2 OH.
  • R c5 is methyl.
  • -P(O)R c7 R c8 is I .
  • R c7 and R c8 are each independently C1-6 alkyl.
  • R c7 and R c8 are each methyl.
  • R c9 and R cl ° are each independently C1-6 alkyl. In some embodiments, R c9 and R cl ° are each methyl. In some embodiments, -S(O)(NR cl l )R c12 is . In some embodiments, R cl 1 is hydrogen or C1-6 alkyl. In some embodiments, R cl 1 is hydrogen or methyl. In some embodiments, R cl2 is C1-6 alkyl or C3-10 cycloalkyl. In some embodiments, R cl2 is cyclopropyl.
  • -S(O)2R c13 is .
  • R cl3 is C1-6 alkyl.
  • R cl3 is methyl.
  • R cl4 and R cl5 are each independently hydrogen, C3-10 cycloalkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.
  • ring A is phenyl substituted with S(O)2NR al4 R a15 . In some embodiments, ring A is phenyl substituted some embodiments, ring A is phenyl substituted with
  • L is a bond.
  • L is a bond
  • ring B is cyclopentyl.
  • L is a bond
  • ring B is cyclohexyl.
  • ring A is phenyl substituted bond
  • ring B is cyclopentyl or cyclohexyl
  • R c is -
  • ring A is phenyl substituted bond
  • ring B is cyclopentyl or cyclohexyl
  • R is .
  • ring A is phenyl
  • L is a bond.
  • any of the compounds described herein, such as a compound of Formula (I) or (la), or any variation thereof, or a compound of Table 1 may be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom).
  • the compound is deuterated at a single site.
  • 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) or (la), 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.
  • 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.
  • compositions and methods provided herein embrace all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan.
  • the salts of the compounds provided herein are pharmaceutically acceptable salts.
  • 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. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium croscarmellose, 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) or (la), or a compound of Table 1, 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.
  • compositions described herein may be sterile or contain components that are sterile. Sterilization can be achieved by methods known in the art. Any of the 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.
  • 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.
  • 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.
  • provided herein is a method of inhibiting KIF18A comprising contacting a cell with an effective amount of a compound or a pharmaceutical composition as described herein. In some embodiments, provided herein are methods of inhibiting KIF18A comprising contacting a cell with an effective amount of a compound Formula (I) or (la), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of inhibiting KIF18A comprising contacting a cell with an effective amount of a pharmaceutical composition comprising a compound a compound Formula (I) or (la), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In one variations of the aforementioned embodiments, the cell is contacted in vitro. In other variations of the aforementioned embodiments, 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. In some embodiments, 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) or (la), or a compound of Table 1, or a pharmaceutically acceptable salt thereof.
  • 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 pharmaceutical composition comprising a compound a compound Formula (I) or (la), or a compound of Table 1, 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 lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell- lymphoma, Hodgkin's lymphoma, non-Hodg
  • 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.
  • provided herein are methods of treating cancer, comprising administering to an individual in need thereof a compound of Formula (I) or (la), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I) or (la), or a compound of Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a cancer.
  • kits for 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.
  • cancers are 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, myel
  • 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.
  • the amount of the chemical entity administered will be dependent, for example, on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
  • 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 pharmacokinetic s .
  • 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.
  • 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.
  • sustained or controlled release dosage forms e.g., controlled/sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms
  • 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 croscarmellose, 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).
  • 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 compound 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.
  • composition will comprise from about 0.2 to 2% of a compound disclosed and/or described herein in solution.
  • 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.
  • additional medicinal agents include those described herein.
  • Kits [0091] 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.
  • the kits 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.
  • 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.
  • the diseases or conditions described 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 lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell- lymphoma, Hodgkin's lymphoma, non-Hodg
  • a particular enantiomer of a compound 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. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired 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.
  • compounds provided herein may be synthesized according to Scheme 1, Scheme 2, Scheme 3, and/or Scheme 4.
  • the groups R C6 , Ring A, L, Ring B, Y 4 , m, R B , R al5 , and R al6 , as shown in Schemes 1-4 below, are as defined for the compounds of Formula I.
  • An alternate route to compounds of Formula I proceeds from 6-nitroindole 2-A via two steps to provide ketone 2-E, as outlined in Scheme 2.
  • a Pd-catalyzed addition of 2-A to an aryl nitrile 2-C provides ketone 2-D, followed by alkylation with a base, such as NaH, and an alkylating agent, such as alkyl bromide, to provide 2-E (wherein R represents L, ring B, and 0 to 4 R B ).
  • the steps may also be reversed, where alkylation of 2-A provides indole 2- B and the subsequent Pd-catalyzed addition of 2-B to aryl nitrile 2-C provides 2-E.
  • Reduction of 2-E for example with H2 gas and Pd-C or with Fe and HO Ac, provides aniline 2-F, which may be reacted with sulfonylating agents such as sulfonyl chlorides or sulfonic acid anhydrides in the presence of a base, such as iPr NEt, to provide compounds of Formula I.
  • sulfonylating agents such as sulfonyl chlorides or sulfonic acid anhydrides in the presence of a base, such as iPr NEt
  • Reduction of 3-D for example with H2 gas and Pd- C or with Fe and HOAc, provides aniline 3-E, which is reacted with a sulfonylating agent such as a sulfonyl chloride or sulfonic acid anhydride in the presence of a base, such as i Pr NEt, to provide compounds of Formula I.
  • a sulfonylating agent such as a sulfonyl chloride or sulfonic acid anhydride in the presence of a base, such as i Pr NEt
  • An aryl ring A may contain functional groups that can be transformed into other substituents.
  • One example is described in Scheme 4.
  • intermediate 2-E of Scheme 2 or 3-D of Scheme 3 contains a bromo substituent, as in 4-Ai or 4-Aii
  • the bromide can be converted to a a benzylthioether, for example with benzylthiol and a catalyst such as Pd2(dba)3 and Xantphos, to provide 4-Bi and 4-Bii respectively (wherein R represents L, ring B, and 0 to 4 R B ).
  • a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein ring A is Ce-14 aryl or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, Ci-6 alkyl optionally substituted with one or more substituents T 1 , 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T 2 , -NR al C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N S(O)R a8 R a9 , -OR al °, -S(O)R a11 , -S(O)(NR al2 )R a13 , - S(O) 2 NR al4 R a15 , -S(O) 2 R a16 , -(CR al7 R al8
  • L is a bond, CR bl R b2 , or O;
  • R bl and R b2 are each independently H or C1-3 alkyl;
  • ring B is C3-8 cycloalkyl, C5-7 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;
  • each R B group is independently halo, C1-6 alkyl optionally substituted with one or more halo, or C2-6 alkenyl; or two vicinal R B groups are taken together with the carbon atoms to which they are attached to form C3-10 cycloalkyl; or two geminal R B groups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl;
  • m is 0, 1, 2, 3, or 4;
  • Y 1 is N or CR cl ;
  • Y 2 is N or CR C2 ;
  • Y 3 is N or CR C3 ;
  • Y 4 is N or CH
  • R C1 , R C2 , and R C3 are each independently hydrogen, halo, cyano, -OH, -OC1-6 alkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH;
  • R cl -R c15 are each independently hydrogen, C3-10 cycloalkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.
  • a pharmaceutical composition comprising a compound of any one of embodiments 1-26, 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 1-26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 27.
  • 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 1-26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 27.
  • 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 1-26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 27.
  • 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
  • BSA bovine serum albumin
  • PCC pyridinium chlorochromate
  • PE petroleum ether
  • Step 1 To a mixture of 3 -bromobenzonitrile (3.4 g, 19 mmol), 6-nitro- 1 / -indole
  • Step 2 To a mixture of A-01 (0.86 g, 2.5 mmol), bromocyclopentane (0.35 pL, 3.2 mmol), and DMF (6 mL) was added tetrabutylammonium iodide (27 mg, 74 pmol), K- 2CO3 (1.5 g, 11 mmol). The mixture was stirred at 90 °C for 12 h, combined with EtOAc (20 mL), washed with H 2 O (10 mL x 3) and brine (10 mL), concentrated under reduced pressure to give a residue.
  • Step 1 To a mixture of 6-nitro-177-indazole-3-carbaldehyde (4.0 g, 21 mmol) and bromocyclohexane (4.7 mL, 38 mmol), and DME (40 mL) was added K2CO3 (11 g, 77 mmol), and tetrabutylammonium iodide (2.5 g, 6.6 mmol). The mixture was stirred at 90 °C for 6 h. H 2 O (80 mL) and EtOAc (150 mL) were added, the mixture was filtered.
  • K2CO3 11 g, 77 mmol
  • tetrabutylammonium iodide 2.5 g, 6.6 mmol
  • Step 2 1 -Bromo-3-iodo-benzene (1.8 mL, 14 mmol) was added to a solution of lithium chloro (isopropyl)magnesium chloride (1.3 M, 20 mL) and THF (8 mL). The mixture was stirred at -78 °C for 2 h to provide 28 mL of 0.5 M (3-bromophenyl)-magnesium chloride in THF.
  • Step 3 To a mixture of A-05 (1.70 g, 4.0 mmol, 1.0 eq) in CH2CI2 (15 mL) was added PCC (1.7 g, 7.9 mmol). The mixture was stirred at 20 °C for 2 h, concentrated, and purified by silica chromatography (0-100% EtOAc in PE) to afford the compound (3- bromophenyl)(l-cyclohexyl-6-nitro-177-indazol-3-yl)methanone (A-03, 1.3 g).
  • Step 1 To a mixture of 2-bromofuran (4.0 g, 26 mmol) and THF (50 mL) at -40 °C was added dropwise LDA (2 M, 16 mL, 32 mmol) and A-04 (4.0 g, 13 mmol). The mixture was stirred at -40 °C for 1 h, concentrated, treated with aqueous NaHCOa (30 mL), and extracted with EtOAc (2 x 30 mL).
  • Step 2 To a 0 °C mixture of A-07.2 (3.0 g, 6.0 mmol) and CH2CI2 (30 mL) was added PCC (3.0 g, 12 mmol), silica gel (4 g), and NaOAc (1.0 g, 18 mmol).
  • Step 1 A mixture of A-02 (0.45 g, 1.1 mmol), phenylmethanethiol (0.19 mL, 1.6 mmol), dioxane (3 mL), iPnNEt (0.48 mL, 2.7 mmol), Xantphos (63 mg, 0.11 mmol), Pd2(dba)3 (50 mg, 55 pmol) was stirred at 110 °C for 12 h. The mixture was poured into H 2 O (30 mL) and extracted with EtOAc (2 x 30 mL).
  • Step 2 To a mixture of A-10 (0.32 g, 0.71 mmol), HO Ac (0.9 mL), and H 2 O (0.1 mL) was added NCS (0.28 g, 2.1 mmol) and mixture was stirred at 25 °C for 2 h, poured into H 2 O (30 mL), and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL), dried over Na 2 SO 4 , and concentrated to provide crude 3-(l-cyclopentyl- 6-nitro-1H -indole-3-carbonyl)benzenesulfonyl chloride (A-ll, 0.58 g).
  • Step 3 A mixture of A-ll (0.18 g, 0.40 mmol), 2- methylpropan-2-amine (50 pL, 0.48 mmol), CH2CI2 (1 mL) was added iPnNEt (0.21 mL, 1.2 mmol). The mixture was stirred at 25 °C for 1 h, poured into water (30 mL), and extracted with EtOAc (2 x 30 mL).
  • a mixture of A-09 (0.10 g, 0.21 mmol), MeOH (4 mL), 10% Pd/C (50 mg) was stirred under th (15 psi) at 25 °C for 1.5 h.
  • the mixture was purged with N2, filtered through celite, and concentrated to provide -(6-amino- l -cyclopcntyl-//H-indolc-3-carbonyl)- N-(tert-butyl) benzenesulfonamide (A-15, 95 mg).
  • a mixture of A-22 (0.40 g, 1.4 mmol), methanesulfonamide (0.40 g, 4.2 mmol), DMF (8 mL), Cui (0.27 g, 1.4 mmol), A7,A2-dimethylcyclohexanel,2-diamine (0.20 g, 1.4 mmol) and K3PO4 (0.88 g, 4.2 mmol) was stirred t 150 °C for 1.5 h in a microwave reactor.
  • A-(l-(3,3-dimethylcyclopentyl)indolin-6-yl)methanesulfonamide (A-28) was prepared from
  • 6-bromo- 1 -cyclopentyl- IH-pyrrolo [3, 2-c]pyridine (A-40.1) was prepared from 6- bromo- 1 H-pyrrolo
  • a mixture of A-18 (35 mg, 79 pmol), CH2CL2 (2 mL), EhN (55 pL, 0.40 mmol), and methylsulfonyl methanesulfonate (28 mg, 0.16 mmol) was stirred at 25 °C for 1 h, poured into H 2 O (10 mL), and extracted with EtOAc (2 x 10 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, and concentrated.
  • Example 2 Synthesis of 2V-(l-cyclopentyl-3-(3-((3,3-difluoroazetidin-l- y 1 )su 11'onyl )benzoyl)-lH-indol -6-yl) met hanesullonam ide [0141] A degassed mixture of A-53 (40 mg, 0.14 mmol), 3-(3,3-difluoroazetidin-l- yl)sulfonylbenzonitrile (0.11 g, 0.43 mmol), [(Phen)Pd(OAc)2] (5 mg), AcOH (25 pL, 0.43 mmol), 1,4-dioxane (3 mL), H 2 O (0.1 mL) was stirred at 140 °C for 2 h in a microwave reactor.
  • Step 1 To a mixture of A-40.1 (1.2 g, 4.5 mmol) and dichloroethane (50 mL) was added dropwise AlCh (1.2 mL, 23 mmol) and the mixture was stirred at 25 °C for 0.5 h. 3- bromobenzoyl chloride (1.7 mL, 13 mmol) was added dropwise at 25 °C and the mixture was stirred at 80 °C for 2 h. The mixture was poured into ice-water (20 mL), the pH was adjust to 3 with 1 M HC1, EtOAc (20 mL) added, and a precipitate removed by filtration.
  • Step 2 A mixture of A-54 (0.60 g, 1.3 mmol), dioxane (23 mL), Xantphos (0.13 g, 0.25 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), iP NEt (0.60 mL, 3.4 mmol), and phenylmethanethiol (0.15 mL, 1.3 mmol) was stirred under N2 at 70 °C for 6 h, combined with with H 2 O (50 mL) and extracted with EtOAc (30 mL).
  • a mixture of A-55 (0.23 g, 0.47 mmol), H 2 O (0.5 mL), HOAc (5 mL), and NCS (0.19 g, 1.4 mmol) at 0 °C was stirred at 25 °C for 1 h, diluted with H 2 O (50 mL), and extracted with EtOAc (30 mL).
  • Step 4 A mixture of A-56 (42 mg, 83 umol), methanesulfonamide (28 mg, 0.29 mmol), Cui (20 mg, 0.11 mmol), N N 2 -dimethylcyclohexane-l,2-diamine (15 mg, 0.11 mmol), K3PO4 (60 mg, 0.28 mmol), and DMF (2 mL) was stirred under N2 at 140 °C for 2.5 h.
  • 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 KC1, 1 mM EGTA, 1 mM DTT, 0.01% BSA, 0.005% Tween-20, 1 pM 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 pL 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 pL 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.
  • Test compounds were added to cells in a 20x dilution scheme by adding 5 pL of serially diluted compound to the plate, and the treated cells were incubated for an additional 7 days in a 37 °C, 5% CO2 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-Gio® 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de manière générale des inhibiteurs de KIF18A, des compositions associées, et des procédés d'utilisation desdits composés et des compositions associées. Plus spécifiquement, la présente invention concerne des inhibiteurs d'indole et d'indazole de KIF18A et des procédés d'utilisation de ceux-ci pour traiter une maladie médiée par KIF18A, telle que le cancer.
PCT/US2024/036249 2023-06-29 2024-06-28 Inhibiteurs d'aryl indol-3-yl cétone et d'aryl indazol-3-yl cétone de kif18a WO2025007055A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363524077P 2023-06-29 2023-06-29
US63/524,077 2023-06-29

Publications (1)

Publication Number Publication Date
WO2025007055A1 true WO2025007055A1 (fr) 2025-01-02

Family

ID=91966834

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/036249 WO2025007055A1 (fr) 2023-06-29 2024-06-28 Inhibiteurs d'aryl indol-3-yl cétone et d'aryl indazol-3-yl cétone de kif18a

Country Status (1)

Country Link
WO (1) WO2025007055A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5846514A (en) 1994-03-25 1998-12-08 Isotechnika, Inc. Enhancement of the efficacy of nifedipine by deuteration
WO2001028557A1 (fr) * 1999-10-18 2001-04-26 University Of Connecticut Derives indoliques cannabimimetiques
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
WO2012137089A1 (fr) * 2011-04-05 2012-10-11 Pfizer Limited Dérivés de pyrrolo-[2,3-d]pyrimidine en tant qu'inhibiteurs des kinases associées à la tropomyosine
WO2013010136A2 (fr) * 2011-07-13 2013-01-17 Pharmacyclics, Inc. Inhibiteurs de tyrosine kinase de bruton
US20220372018A1 (en) * 2019-08-02 2022-11-24 Amgen Inc. Kif18a inhibitors

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5846514A (en) 1994-03-25 1998-12-08 Isotechnika, Inc. Enhancement of the efficacy of nifedipine by deuteration
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
WO2001028557A1 (fr) * 1999-10-18 2001-04-26 University Of Connecticut Derives indoliques cannabimimetiques
WO2012137089A1 (fr) * 2011-04-05 2012-10-11 Pfizer Limited Dérivés de pyrrolo-[2,3-d]pyrimidine en tant qu'inhibiteurs des kinases associées à la tropomyosine
WO2013010136A2 (fr) * 2011-07-13 2013-01-17 Pharmacyclics, Inc. Inhibiteurs de tyrosine kinase de bruton
US20220372018A1 (en) * 2019-08-02 2022-11-24 Amgen Inc. Kif18a inhibitors

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"Methods in Molecular BiologyTM", vol. 164, 2001, HUMANA PRESS, article "Assays for Kinesin Microtubule-Stimulated ATPase Activity"
"Remington's Pharmaceutical Sciences", MACK PUBLISHING COMPANY
BERGE ET AL.: "Pharmaceutical Salts", J. PHARMACEUTICAL SCIENCES, vol. 66, no. 1, January 1977 (1977-01-01), pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; 6 October 2005 (2005-10-06), DENG HONGFENG ET AL: "Potent cannabinergic indole analogues as radioiodinatable brain imaging agents for the CB1 cannabinoid receptor.", XP002812301, Database accession no. NLM16190764 *
DEAN, D.: "Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development", CURR. PHARM. DES., vol. 6, no. 10, 2000
EVANS, E.: "Synthesis of radiolabeled compounds", J. RADIOANAL. CHEM., vol. 64, no. 1-2, 1981, pages 9 - 32
KABALKA, G ET AL.: "The Synthesis of Radiolabeled Compounds via Organometallic Intermediates", TETRAHEDRON, vol. 45, no. 21, 1989, pages 6601 - 21
M. WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS

Similar Documents

Publication Publication Date Title
CA2663401C (fr) Composes de pyrido (2, 3-d) pyrimidin0ne et leur utilisation en tant qu'inhibiteurs de pi3
CA2695004E (fr) Composes et procedes pour la modulation des kinases et leurs indications
AU2006334899B2 (en) Triazole derivatives
CA3051206A1 (fr) Composes bicycliques utilises en tant qu'inhibiteurs allosteriques de shp2
WO2021021986A1 (fr) Amides hétérobicycliques servant d'inhibiteurs de cd38
CA2932169A1 (fr) Derives substitues de 1h-pyrrolo[2,3-b]pyridine et 1h-pyrazolo[3,4-b]pyridine en tant qu'inhibiteurs de kinases 2 inductibles par un sel (sik2)
CA3216800A1 (fr) Inhibiteurs chromenone allosteriques de la phosphoinositide 3-kinase (pi3k) pour le traitement d'une maladie
EP4392407A1 (fr) Inhibiteurs spiro-indoliniques de la kif18a
EP3814342A1 (fr) Inhibiteurs de sarcomères cardiaques
CN110167937A (zh) 作为蛋白质聚集调节剂的二环双-杂芳基衍生物
AU2020332462B2 (en) Azaheteroaryl compound and application thereof
JP2024518824A (ja) Ｅｎｌ／ａｆ９ ｙｅａｔｓのｃ結合阻害剤
WO2023076866A1 (fr) Inhibiteurs sulfoximines tricycliques d'enpp1
JP2023545219A (ja) Ｂｃｒ－ａｂｌチロシンキナーゼの阻害のための７－アザインドール化合物
AU2007315374B2 (en) Triazabenzo[e]azulene derivatives for the treatment of tumors
WO2021202900A1 (fr) Composés de 1,6-naphtyridine et procédés de modulation de csk et leurs indications
CA2914500C (fr) Inhibiteur quinoleique du recepteur d'origine nantaise mst1r
KR20230015404A (ko) 무스카린성 아세틸콜린 수용체 m5의 경쟁적 억제제 및 비경쟁적 억제제
WO2025007055A1 (fr) Inhibiteurs d'aryl indol-3-yl cétone et d'aryl indazol-3-yl cétone de kif18a
CN118103352A (zh) Kif18a的螺吲哚啉抑制剂
CA3199333A1 (fr) Modulateurs de traduction d'arnm c-myc et leurs utilisations dans le traitement du cancer
EP4532496A1 (fr) Nouveaux inhibiteurs de par-2
TW202506680A (zh) 作為ｐａｒｐ１抑制劑之雜環化合物

Legal Events

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

Ref document number: 24746524

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载