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WO2025080589A1 - Procédés de préparation d'inhibiteurs de kras - Google Patents

Procédés de préparation d'inhibiteurs de kras Download PDF

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Publication number
WO2025080589A1
WO2025080589A1 PCT/US2024/050386 US2024050386W WO2025080589A1 WO 2025080589 A1 WO2025080589 A1 WO 2025080589A1 US 2024050386 W US2024050386 W US 2024050386W WO 2025080589 A1 WO2025080589 A1 WO 2025080589A1
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Prior art keywords
compound
formula
alkyl
independently selected
dichlorophenyl
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Inventor
Zhongjiang JIA
Michelle KROC
Minyan LI
Yi Li
Qiyan Lin
Pingli Liu
Timothy Martin
Bardia SOLTANZADEH
Naijing SU
Joseph Tassone
Michael Xia
Jiacheng Zhou
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Incyte Corp
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Incyte Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
    • C07D265/26—Two oxygen atoms, e.g. isatoic anhydride
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the Ras family is comprised of three members: KRAS, NRAS and HRAS.
  • RAS mutant cancers account for about 25% of human cancers.
  • KRAS is the most frequently mutated isoform accounting for 85% of all RAS mutations whereas NRAS and HRAS are found mutated in 12% and 3% of all Ras mutant cancers respectively (D. Simanshu, et al., Cell, 2017, 170(1), 17-33).
  • KRAS mutations are prevalent amongst the top three most deadly cancer types: pancreatic (97%), colorectal (44%), and lung (30%) (A. D. Cox, et al. Nat. Rev. Drug. Discov., 2014, 13(11), 828-51 ).
  • the articles “a” and “an” refer to one or to more than one (/.e., to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the present disclosure also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • variables defining divalent linking groups may be described. Where the structure requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • substituted means that an atom or group of atoms formally replaces hydrogen as a “substituent” attached to another group.
  • substituted refers to any level of substitution, e.g., mono-, di-, tri-, tetra- or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to be understood that substitution at a given atom results in a chemically stable molecule.
  • the phrase “optionally substituted” means unsubstituted or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a substituent.
  • a single divalent substituent e.g., oxo, can replace two hydrogen atoms.
  • C n.m indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C- , CI_ 6 and the like.
  • alkyl employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched.
  • C n.m alkyl refers to an alkyl group having n to m carbon atoms.
  • An alkyl group formally corresponds to an alkane with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound.
  • the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1 -butyl, n-pentyl, 3-pentyl, n-hexyl, 1 ,2,2-trimethylpropyl and the like.
  • halo refers to fluoro, chloro, bromo and iodo.
  • halo refers to a halogen atom selected from F, Cl, or Br.
  • halo groups are F.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom.
  • the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C 3.6 monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1 .1 ,1]pentanyl, bicyclo[2.1 ,1]hexanyl, and the like.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the protecting group is methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), allyl, t-butyldimethylsilyl (TBDMS or TBS), or pivoyl (Piv).
  • the protecting group is 2-(trimethylsilyl)ethoxymethyl (SEM), or tosyl (Ts).
  • the protecting group is tert-butoxycarbonyl (Boc).
  • protecting group reagent refers to a reactant that installs a protecting group on another reactant in a process.
  • Protecting group reagents include reactants that protect a free nitrogen atom or free oxygen atom. Examples of protecting group reagents include but are not limited to MOMCI, MEMCI, BOC2O, TrtCI, SEMCI, BnCI, PivCI, TBDPSCI, TIPSCI, TMSCI, and BzCI.
  • coupling agent refers to a chemical species that aids in the formation of a carbon-carbon bond in a reaction between a species having a leaving group and a reactive species.
  • exemplary coupling reagents include, but are not limited to, a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), bis(di-tert-butyl)- dimethylaminophenylphosphone dichloride palladium (II) (Pd-132), bis(triphenylphosphine)palladium(ll) dichloride, and palladium (II) acetate in combination with reagents such as n-Bu 4 NOAc, Cs 2 CO 3 , piperidine, copper iodide, diethylamine, K 2 CO 3 , NiCI 2 -glyme, NiBr 2 -glyme, potassium t-butoxide, potassium phosphate, and KOH.
  • reagents such as
  • alkylating reagent refers to chemical species that installs an alkyl group as defined supra on a reactant.
  • alkylating agents include, but are not limited to, haloalkanes, such as bromoalkanes and iodoalkanes, e.g., Mel, and alkyl sulfonate esters, such as alkyl methanesulfonates, alkyl arenesulfonates, or alkyl trifluoromethanesulfoneates.
  • Examples of carbonylating agents include, but are not limited to, phosgene, triphosgene, and 1 ,1’-carbonyldimidazole.
  • preparation of compounds can involve the addition of acids or bases to effect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts.
  • Organic acids include formic acid, acetic acid, propionic acid, butanoic acid, benzoic acid, 4-nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tartaric acid, trifluoroacetic acid, propiolic acid, butyric acid, 2-butynoic acid, vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid and decanoic acid.
  • base refers to any species that contains a filled orbital containing an electron pair which is not involved in bonding.
  • Example bases include LiOH, NaOH, KOH, Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , and Cs 2 CO 3 .
  • Some example strong bases include, but are not limited to, hydroxide, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wherein; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, TMS and cyclohexyl substituted amides.
  • Brine is sat. aq. sodium chloride. In vacuo is under vacuum.
  • Atropisomers can exist in the form of atropisomers (/.e., conformational diastereoisomers) that can be stable at ambient temperature and separable, e.g., by chromatography.
  • compounds provided herein can exist in the form of atropisomers in which the conformation of the dichlorophenyl relative to the remainder of the molecule is as shown by the partial formulae Formula (ll-A) or Formula (ll-B) below.
  • Reference to the compounds described herein or any of the embodiments is understood to include all such atropisomeric forms of the compounds, including, without limitation, the atropisomeric forms represented by Formula (ll-A) or Formula (ll-B) below.
  • the asymmetry of atropisomers is assigned as either R a or S a , as determined by conventional methods of characterizing points of asymmetry.
  • R PG is a nitrogen protecting group
  • R 2 is CH 2 CH 2 CN.
  • R PG is a hydrolysable protecting group and the deprotecting comprises hydrolyzing the compound of Formula II. In some embodiments of the processes herein, R PG is tert-butyloxycarbonyl. In other embodiments, the deprotecting comprises reacting the compound of Formula II with an acid. In some embodiments, the deprotecting comprises reacting the compound of Formula II with a Lewis acid. In yet other embodiments, the acid is HCI. In other embodiments, the acid is a trialkylsilyl halide, for example TMSI (trimethylsilyl iodide).
  • the reaction can be carried out at a temperature in the range from about 0 °C to about 100 °C, such as a temperature of about 5 °C, about 10 °C, about 15 °C, about 20 °C, about 25 °C, about 30 °C, about 40 °C, about 50 °C, about 60 °C, about 70 °C, about 80 °C, about 90 °C, or about 100 °C.
  • the reaction can be carried out at r.t.
  • R 60 is selected from C1.3 alkyl, halo, and C(O)R b6 °;
  • R 3 is methyl
  • the reaction can be carried out in the presence of a polar aprotic solvent or mixtures thereof, e.g., THF, 1 ,4-dioxane, MeCN, DMF, DMSO or NMP.
  • a polar aprotic solvent or mixtures thereof e.g., THF, 1 ,4-dioxane, MeCN, DMF, DMSO or NMP.
  • the reaction can be carried out at a temperature in the range from about 0 °C to about 150 °C, such as a temperature of about 5 °C, about 10 °C, about 15 °C, about 20 °C, about 25 °C, about 30 °C, about 40 °C, about 50 °C, about 60 °C, about 70 °C, about 80 °C, about 90 °C, about 100 °C, about 110 °C, about 120 °C, about 130 °C, about 140 °C, about 150 °C.
  • the reaction can be carried out at a temperature from about 80 °C to about 90 °C, or from about 80 °C to about 85 °C.
  • R 2 is CH2CH2CN.
  • X c is Cl, Br, or I
  • R 2 is selected from C 2 -4 alkyl optionally substituted with CN;
  • Cy 1 is phenyl; wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from R 10 ;
  • R 3 is C1-3 alkyl optionally substituted with 1 , 2, or 3 substituents independently selected from R 30 ; each R 10 is independently selected from C1.3 alkyl and halo; and each R 30 is independently selected from C1.3 alkyl, halo, and D; comprising halogenating a compound of Formula VI:
  • R 3 is methyl
  • the halogenating can be carried out in the presence of a base.
  • the base is a phosphate base.
  • the base is trisodium phosphate.
  • the reaction can be carried out in the presence of a polar aprotic solvent or mixtures thereof, e.g., THF, 1 ,4-dioxane, or MeCN.
  • the reaction can be carried out at a temperature in the range from about 0 °C to about 50 °C, such as a temperature of about 5 °C, about 10 °C, about 15 °C, about 20 °C, about 25 °C, about 30 °C, about 40 °C, or about 50 °C. In some embodiments, the reaction can be carried out at a temperature from about 20 °C to about 30 °C. In some embodiments, the reaction can be carried out at about r.t.
  • R a is C1-3 alkyl
  • R 2 is selected from C 2 -4 alkyl optionally substituted with CN;
  • Cy 1 is phenyl; wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from R 10 ;
  • R 3 is C1-3 alkyl optionally substituted with 1 , 2, or 3 substituents independently selected from R 30 ; each R 10 is independently selected from C1.3 alkyl and halo; and each R 30 is independently selected from C1.3 alkyl, halo, and D; to form the compound of Formula VI.
  • the reaction can be carried out in the presence of a hydroxylic solvent or mixtures thereof, e.g., water, MeOH or EtOH. In some embodiments, the reaction can be carried out in the presence of water. In some embodiments, the reaction can be carried out in the presence of water and one or more water-miscible co-solvents, e.g., THF, 1 ,4-dioxane, MeCN, MeOH or EtOH.
  • a hydroxylic solvent or mixtures thereof e.g., water, MeOH or EtOH.
  • the reaction can be carried out in the presence of water.
  • the reaction can be carried out in the presence of water and one or more water-miscible co-solvents, e.g., THF, 1 ,4-dioxane, MeCN, MeOH or EtOH.
  • R 3 is methyl
  • the reacting is performed in the presence of a base.
  • the base is a trialkylamine base such as NEt 3 or DIPEA.
  • the reacting is performed in the absence of a base.
  • the compound of Formula IX is a salt thereof. In some embodiments, the compound of Formula IX is an oxalate salt.
  • the reaction can be carried out in the presence of a polar aprotic solvent or mixtures thereof, e.g., THF, 1 ,4-dioxane, MeCN, DMF, DMSO or NMP.
  • a polar aprotic solvent or mixtures thereof e.g., THF, 1 ,4-dioxane, MeCN, DMF, DMSO or NMP.
  • Cy 1 is 2,3-dichlorophenyl.
  • R 3 is methyl
  • R a is ethyl.
  • X a is Cl or OH.
  • X a is Cl.
  • X a is OH.
  • the reducing comprises reacting the compound of Formula X with a reducing agent.
  • the reducing agent can be a silane reducing agent such as polymethylhydrosiloxane (PMHS).
  • the reaction can be carried out in the presence of a copper catalyst formed by a suitable copper (II) salt such as Cu(OAc) 2 and a suitable ligand such as Xantphos or DPEphos.
  • the reducing agent can be a borohydride such as NaBH 4 or NaBH 3 CN.
  • the reaction can be carried out in the presence of suitable solvent or mixtures thereof, e.g., toluene, tert-butanol, THF, 1 ,4-dioxane, MeCN or pyridine.
  • suitable solvent or mixtures thereof e.g., toluene, tert-butanol, THF, 1 ,4-dioxane, MeCN or pyridine.
  • the reaction can be carried out at a temperature in the range from about 0 °C to about 100 °C, such as a temperature of about 5 °C, about 10 °C, about 15 °C, about 20 °C, about 25 °C, about 30 °C, about 40 °C, about 50 °C, about 60 °C, about 70 °C, about 80 °C, about 90 °C, or about 100 °C.
  • the reaction can be carried out at a temperature from about 40 °C to about 70 °C, from about 50 °C to about 60 °C or at about 50 °C or about 60 °C.
  • X d is Cl, Br, or I. In some embodiments, X d is Cl.
  • the reaction can be carried out in the presence of suitable solvent or mixtures thereof, e.g., toluene, THF, 1 ,4-dioxane, N, /-diethylaniline, or MeCN.
  • suitable solvent or mixtures thereof e.g., toluene, THF, 1 ,4-dioxane, N, /-diethylaniline, or MeCN.
  • Cy 1 is 2,3-dichlorophenyl.
  • R a is ethyl
  • Cy 1 is 2,3-dichlorophenyl.
  • reaction can be carried out in the presence of suitable solvent or mixtures thereof, e.g., toluene, xylene or DMSO.
  • suitable solvent or mixtures thereof e.g., toluene, xylene or DMSO.
  • X b is Cl, Br, or I
  • R b is methyl
  • X b is Br.
  • the hydrolyzing comprises reacting the compound of Formula XVI in the presence of a base.
  • suitable bases include alkali metal carbonate bases such as K2CO3 or CS2CO3.
  • suitable bases include alkali or alkaline earth hydroxide bases such as NaOH or KOH.
  • suitable bases include alkali metal trialkylsiloxide bases such as NaOTMS or KOTMS.
  • the base is NaOTMS.
  • the base is NaOH.
  • the halogenating comprises reacting the compound of Formula VII with a halogenating agent.
  • the halogenating is brominating.
  • the halogenating agent is a brominating agent.
  • the halogenating agent is /V-bromosuccinimide (NBS).
  • the reaction can be carried out in the presence of a suitable base.
  • the base is an alkali metal carbonate base e.g., K 2 CO 3 or Cs 2 CO 3 .
  • the base is an alkali metal fluoride base, e.g., KF or CsF.
  • the reaction can be carried out at a temperature in the range from about 0 °C to about 100 °C, such as a temperature of about 5 °C, about 10 °C, about 15 °C, about 20 °C, about 25 °C, about 30 °C, about 40 °C, about 50 °C, about 60 °C, about 70 °C, about 80 °C, about 90 °C, or about 100 °C.
  • the reaction can be carried out at a temperature from about 0 °C to about 50 °C, or from about 5 °C to about 50 °C., such as at about 20 °C.
  • R 2 is CH 2 CH 2 CN.
  • R PG is tert-butyloxycarbonyl.
  • the compound of Formula I is 3-((R a )-1- ((1R,4R,5S)-2-azabicyclo[2.1 .1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2- azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 /-/-pyrrolo[3,2- c]quinolin-8-yl)propanenitrile (Compound 1 ).
  • the compound of Formula I is 3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1 ,1]hexan-5-yl)-2-((1 R,3R,5R)-2- (cyclopropanecarbonyl)-2-azabicyclo[3.1 ,0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4- methyl-1 /-/-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile monohydrochloride salt (Compound 1- HCI).
  • the compound of Formula I is 3-((R a )-1-((1R,4R,5S)-2- azabicyclo[2.1.1 ]hexan-5-yl)-2-((1 R,3R,5R)-2-(cyclopropanecarbonyl)-2- azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 /-/-pyrrolo[3,2- c]quinolin-8-yl)propanenitrile monohydrochloride salt dihydrate (Compound I-HCI.2H2O).
  • the compound of Formula I is 3-((S a )-1-((1R,4R,5S)-2- azabicyclo[2.1.1 ]hexan-5-yl)-2-((1 R,3R,5R)-2-(cyclopropanecarbonyl)-2- azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 /-/-pyrrolo[3,2- c]quinolin-8-yl)propanenitrile.
  • the compound of Formula II is tertbutyl 5-(8-(2-cyanoethyl)-2-(2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3- dichlorophenyl)-6-fluoro-4-methyl-1 H-pyrrolo[3,2-c]quinolin-1 -yl)-2-azabicyclo[2.1 .1 ]hexane- 2-carboxylate.
  • the compound of Formula II is tert-butyl (1 R,4R,5S)-5-((S a )-8-(2-cyanoethyl)-2-((1 R,3R,5R)-2-(cyclopropanecarbonyl)-2- azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H-pyrrolo[3,2- c]quinolin-1-yl)-2-azabicyclo[2.1 ,1]hexane-2-carboxylate.
  • the compound of Formula III is tert-butyl (1 R,4R,5S)-5-((6-(2-cyanoethyl)-3-(((1R,3R,5R)-2-(cyclopropanecarbonyl)-2- azabicyclo[3.1.0]hexan-3-yl)ethynyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinolin-4- yl)amino)-2-azabicyclo[2.1 ,1]hexane-2-carboxylate (Compound 3*).
  • the compound of Formula III is tert-butyl (1 R,4R,5S)-5-(((R a )-6-(2-cyanoethyl)-3- (((1 R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1 ,0]hexan-3-yl)ethynyl)-7-(2,3- dichlorophenyl)-8-fluoro-2-methylquinolin-4-yl)amino)-2-azabicyclo[2.1 .1 ]hexane-2- carboxylate (Compound 3).
  • the compound of Formula III is tert-butyl (1 R,4R,5S)-5-(((S a )-6-(2-cyanoethyl)-3-(((1 R,3R,5R)-2-(cyclopropanecarbonyl)-2- azabicyclo[3.1.0]hexan-3-yl)ethynyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinolin-4- yl)amino)-2-azabicyclo[2.1 ,1]hexane-2-carboxylate.
  • the compound of Formula V is cyclopropyl(3-ethynyl-2-azabicyclo[3.1 .0]hexan-2-yl)methanone. In some embodiments of the processes herein, the compound of Formula V is cyclopropyl((1 R,3R,5R)-3-ethynyl-2- azabicyclo[3.1.0]hexan-2-yl)methanone (Compound 5).
  • the compound of Formula VII is tert-butyl (1 R,4R,5S)-5-(((S a )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3- (ethoxycarbonyl)-8-fluoro-2-methylquinolin-4-yl)amino)-2-azabicyclo[2.1 ,1]hexane-2- carboxylate.
  • the compound of Formula X is ethyl 4-chloro-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate (Compound 10*).
  • the compound of Formula X is ethyl (R a )-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3- carboxylate (Compound 10).
  • the compound of Formula X is ethyl (S a )-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2- methylquinoline-3-carboxylate.
  • the compound of Formula XIII is 6- bromo-7-(2,3-dichlorophenyl)-8-fluoro-2H-benzo[d][1 ,3]oxazine-2,4(1 H)-dione. In some embodiments of the processes herein, the compound of Formula XIII is (R a )-6-bromo-7-(2,3- dichlorophenyl)-8-fluoro-2H-benzo[d][1 ,3]oxazine-2,4(1H)-dione.
  • the compound of Formula XIII is (S a )-6-bromo-7-(2,3-dichlorophenyl)- 8-fluoro-2H-benzo[d][1 ,3]oxazine-2,4(1H)-dione.
  • the compound of Formula XIV is ethyl 3-oxobutanoate.
  • the compound of Formula XV is 3- amino-6-bromo-2',3'-dichloro-2-fluoro-[1 ,1'-biphenyl]-4-carboxylic acid. In some embodiments of the processes herein, the compound of Formula XV is (R a )-3-amino-6- bromo-2',3'-dichloro-2-fluoro-[1 ,1'-biphenyl]-4-carboxylic acid.
  • the compound of Formula XVI is methyl (R a )-3- amino-6-bromo-2',3'-dichloro-2-fluoro-[1 ,1'-biphenyl]-4-carboxylate. In some embodiments of the processes herein, the compound of Formula XVI is methyl (S a )-3-amino-6-bromo-2',3'- dichloro-2-fluoro-[1 , 1 '-biphenyl]-4-carboxylate.
  • the process can include employing Compound 4 as a feedstock for the manufacture.
  • the process can include converting Compound 4 to manufacture Compound 1 , Compound 1-HCI, Compound-1-HCI.2H 2 O, Compound 2, or Compound 3.
  • the process can include employing Compound 6 as a feedstock for the manufacture.
  • the process can include converting Compound 6 to manufacture Compound 1 , Compound 1-HCI, Compound-1-HCI.2H 2 O, Compound 2, Compound 3 or Compound 5.
  • the process can include employing Compound 7 as a feedstock for the manufacture.
  • the process can include converting Compound 7 to manufacture Compound 1 , Compound 1-HCI, Compound-1-HCI.2H 2 O, Compound 2, Compound 3, Compound 5 or Compound 6.
  • an atropisomer of the compound of Formula II, III, IV, V, VI is a compound of Formula II, III, IV, V, VI.
  • the mixture of atropisomers of the compound of Formula II, III, IV, V, VI, VII, VIII, IX or X is separated into isolated stereoisomers of the corresponding compound.
  • one stereoisomer of the compound of Formula II, III, IV, V, VI, VII, VIII, IX or X is racemized to form a second mixture of stereoisomers of the corresponding compound.
  • the second mixture of stereoisomers of the compound of Formula II, III, IV, V, VI, VII, VIII, IX or X is separated into isolated stereoisomers of the corresponding compound.
  • VIII, IX or X can be obtained compared to a single chiral separation to isolate a single atropisomer from a racemic mixture.
  • R 3 is Ci- 3 alkyl optionally substituted with 1 , 2, or 3 substituents independently selected from R 30 ; each R 10 is independently selected from C1.3 alkyl and halo; each R 30 is independently selected from C1.3 alkyl, halo, and D;
  • Cy 1 is 2,3-dichlorophenyl.
  • R 3 is methyl
  • the compound of Formula II is tert-butyl (1 R,4R,5S)-5-(8-(2-cyanoethyl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2- azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H-pyrrolo[3,2- c]quinolin-1-yl)-2-azabicyclo[2.1 ,1]hexane-2-carboxylate.
  • the compound of Formula II is tert-butyl (1 R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1 R,3R,5R)-2- (cyclopropanecarbonyl)-2-azabicyclo[3.1 ,0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4- methyl-1 H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1 ,1]hexane-2-carboxylate.
  • R PG is a nitrogen protecting group
  • R 2 is selected from C 2 -4 alkyl optionally substituted with CN;
  • R 60 is selected from Ci. 3 alkyl, halo, and C(O)R b6 °;
  • R 2 is CH 2 CH 2 CN.
  • Cy 1 is 2,3-dichlorophenyl.
  • R 3 is methyl
  • R PG is tert-butyloxycarbonyl.
  • X c is Cl, Br, or I
  • R PG is a nitrogen protecting group
  • Cy 1 is phenyl; wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from R 10 ;
  • R PG is tert-butyloxycarbonyl.
  • the compound of Formula IV is tert-butyl (1 ,4R,5S)-5-((6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2- methylquinolin-4-yl)amino)-2-azabicyclo[2.1 ,1]hexane-2-carboxylate.
  • the compound of Formula IV is tert-butyl (1 ,4R,5S)-5-(((S a )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2- methylquinolin-4-yl)amino)-2-azabicyclo[2.1 ,1]hexane-2-carboxylate.
  • R PG is a nitrogen protecting group
  • R 2 is selected from C 2 -4 alkyl optionally substituted with CN;
  • Cy 1 is phenyl; wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from R 10 ;
  • R 3 is C1-3 alkyl optionally substituted with 1 , 2, or 3 substituents independently selected from R 30 ; each R 10 is independently selected from C1.3 alkyl and halo; and each R 30 is independently selected from C1.3 alkyl, halo, and D.
  • Cy 1 is 2,3-dichlorophenyl.
  • R 3 is methyl
  • the compound of Formula VI is 4-((2-(tert-butoxycarbonyl)-2- azabicyclo[2.1.1 ]hexan-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2- methylquinoline-3-carboxylic acid.
  • the compound of Formula VI is (R a )-4-(((1 R,4R,5S)-2-(tert-butoxycarbonyl)-2- azabicyclo[2.1.1 ]hexan-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2- methylquinoline-3-carboxylic acid.
  • the compound of Formula VI is (S a )-4-(((1R,4R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1 ,1]hexan-5-yl)amino)-6-(2- cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid.
  • R a is C1.3 alkyl
  • Cy 1 is phenyl; wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from R 10 ;
  • R a is ethyl
  • R 2 is CH 2 CH 2 CN.
  • Cy 1 is 2,3-dichlorophenyl.
  • R PG is tert-butyloxycarbonyl.
  • the compound of Formula VII is tert-butyl 5-((6-(2-cyanoethyl)- 7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinolin-4-yl)amino)-2- azabicyclo[2.1 ,1]hexane-2-carboxylate.
  • the compound of Formula VII is tert-butyl (1R,4R,5S)-5-(((R a )-6-(2- cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinolin-4-yl)amino)- 2-azabicyclo[2.1 ,1]hexane-2-carboxylate.
  • Cy 1 is phenyl; wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from R 10 ;
  • X a is chloro
  • R a is ethyl
  • R 2 is CH 2 CH 2 CN.
  • Cy 1 is 2,3-dichlorophenyl.
  • the compound of Formula VIII is ethyl (S a )-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8- fluoro-2-methylquinoline-3-carboxylate.
  • R 2a is selected from C 2.4 alkyl and C 2.4 alkenyl, both of which are optionally substituted with CN;
  • R 3 is C1-3 alkyl optionally substituted with 1 , 2, or 3 substituents independently selected from R 30 ; each R 10 is independently selected from C1.3 alkyl and halo; and each R 30 is independently selected from C1.3 alkyl, halo, and D.
  • R a is ethyl
  • Cy 1 is 2,3-dichlorophenyl.
  • the compound of Formula X is ethyl (S a )-4-chloro-6-(2-cyanoethyl)-7-(2,3- dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate.
  • R 2 is selected from C 2 -4 alkenyl optionally substituted with CN;
  • R a is ethyl
  • Cy 1 is 2,3-dichlorophenyl.
  • the compound of Formula XI is ethyl 6-(2-cyanovinyl)-7-(2,3- dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate. In some embodiments of the processes herein, the compound of Formula XI is ethyl (R a )-6-(2-cyanovinyl)-7-(2,3- dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate.
  • Cy 1 is phenyl; wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from R 10 ;
  • R 3 is Ci- 3 alkyl optionally substituted with 1 , 2, or 3 substituents independently selected from R 30 ; each R 10 is independently selected from C1.3 alkyl and halo; and each R 30 is independently selected from C1.3 alkyl, halo, and D.
  • Cy 1 is phenyl; wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from R 10 ; and each R 10 is independently selected from C1.3 alkyl and halo.
  • the compound of Formula XIII is 6-bromo-7-(2,3- dichlorophenyl)-8-fluoro-2H-benzo[d][1 ,3]oxazine-2,4(1H)-dione.
  • the compound of Formula XIII is (R a )-6-bromo-7-(2,3-dichlorophenyl)- 8-fluoro-2H-benzo[d][1 ,3]oxazine-2,4(1H)-dione.
  • the compound of Formula XV is (S a )-3-amino-6-bromo-2',3'-dichloro-2-fluoro-[1 ,1'-biphenyl]-4-carboxylic acid.
  • X b is Cl, Br, or I
  • R b is Ci- 3 alkyl
  • Cy 1 is phenyl; wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from R 10 ; and each R 10 is independently selected from C1.3 alkyl and halo.
  • R b is methyl
  • Cy 1 is 2,3-dichlorophenyl.
  • the compound of Formula XVI is methyl 3-amino-6-bromo- 2',3'-dichloro-2-fluoro-[1 ,1'-biphenyl]-4-carboxylate.
  • the compound of Formula XVI is methyl (Ra)-3-amino-6-bromo-2',3'-dichloro-2-fluoro- [1 ,1'-biphenyl]-4-carboxylate.
  • R b is methyl
  • Cy 1 is 2,3-dichlorophenyl.
  • the compound of Formula XVII is methyl 3-amino-2',3'- dichloro-2-fluoro-[1 , 1 '-biphenyl]-4-carboxylate.
  • Step 6b Ethyl 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3- carboxylate:
  • the title compound can alternatively be prepared by the following process.
  • a solution of methyl 3-amino-2',3'-dichloro-2-fluoro-[1 ,1'-biphenyl]-4-carboxylate (100 g, 0.254 mol), ethyl acetoacetate (33.1 g, 0.51 mol) and p-toluenesulfonic acid (2,2 g, 0.013 mol) in xylene (1 L) was refluxed for 5 h to azeotropically remove water.
  • Sodium ethoxide 26 g, 0.381 mol
  • the mixture was cooled to r.t.
  • Step 9 Ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2- methylquinoline-3-carboxylate: A mixture of ethyl 6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2- methylquinoline-3-carboxylate (60 g, 134 mmol), benzyltriethylammonium chloride (31 g, 135 mmol), A/,A/-dimethylaniline (49.1 g, 405 mmol) in MeCN (300 mL) was added phosphorus oxychloride (62 g, 405 mmol) at below 20 °C.
  • Step 14a tert-Butyl (1/?,4/?,5S)-5-(((/? a )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3- (ethoxycarbonyl)-8-fluoro-2-methylquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2- carboxylate:
  • the title compound can be alternatively prepared by the following method.
  • Step 15 (/? a )-4-(((1/?,4/?,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexan-5- yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3- carboxylic acid:
  • the alternative atropisomer (S a )-4-(((1R,4R,5S)-2-(tert-butoxycarbonyl)-2- azabicyclo[2.1.1 ]hexan-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2- methylquinoline-3-carboxylic acid is prepared by an analogous route by performing processes analogous to Steps 14 and 15b starting from ethyl (S a )-4-chloro-6-(2-cyanoethyl)- 7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate instead of ethyl (R a )-4- chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate.
  • the title compound can be alternatively prepared by the following process.
  • Sodium trimethylsilanolate (338 g, 95%) was added to a solution of tert-butyl (1 R,4R,5S)-5-(((R a )-6- (2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinolin-4- yl)amino)-2-azabicyclo[2.1 ,1]hexane-2-carboxylate (1400 g, 2.231 mol) in THF (14 L) and water (80 mL) at r.t. The mixture was heated to 50 °C for 1-3 h to complete the reaction.
  • Tris(dibenzylideneacetone)dipalladium(0) (2.75 g, 3 mmol) was added to the mixture.
  • the mixture was subsurface purged with nitrogen gas for another 15 min. before heating at 70 °C for 1 h.
  • the reaction mixture was cooled to r.t. and added to half saturated aq. NaHCO 3 (2200 mL).
  • the solids were isolated by filtration and the wet cake was washed with water (600 mL).
  • the solids were dried under vacuum at about 50 °C and purified by silica gel column eluted with 0-2% MeOH in EtOAc to give the title compound (142 g, 96% yield).
  • Example 3 Alternative synthesis for preparing ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3- dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate (step 13 of Example 1)
  • Halfsaturated sodium bicarbonate (2.3 L) was added to the mixture and the mixture was warmed up to r.t.
  • the mixture was filtered over diatomaceous earth to remove white solids and the filter bed was rinsed with toluene (1.5 L).
  • the organic layer was separated from the filtrate and washed with water (2x1 .15 L) and saturated brine (1.15 L).
  • the mixture was cooled to 10-15 °C and 6M HCI was added to adjust the mixture pH 2-3 (solids precipitated out as the pH adjustment) and agitated for additional 2-3 h.
  • the solids were isolated and rinsed with water (300 mL). The wet solids were dried under vacuum at 50-55 °C.
  • Free base to a mixture of the wet cake in toluene (225 mL) and water (225 mL) was added 30% aq. NaOH at 10-15 °C to pH 9-10. The mixture was agitated for 30 min. and the organic phase was separated. To the aqueous phase was added 6 M aq. HCI at 10-15 °C to pH 2-3 (solids predicated). The mixture was then cooled to 3-8 °C and agitated for 1 h. The solids were isolated and washed with water (40 mL).
  • the combined organic phase was concentrated under vacuum and the residual was azeotroped with MeCN.
  • the residue was dissolved in (140 mL) and activated charcoal (2 gram) was added.
  • the mixture was agitated at 25-30 °C for 2 h.
  • the mixture was filtered, and the filter bed is rinsed with MeCN (85 mL).
  • the combined filtrate and rinse were added to a solution of oxalic acid (120 g) in MeCN (850 mL) at 40-45 °C.
  • the solution was cooled to 3-7°C and agitated for 1 h.
  • the solids were isolated and rinsed with MeCN (110 mL).

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Abstract

La présente invention concerne des procédés efficaces et évolutifs pour préparer un inhibiteur de KRAS.
PCT/US2024/050386 2023-10-09 2024-10-08 Procédés de préparation d'inhibiteurs de kras Pending WO2025080589A1 (fr)

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