WO2022087375A1 - Novel heterocyclic compounds - Google Patents

Novel heterocyclic compounds Download PDF

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Publication number
WO2022087375A1
WO2022087375A1 PCT/US2021/056202 US2021056202W WO2022087375A1 WO 2022087375 A1 WO2022087375 A1 WO 2022087375A1 US 2021056202 W US2021056202 W US 2021056202W WO 2022087375 A1 WO2022087375 A1 WO 2022087375A1
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ealkyl
ealkylene
heteroaryl
compound
pharmaceutically acceptable
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PCT/US2021/056202
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French (fr)
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Prasad V. Chaturvedula
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Spectrum Pharmaceuticals, Inc.
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Publication of WO2022087375A1 publication Critical patent/WO2022087375A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • KRAs The well-known role of KRAs in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractable target of the pharmaceutical industry for cancer therapy. Notwithstanding thirty years of large scale discovery efforts to develop inhibitors of KRas for treating cancer, progress has been very limited in developing safe and efficacious KRas inhibitors.
  • KRas G12C Despite many failed efforts to target KRas, compounds that inhibit KRas activity are still highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors. Clearly there remains a continued interest and effort to develop inhibitors of KRas, particularly inhibitors of activating KRas mutants, including KRas G12C.
  • An aspect of the patent document provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, Formula I Wherein A is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R 6 ;
  • B is a bond, O, S or NR a ;
  • R 2 is seleted from hydrogen, C(O)OR m , C(O)N(R m ) 2 , C(O) Ci-ealkyl, haloalkyl, Ci-ealkyl, hydroxyCi-ealkyl, dihydroxyCi-ioalkyl, cycloalkyl, heterocycloalkyl, Ci-ealkylene-cycloalkyl, Ci- ealkylene-heterocycloalkyl, Ci-ealkylene-aryl, Ci-ealkylene-heteroaryl, Ci-6alkylene-N(R m ) 2 , Ci- 6alkylene-N(R m )(COR m ), Ci-6alkylene-N(R m )(Ci-6alkylene-aryl), Ci-ealkylene-N(R m )(Ci- ealkylene-heteroaryl), Ci-6alkylene-N(R m )(C(O
  • R 3 in each instance is independently Ci-ealkyl, Ci-ealkylene-CN, oxo, haloalkyl, hydroxyl or halogen;
  • L is a bond, --C(O)--, or Ci-salkylene
  • R 4 hydrogen, cycloalkyl, heterocyclyl, aryl, Ci-ealkylene-aryl, Ci-ealkylene-heteroaryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl moiety of these substituents is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-ealkyl, OCi-ealkyl, hydroxyCi-ealkyl, Ci-6alkylene-N(R m ) 2 , Ci- 6alkylene-N(R m )(COR m ), CN, CFs, OH, N(R m ) 2 , haloCi-ealkyl, and cycloalkyl;
  • R 5 is selected from the group consisting of H, cyano, OR m , C(O)OR m , C(O)N(R m ) 2 , C(O) Ci- ealkyl, and haloalkyl (e.g. CFs),
  • R 6 is oxo, Ci-ealkyl, OCi-ealkyl, hydroxylCi-ealkyl, Ci-ealkylene-CN, Ci-ealkylene OCi-ealkyl, C2-C4 alkynyl, haloalkyl, heteroalkyl, cyano, C(O)OR m , C(0)N(R m ) 2 , N(R m ) 2 , , Ci-ealkylene- N(R m ) 2 , Ci-ealkylene-aryl, Ci-ealkylene-heteroaryl; C(O)OCi-ealkyl, C(0)N(R m ) 2 , C(O)Ci- ealkyl;
  • R a hydrogen, Ci-ealkyl, heteroalkyl, C(O)Ci-ealkyl, C(O)R m or C(0)N(R m ) 2
  • R b is selected from the group consisting of hydrogen, deuterium, halogen, Ci-ealkyl, OCi-ealkyl, hydroxyl-Ci-ealkyl, halo-Ci-ealkyl, N(R m )(C(O) Ci-ealkyl), Ci-ealkylene-OCi-ealkyl, Ci-ealkylene- heteroaryl, and Ci-ealkylene-aryl,
  • R c and R d are independently selected from the group consisting of hydrogen, deuterium, CN, halogen, Ci-ealkyl, halo-Ci-ealkyl, hydroxyl-Ci-ealkyl, Ci-ealkylene-OCi-ealkyl, Ci-ealkylene- N(Ci-6alkyl)(halo-Ci-6alkyl), , Ci-6alkylene-N(R m ) 2 , Ci-6alkylene-N(R m )(COR m ), CON(R m ) 2 , cycloalkyl, heterocycloalkyl, heteroCi-ealkyl, heteroaryl, aryl, Ci-ealkylene-heteroaryl, Ci- ealkylene-aryl, Ci-ealkylene-cycloalkyl, and Ci-ealkylene-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, heteroary
  • R a and R d optionally link up to form a 5 to 8 membered, partially unsaturated ring, wherein the ring is optionally substituted with oxo or Ci-ealkyl;
  • R m in each instance is independently hydrogen or Ci-ealkyl, acyl, heteroalkyl, hydroxyl-Ci-ealkyl or halo-Ci-ealkyl.
  • m is 0, 1 or 2;
  • n is 0, 1 or 2; and
  • p is 0, 1 or 2.
  • compositions comprising a therapeutically effective amount of a compound of Formula (I) disclosed herein or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Another aspect provides a method for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of Formula (I) disclosed herein or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
  • Another aspect provides a method for treating cancer comprising administering to a subject having cancer a therapeutically effective amount of a compound of Formula (I) disclosed herein or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
  • Figure 1 shows the synethesis of an example compound of Formula I.
  • Figure 2 shows the synethesis of an example compound of Formula I.
  • Figure 3 shows the synethesis of an example compound of Formula I.
  • Figure 4 shows two example compounds and their activities.
  • This patent document discloses a novel class of KRas G12C inhibitors. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12C.
  • acyl refers to -C(O)CH 3 , -C(O)CH 2 CH 3 , -C(O)CH 2 CH 2 CH 3 , or - C(O)CH 2 CH 2 CH 2 CH 3 .
  • alkyl refers to a hydrocarbon or a hydrocarbon chain which may be either straight-chained or branched.
  • Ci-6 alkyl refers to alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. Non-limiting examples include groups such as CH 3 , (CH 2 ) 2 CH 3 , CH 2 CH(CH 3 )CH 3 , and the like.
  • C 2 -5 alkyl refers to alkyl groups having 2, 3, 4 or 5 carbon atoms.
  • alkylene refers to a methylene or a hydrocarbon chain which may be either straight-chained or branched. Different from alkyl which has only one point of bonding with other groups or atoms, alkylene has two points of bonding. Non-limiting examples include groups such as CH 2 , (CH 2 ) 2 , CH 2 CH(CH 3 ), and the like.
  • a Ci-ealkylene has 1, 2, 3, 4, 5 or 6 carbons.
  • C 2 -io alkenyl refers to a hydrocarbon chain, straight-chained or branched with one or more double bonds in the chain. As is generally known in the art, a double bond requires two adjacent sp2 hybridized carbons.
  • alkelene refers to a hydrocarbon chain, straight-chained or branched, with one or two double bonds in the chain. Different from alkenyl which has only one point of bonding with other groups or atoms, alkelene has two points of bonding.
  • alkylene-CN referes to an alkyl chain having a CN group. Examples include CH2CH2CN and CH2CN.
  • cycloalkyl refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 ring carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted.
  • cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • aryl group refers to a Ce-14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted.
  • aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.
  • arylene refers to a Ce-14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted. Different from aryl, arylene has two points of bonding with other groups or atoms. Examples of aryl groups include, without limitation, phenylene, naphthylene, anthracenylene, fluorenylene, and dihydrobenzofuranylene.
  • haloalkyl refers to a Ci-ioalkyl chain, straight or branched, in which one or more hydrogen has been replaced by a halogen.
  • Non-limiting examples of haloalkyls include CHF2, CFH2, CF3, CH2CF2, CH2CF3, and CH2CH2F.
  • the alkyl in haloalkyl has 1, 2, 3 or 4 carbons.
  • heteroalky 1 refers to a Ci-ioalkyl group, straight or branched, wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from the group consisting of O, S, N andNR m .
  • the alkyl in heteroalkyl has 1 to 10 carbons.
  • the alkyl in heteroalkyl has 2, 3, 4 or more than 2 carbons.
  • hydroxyalkyl refers to to a Ci-ioalkyl chain, straight or branched, wherein a carbon is substituted with a hydroxyl group.
  • the carbon the hydroxyl is attached to is a primary carbon or secondary carbon.
  • the alkyl in hydroxylalkyl has 2, 3, 4 or more than 2 carbons.
  • dihydroxy alkyl refers to to a C2-ioalkyl chain, straight or branched, wherein two carbons are each substituted with a hydroxyl group.
  • the alkyl in dihydroxylalkyl has 2, 3, 4 or more than 2 carbons.
  • heterocyclyl or “heterocyclic” group is a ring structure having from about 3 to about 12 atoms, for example 4 to 8 atoms (4, 5, 6, 7 or 8 membered ring), wherein one or more atoms are selected from the group consisting of N, O, and S, the remainder of the ring atoms being carbon.
  • the heterocyclyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system.
  • heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, oxazepanyl, azabicyclohexanes, azabi cycloheptanes and oxa azabiocycloheptanes. Specifically excluded from the scope of this term are compounds having adjacent annular O and/or S atoms. In some embodiments, the heteroch
  • heteroaryl refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 n electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S.
  • heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,
  • biologically active agent refers to any agent capable of eliciting a response in a biological system such as, for example, living cell(s), tissue(s), organ(s), and being(s).
  • Biologically active agents can include natural and/or synthetic agents.
  • a biologically active agent is intended to be inclusive of any substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or in the enhancement of desirable physical or mental development and conditions in a subject.
  • halogen refers to F, Cl, Br or I.
  • subject refers to humans or animals including for example sheep, horses, cattle, pigs, dogs, cats, rats, mice, birds, and reptiles.
  • subject is a human or other mammal.
  • KRas G12C-associated disease or disorder refers to diseases or disorders associated with or mediated by or having a KRas G12C mutation.
  • a nonlimiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.
  • an effective amount or “therapeutically effective amount” of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
  • pharmaceutically acceptable refers 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, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier refers to a chemical compound that facilitates the delivery or incorporation of a compound or therapeutic agent into cells or tissues.
  • pharmaceutically acceptable salts means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
  • Non-limiting examples of such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy- 2-ene- 1 -carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene- 1 -carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid,
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
  • Non-limiting examples of acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylgl ucamine. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).
  • pharmaceutical composition refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or additional carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a pharmaceutical composition exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.
  • pharmaceutically acceptable salts of the compounds disclosed herein are provided.
  • treating or “treatment” of any disease or condition refers, in some embodiments, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • treating or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treating” or “treatment” refers to delaying the onset of the disease or disorder, or even preventing the same.
  • “Prophylactic treatment” is to be construed as any mode of treatment that is used to prevent progression of the disease or is used for precautionary purpose for persons at risk of developing the condition.
  • An aspect of the disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof, Formula I
  • A is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R 6 ;
  • B is a bond, O, S, Cmalkylene, Ci-salkyleneO or NR a ;
  • R 2 is selected from hydrogen, C(O)OR m , C(O)N(R m ) 2 , C(O) Ci-ealkyl, haloalkyl, Ci-ealkyl, hydroxyCi-ealkyl, dihydroxyCi-ioalkyl, cycloalkyl, heterocycloalkyl, Ci-ealkylene-cycloalkyl, Ci- ealkylene-heterocycloalkyl, Ci-ealkylene-aryl, Ci-ealkylene-heteroaryl, Ci-6alkylene-N(R m ) 2 , Ci- 6alkylene-N(R m )(COR m ), Ci-6alkylene-N(R m )(Ci-6alkylene-aryl), Ci-6alkylene-N(R m )(Ci- ealkylene-heteroaryl), Ci-6alkylene-N(R m )(C(O)Ci-6
  • R 3 is independently Ci-ealkyl, Ci-ealkylene-CN, oxo, haloalkyl, hydroxyl or halogen;
  • R 4 is selected from the group consisitng of hydrogen, cycloalkyl, heterocyclyl, aryl, Ci- ealkylene-aryl, Ci-ealkylene-heteroaryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, aryl, or heteroaryl moiety of these substituents is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-ealkyl, hydroxyCi-ealkyl, dihydroxyalkyl, Ci-6alkylene-N(R m ) 2 , Ci-6alkylene-N(R m )(COR m ), CN, CF 3 , OH, N(R m ) 2 , haloCi-ealkyl, and cycloalkyl;
  • R 5 is selected from the group consisitng of hydrogen, cyano, OR m , C(O)OR m , C(O)N(R m )2, C(O) Ci-ealkyl, halo Ci-salkyl, and CFs;
  • R 6 is oxo, Ci-ealkyl, OCi-ealkyl, hydroxylCi-ealkyl, Ci-ealkylene-CN, Ci-ealkylene OCi-ealkyl, C2-C4 alkynyl, haloalkyl, heteroalkyl, cyano, C(O)OR m , C(O)N(R m )2, N(R m )2, Ci-ealkylene- N(R m )2, Ci-ealkylene-aryl, Ci-ealkylene-heteroaryl; C(O)OCi-ealkyl, C(O)N(R m )2, C(O)Ci- ealkyl;
  • R a is selected from the group consisitng of hydrogen, Ci-ealkyl, heteroalkyl, C(O)Ci-ealkyl, C(O)R m and C(O)N(R m ) 2 ,
  • R b is selected from the group consisting of hydrogen, deuterium, halogen, Ci-ealkyl, OCi-ealkyl, hydroxyl-Ci-ealkyl, halo-Ci-ealkyl, N(R m )(C(O) Ci-ealkyl), Ci-ealkylene-OCi-ealkyl, Ci-ealkylene- heteroaryl, and Ci-ealkylene-aryl,
  • R c and R d are independently selected from the group consisting of hydrogen, deuterium, CN, halogen, Ci-ealkyl, halo-Ci-ealkyl, hydroxyl-Ci-ealkyl, Ci-ealkylene-OCi-ealkyl, Ci-ealkylene- N(Ci-6alkyl)(halo-Ci-6alkyl), , Ci-6alkylene-N(R m ) 2 , Ci-6alkylene-N(R m )(COR m ), CON(R m ) 2 , cycloalkyl, heterocycloalkyl, heteroCi-ealkyl, heteroaryl, aryl, Ci-ealkylene-heteroaryl, Ci- ealkylene-aryl, Ci-ealkylene-cycloalkyl, and Ci-ealkylene-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, heteroary
  • R m in each instance is independently hydrogen, Ci-ealkyl, acyl, heteroalkyl, hydroxyl-Ci-ealkyl or halo-Ci-ealkyl, wherein optionally two R m together with the nitrogen they are attached to link up to form a heterocyclic ring; m is 0, 1 or 2; n is 0, 1 or 2; and p is 0, 1 or 2.
  • a subsitutent designator may be present in multiple moieties of a compound. Unless noted otherwise, the subsitutent designator can be same or different.
  • the R m of Ci-6alkylene-N(R m for R 2 is independent from the R m of Ci- 6alkylene-N(R m )2 for R 4 and they can be same or different.
  • the two R m s in N(R m )2 for R 6 can be same or different.
  • R a is hydrogen, or Ci-ealkyl.
  • R b is selected from hydrogen, deuterium, halogen, Ci-ealkyl, halo-Ci-ealkyl, hydroxyl-Ci-ealkyl, and N(R m )(C(O)Ci-6alkyl).
  • R b is H, deuterium or F.
  • R c and R d are selected from the group consisting of hydrogen, deuterium, halogen, CN, Ci-ealkyl, halo-Ci-ealkyl, hydroxyl-Ci-ealkyl, CON(R m )2, Ci-ealkylene-OCi-ealkyl, Ci-ealkylene- N(R m )2, Ci-6alkylene-N(R m )(COR m ), heterocycloalkyl, heteroaryl, aryl, Ci-ealkylene- heterocycloalkyl, Ci-ealkylene-heteroaryl, Ci-ealkylene-aryl, wherein the heterocycloalkyl, heteroaryl, or aryl moiety of these substituents (heteroaryl, aryl, Ci-ealkylene-heterocycloalkyl, Ci- ealkylene-heteroaryl, Ci-ealkylene-aryl) is
  • R c and R d are hydrogen or deuterium and the other is not hydrogen or deuterium. In some embodiments, R c and R d are both H. In some embodiments, R b is fluorine.
  • one of R c and R d is Ci-salkylene-heterocycloalkyl, Ci- lalkylene-cycloalkyl. heteroaryl or Ci-salkylene-heteroaryl, each of which is optionally substituted with one or more of halogen, CN, haloalkyl, hydroxyl, oxo, Ci-ealkyl, OCi-ealkyl, hydroxyCi- ealkyl, cycloalkyl, or heterocycloalkyl.
  • one of R c and R d is Cl-3alkylene- heterocycloalkyl, wherein the heterocycloalkyl is 5 or 6 membered and is optionally substituted with one or more of halogen, Cl-6alkyl, OCl-6alkyl or cycloalkyl.
  • R a is F, R c and R d are hydrogen.
  • A is a 5 or 6 membered cyclic ring. In some embodiments, A is a spirocyclic ring system.
  • spirocyclic ring systems with attached R 1 include:
  • R 2 is selected from the group consisting of heteroaryl, Ci- salkylene-heterocycloalkyl, Ci-salkylene-cycloalkyl, and Ci-salkylene-heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, haloalkyl, hydroxyl, oxo, Ci-ealkyl, OCi-ealkyl, hydroxyCi-ealkyl, cycloalkyl, or heterocycloalkyl.
  • R 2 is Ci-salkylene-heterocycloalkyl, wherein the heterocycloalkyl is 5 or 6 membered and is optionally substituted with one or more of halogen, Ci-ealkyl, OCi-ealkyl or cycloalkyl.
  • R 2 is Ci-6alkylene-N(R m )2.
  • B is O or S.
  • R 2 is heterocycloalkyl, and B is a bond.
  • B is O, and R 2 is optionally substituted Ci-ealkylene- heterocycloalkyl.
  • B is a bond, and R 2 is selected from the group consisting of cyano, C(O)OR m , C(O)N(R m )2, C(O) Ci-ealkyl, haloalkyl, heterocycloalkyl, spirocyclic ring, and bridged ring, wherein the heterocycloalkyl, spirocyclic ring, and bridged ring are optionally substituted.
  • B is O
  • R 2 is selected from the group consisting of C(O)OR m , C(O)N(R m )2, C(O) Ci-ealkyl, haloalkyl, heterocycloalkyl, spirocyclic ring, and bridged ring, wherein the heterocycloalkyl, spirocyclic ring, and bridged ring are optionally substituted.
  • B is O
  • R 2 is optionally substituted heterocycloalkyl or optionally substituted Ci-ealkylene-heterocycloalkyl, wherein the heterocycloalkyl is a fused bicylic ring.
  • fused bicylic rings include the following, where any ring atom of the bicyclic system can be attached to B directly or via a Ci-ealkylene chain.
  • B is O
  • R 2 is one of the following, wherein the nitrogen of the heterocyclic rings is optionally substituted with a Ci-ealkyl and each of the chiral centers can be R, or S.
  • the compound can be an individual enantiomer, a racemi mixture and or a mixture of diasteromers.
  • R m is as defined above.
  • R m is H or Ci-ealkyl (e.g. methyl, ethyl or propyl).
  • B is a bond
  • R 2 is a spirocyclic ring system or a bridged ring system.
  • the spirocyclic ring system or a bridged ring system can be optionally substituted with R e .
  • the spirocyclic ring or bridged ring is attached to the core aryl group through its ring nitrogen.
  • the optional sustituent may be on any ring atoms.
  • the optional sustituent is attached to the second nitrogen of the spirocyclic ring or bridged ring.
  • bridged ring systems include diazabi cycloheptanes and diazabi cyclooctanes.
  • the bridged ring system is diazabicyclo [3.2.1]octan-8-yl or diazabicyclo [3.2.1]octan-3-yl.
  • Nonlimiting examples of spirocyclic ring system include the following:
  • R e is selected from Ci-ealkyl, Ci-ealkylene-CN, haloalkyl, Ci-ealkylene-OCi-ealkyl, C(O)OR m , C(O)N(R m ) 2 , Ci-6alkylene-N(R m ) 2 heteroaiyl, C(O)Ci- 6 alkyl, C(O)R m and C(O)N(R m ) 2 .
  • R 2 is heterocycloalkyl
  • B is a bond
  • B is a NH or NR a
  • R 2 can be any of the above desribed heterocycloalkyls.
  • R 2 heterocyclyls include azetidinyl
  • Ci-salkylene -substituted azetidinyl e.g., methylazetidinyl
  • halo-substituted azetidinyl e.g., difluoroazetidinyl
  • tetrahydropyran pyrrolidinyl
  • Ci-salkylene-substituted pyrrolidinyl e.g., methylpyrrolidinyl, dimethylpyrrolidinyl, and isopropylpyrrolidinyl
  • cycloalkylene-Ci-salkylene- pyrrolidinyl hydroxypyrrolindinyl
  • halo-substituted pyrrolidinyl e.g., fluoropyrrolidinyl and difluoropyrrolidinyl
  • methoxyethylpyrrolidinyl e.g., (N-methyl)methoxypyrroli
  • B is O or NH.
  • p is 1.
  • m is 0.
  • R 4 is aryl or heteroaryl, wherein each of aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, Ci-ealkyl, OCi-ealkyl, hydroxyCi-ealkyl, dihydroxyalkyl, CN, CFs, N(R m )2, haloCi-ealkyl, and cycloalkyl.
  • R 4 is optionally substituted naphthalyl, indoyl, indazolyl, quinolinyl, isoquinolinyl, pyridinyl or benzo[d]thiazolyl optionally substituted with one or more of halogen, Ci-ealkyl, hydroxyCi-ealkyl, CN, CF3, N(R m )2, haloCi-ealkyl, and cycloalkyl.
  • L is a bond.
  • Nonlimiting examples of R 4 include the following. Any carbon of the rings can be substituted with one or more of halogen, Ci-ealkyl, hydroxyCi-ealkyl, CN, CF3, N(R m )2, haloCi- ealkyl, and cycloalkyl.
  • the wilggly line is merely an example point of attachment and any atom ring can be attached to L as long as it is chemically feasible in compliance with valency rule.
  • L is a bond and the ring is substituted with one or more halogens.
  • R 5 is selected from the group consisting of hydrogen, CN, OR m , C(O) Ci-ealkyl, and CF3. In some embodiments, R 5 is selected from the group consisting of CN, C(O) Ci-ealkyl, and CFs. In some embodiments, R 5 is CN.
  • A is an optionally substituted 4, 5, or 6-membered ring. In some embodiments, A is a 6-membered ring.
  • A is ⁇ — f optionally substituted with Ci-salkylene-
  • CN e.g. CH2CN
  • Ci-ealkylene OCi-ealkyl C2-C4 alkynyl, or haloalkyl.
  • R 6 is oxo, Ci-ealkyl, Ci-ealkylene-CN, Ci-ealkylene OCi- ealkyl, C2-C4 alkynyl, haloalkyl, cyano, C(O)OR m , C(O)N(R m ) 2 , Ci-6alkylene-N(R m ) 2 , Ci- ealkylene-aryl, Ci-ealkylene-heteroaryl; C(O)OCi-ealkyl, C(O)N(R m )2, C(O)Ci-ealkyl.
  • R 6 is selected from the group consisting of oxo, Ci-ealkyl, Ci-ealkylene-CN (e.g. CH2CN), C2-C4 alkynyl, haloalkyl, cyano, and C(O)OR m ; and wherein n is 1.
  • R 6 is Ci-ealkylene-CN and n is 1.
  • each of the one or more chiral centers may independently be an R or S configuration.
  • n is 1 and the chiral center in A has an R configuration.
  • Formula I is one of the following compounds.
  • each of the chiral centers may have a R or S configuration.
  • their stereochemistry may be RR, RS, SR, or SS.
  • R 5 is CN, C(O) Ci-ealkyl, C(O)N(R m )2, or CFs.
  • the A ring may be first acylated or sulfonylated before being coupled to Intermediate IV.
  • the R group in the intermediates can be different from the R in Formula I and may undergo additional chemistry conversions if necessary.
  • the R’ and R” may contain additional removable protecting groups.
  • Another aspect of the patent document provides a pharmaceutical composition
  • a pharmaceutical composition comprising a KRas G12C inhibitor of the compound of Formula I disclosed herein and a pharmaceutically acceptable carrier, excipient, or diluent.
  • Compounds of this patent document may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
  • Nonlimiting examples of pharmaceutically acceptable carriers include physiologically acceptable surface active agents, glidants, plasticizers, diluents, excipients, smoothing agents, suspension agents, film forming substances, and coating assistants.
  • Preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents, and the like may be provided in the pharmaceutical composition.
  • sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives.
  • antioxidants and suspending agents may be used.
  • alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents.
  • Suitable exemplary binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like.
  • Suitable exemplary disintegrants include starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethylstarch, and the like.
  • Suitable exemplary solvents or dispersion media include water, alcohol (for example, ethanol), polyol (for example, glycerol, propylene glycol, and polyethylene glycol, sesame oil, com oil, and the like), and suitable mixtures thereof that are physiologically compatible.
  • Suitable exemplary solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzylbenzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like.
  • Suitable exemplary suspending agents include surfactants such as stearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, coconut oil, olive oil, sesame oil, peanut oil, soya and the like; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxy ethylcellulose, hydroxypropylcellulose, and the like.
  • Suitable exemplary isotonic agent includes sodium chloride, glycerin, D-mannose, and the like.
  • Suitable exemplary buffer agents include buffer solutions of salts, such as phosphate, acetates, carbonates, and citrates.
  • Suitable exemplary soothing agents include benzyl alcohol, and the like.
  • Suitable exemplary antiseptic substances include para-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.
  • Suitable exemplary antioxidants include sulfite salts, ascorbic acid, and the like.
  • Suitable exemplary sealers include, but are not limited to HPMC (or hypromellose), HPC, PEG and combinations thereof.
  • Suitable exemplary lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, hardened oil and the like.
  • carriers or excipients include diluents, lubricants, binders, and disintegrants.
  • carriers include solvents, solubilizing agents, suspending agents, isotonic agents, buffer agents, soothing agents, and the like.
  • Acceptable additional carriers or diluents for therapeutic use and the general procedures for the preparation of pharmaceutical compositions are well known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety.
  • the compound of Formula I may also be in its pharmaceutically acceptable salt form.
  • salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic
  • the compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt, wherein the counterion include, for example, chloride, bromide, iodide, — O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
  • the counterion include, for example, chloride, bromide, iodide, — O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, mal
  • kits which includes a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and an instruction for treating or preventing diseases associated with KRas G12C.
  • the kit further includes an additional agent such as anti-cancer agent.
  • Non-limiting examples of the additional anti-cancer agent include alkylating agents: Busulfan, dacarbazine, ifosfamide, hexamethylmelamine, thiotepa, dacarbazine, lomustine, chlorambucil, procarbazine, altretamine, estramustine phosphate, mechlorethamine, streptozocin, temozolomide, Semustine cyclophosphamide; platinum agents: spiroplatin, tetraplatin, ormaplatin, iproplatin, ZD-0473 (AnorMED), oxaliplatin carboplatin, lobaplatin (Aetema), satraplatin (Johnson Matthey), BBR-3464 (Hoffmann-La Roche), SM-11355 (Sumitomo), AP-5280 (Access), cisplatin, arboplatin, cisplatin, satraplatin, oxaliplatin, oxa
  • Vistusertib everolimus/Afinitor, rapamycin, dactolisib, BGT226, SF1126, PKI-587, NVPBE235
  • Pan- HER inhibitor e.g. afatinib, neratinb, AC480.
  • the additional anti-cancer agent is selected from bevacizumab, bortezomib, capecitabine, cetuximab, fluorouracil, imatinib, irinotecan, leucovorin, oxaliplatin, panitumumab, pemetrexed, temozolomide, cisplatin, paclitaxel, erlotinib, sunitinib, lapatinib, sorafenib, carboplatin, doxorubicin, docetaxel, gemcitabine, etoposide, gefitinib, PD153035, cetuximab, bevacizumab, panitumumab, trastuzumab, anti-c-Met antibodies, gefitinib, ZD6474, EMD-72000, pariitumab, ICR-62, CI-1033, lapatinib, AEE788, EKB-5
  • IL-12 alpha.
  • platelet factor-4 suramin
  • SU5416 thrombospondin
  • VEGFR antagonists angiostatic steroids plus heparin
  • Cartilage-Derived Angiogenesis Inhibitory Factor matrix metalloproteinase inhibitors
  • batimastat marimastat
  • angiostatin endostatin
  • 2-methoxyestradiol tecogalan
  • thrombospondin . alpha.
  • V.beta.3 inhibitors linomide, and ADH-1, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine, streptozocin, carboplatin, cisplatin, satraplatin, oxaliplatin, altretamine, ET-743, XL119, dacarbazine, chlormethine, bendamustine, trofosfamide, uramustine, fotemustine, nimustine, prednimustine, ranimustine, semustine, nedaplatin, triplatin tetranitrate, mannosulfan, treosulfan, temozolomide, carboquone, triaziquone, triethylenemelamine, procarbazin, doxorubicin, daunorubicin, epirubicin
  • secondary anticancer agent examples include SHP2 inhibitors (e.g. RMC-4550 and RMC-4630), phosphatase inhibitors (e.g. Tautomycin), CDK 4/6 inhibitors (abemaciclib (Lilly), palbociclib (Pfizer)) and protein-protein interaction disruptors (BI 1701963).
  • SHP2 inhibitors e.g. RMC-4550 and RMC-4630
  • phosphatase inhibitors e.g. Tautomycin
  • CDK 4/6 inhibitors abemaciclib (Lilly), palbociclib (Pfizer)
  • protein-protein interaction disruptors BI 1701963
  • Another aspect of the patent document provides for methods for inhibiting KRas G12C activity in a cell.
  • the method inludes contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of Formula I, pharmaceutically acceptable salt thereof or pharmaceutical composition containing the compound or pharmaceutically acceptable salt thereof.
  • the contacting is in vitro. In some embodiments, the contacting is in vivo.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • “contacting” a KRas G12C with a compound provided herein includes the administration of a compound provided herein to an subject, such as a human, having KRas G12C, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12C.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12C activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12C.
  • the degree of covalent modification of KRas G12C may be monitored in vitro using well known methods, including those described in Example A below.
  • inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12C activity of the amount of phosphylated ERK, including those described in Example B below, to assess the effectiveness of treatment and dosages may be adjusted accordingly by the attending medical practitioner.
  • Another aspect of the patent document provides a method of treating cancer in a subject in need thereof.
  • the method includes administering to the subject a therapeutically effective amount of a compound of Formula I, pharmaceutically acceptable salt thereof or pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof.
  • compositions, kit and method provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinom
  • the suject is a human.
  • the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
  • the subject has been identified or diagnosed as having a cancer having a KRas G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA- approved, assay or kit).
  • the subject has a tumor that is positive for a KRas G12C mutation (e.g., as determined using a regulatory agency-approved assay or kit).
  • the subject can be a subject with a tumor(s) that is positive for a KRas G12C mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject can be a subject whose tumors have a KRas G12C mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
  • the subject is suspected of having a KRas G12C gene-associated cancer.
  • the subject has a clinical record indicating that the subject has a tumor that has a KRas G12C mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • an assay is used to determine whether the suject has KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a suject (e.g., a suject suspected of having a KRas G12C-associated cancer, a patient having one or more symptoms of a KRas G12C-associated cancer, and/or a suject that has an increased risk of developing a KRas G12C-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR).
  • the assays are typically performed, e.g., with
  • the method further includes administering to the subject an additional anti-cancer agent.
  • additional anti-cancer agents are as described above.
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof or a pharmaceutically composition thereof for the methods or kit described herein described herein may be administered to the subject by any suitable means.
  • methods of administration include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through non-oral pathways such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraauricular, which administration includes administration as an aqueous suspension, an oily preparation or the like or as a drip, spray, suppository, salve, ointment or the like; (c) administration via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, intrastemally, or the like, including infusion pump delivery; as well as (d) administration topically; as deemed appropriate by those of skill in the art for
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof or a pharmaceutically composition thereof for administrations described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients.
  • dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.
  • the composition can be a tablet, coated tablet, capsule, caplet, cachet, lozenges, gel capsule, hard gelatin capsule, soft gelatin capsule, troche, dragee, dispersion, powder, granule, pill, liquid, an aqueous or nonaqueous liquid suspension, an oil-in-liquid or oil-in-water emulsion, including sustained release formulations that are known in the art.
  • suspensions, syrups and chewable tablets are especially suitable.
  • the therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof required as a dose will depend on the route of administration, the type of subject, including human, being treated, and the physical characteristics of the specific subject under consideration.
  • the dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • dosages may range broadly, depending upon the desired effects and the therapeutic indication. Typically, dosages may be about 10 microgram/kg to about 100 mg/kg body weight, preferably about 100 microgram/kg to about 10 mg/kg body weight. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art.
  • the dose range of the compound of Formula I, or a pharmaceutically acceptable salt thereof administered to the subject or patient can be from about 0.5 to about 1000 mg/kg of the patient’s body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient.
  • those same dosages, or dosages that are about 0.1% to about 500%, more preferably about 25% to about 250% of the established human dosage may be used.
  • the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of about 0.1 mg to 2000 mg of the active ingredient, preferably about 1 mg to about 500 mg, e.g. 5 to 200 mg.
  • an intravenous, subcutaneous, or intramuscular dose of the active ingredient of about 0.01 mg to about 100 mg, preferably about 0.1 mg to about 60 mg, e.g. about 1 to about 40 mg is used.
  • dosages may be calculated as the free acid.
  • the composition is administered 1 to 4 times per day.
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof may be administered by continuous intravenous infusion, preferably at a dose of up to about 1000 mg per day.
  • a dose of up to about 1000 mg per day it may be necessary to administer the compound of Formula I, or a pharmaceutically acceptable salt thereof disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof is formulated into a dosage form for release for a period of 1 to 12, typically 3 to 12 hours, more typically 6-12 hours after administration.
  • the oral pharmaceutical compositions described herein may be administered in single or divided doses, from one to four times a day.
  • the oral dosage forms may be conveniently presented in unit dosage forms and prepared by any methods well known in the art of pharmacy.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of the compound may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity in an animal model such as mice, rats, rabbits, or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for nearly every class of condition.
  • acceptable animal models may be used to establish efficacy of chemicals to treat such conditions.
  • the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, and route of administration, and regime.
  • human clinical trials can also be used to determine the efficacy of the compound of Formula I, or a pharmaceutically acceptable salt thereof in humans.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the concentration and route of administration to the patient will vary depending on the cancer to be treated.
  • the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-cancer agents, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
  • the organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure.
  • the crude was purified by combi flash using 12 g silica gel column as standard phase and 20-30% ethyl acetate : hexane as mobile phase to get 7-benzyl-2,4-dichloro- 5,6,7,8-tetrahydro-l,7-naphthyridine-3-carbonitrile (180 mg, 21.58% - Yellow solid) and 8-10% methanol : DCM as mobile phase to get 7-benzyl-4-chl oro-2 -hydroxy-5, 6,7, 8-tetrahydro-l, 7- naphthyridine-3-carbonitrile (200 mg, 25.47% - Light brown solid).
  • the crude was purified by combi flash using 24 g silica gel column as standard phase and 2-8% methanol in dichloromethane as mobile phase to get 7-benzyl-N-cyclohexyl-2,4-dihydroxy-5,6,7,8-tetrahydro- l,7-naphthyridine-3 -carboxamide (5.20 g, 85.80% - Off white solid).
  • the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to the crude material.
  • the crude was purified by combi flash using 4 g silica gel column as standard phase and 1.5-2% methanol in dichloromethane as mobile phase. Further this material was purified by prep TLC method (3% methanol in dichloromethane as mobile phase) to get tert-butyl 4-(7-benzyl-3-cyano-2-((l-(dimethylamino)propan-2-yl)oxy)- 5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)piperazine-l-carboxylate (50 mg, 43.85%, light yellow sticky mass).
  • the reaction mixture was filtered, the filtrate was concentrated under reduced pressure .
  • the crude was purified by combi flash using 12 g silica gel column as standard phase and 1-2% methanol in Dichloromethane as mobile phase to get tert-butyl 4-(7- benzyl-3-cyano-2-((l-methylpiperidin-4-yl)amino)-5,6,7,8-tetrahydro-l,7-naphthyridin-4- yl)piperazine-l -carboxylate (900 mg, 64.74%, light yellow sticky solid).
  • the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to the crude material.
  • the crude was mixed with IN7015-088-P1 and purified by combi flash using 12 g silica gel column as standard phase and 1.5-2% methanol in di chloromethane as mobile phase to get benzyl4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-3-cyano- 2-((l-(dimethylamino)propan-2-yl)oxy)-5,8-dihydro-l,7-naphthyridine-7(6H)-carboxylate (80 mg, 35.39%, light yellow sticky solid).
  • Example 2 [0126] To (2,2'-bis(diphenylphosphino)-l,T-binaphthyl) (4 mg, 0.006 mmol) and Tris(dibenzylideneacetone)dipalladium(O) (3 mg, 0.003 mmol) under argon was added toluene (2.0 ml) and the reaction bubbled with Argon for 10 minutes followed by heating to 100°C for 10 minutes.
  • Tris(dihenzylideneacetone)dipalladium(0) (5 mg, 0.006 mmol) under argon was added toluene (4.0 ml) and the reaction bubbled with Argon for 10 minutes followed by heating to 100°C for 10 minutes. The reaction was cooled to room temperature tert-butyl 4-(3-cyano-2-((l- (dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)piperazine-l- carboxylate (50 mg, 0.112 mmol) and Sodium tert-butoxide (13 mg, 0.134 mmol) were added to the dark solution as solids.
  • the reaction mixture was filtered, the filtrate was concentrated under reduced pressure.
  • the brown solid was purified by combi flash using 12 g silica gel column as standard phase and 2-3% methanol in DCM as mobile phase to afford the title compound (450 mg, 65.50%, Light yellow sticky solid).
  • the crude residue was diluted dichloromethane and then carefully treated with ice cooled water at 0 °C, separated the di chloromethane. One more time extracted with di chloromethane. The combained organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to get the first fraction. The aqueous layer was carefully treated with saturated sodium bicarbonate solution at 0 °C and extracted to dichloromethane. The organic layer was separated, dried over sodium sulphate, filtered and concentrated under reduced pressure to get second fraction.
  • the crude material was mixed and purified by combi flash using 80 g silica gel column as standard phase and 20-30% ethyl acetate : hexane as mobile phase to get 7-benzyl-2,4-dichloro-5,6,7,8- tetrahydro-l,7-naphthyridine-3-carbonitrile (3.70 g, 40.34% - Light yellow solid).
  • the reaction mixture was filtered, the filtrate was concentrated under reduced pressure. .
  • the brown solid was purified by combi flash using 12 g silica gel column as standard phase and 2-3% methanol in DCM as mobile phase to afford the title compound (85 mg, 50.29%, Light yellow sticky solid).
  • the resulting mixture was stirred at -40 °C for 30 minutes.
  • the reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure.
  • the reaction mixture was filtered, the filtrate was concentrated under reduced pressure. .
  • the brown solid was purified by combi flash using 12 g silica gel column as standard phase and 2-3% methanol in DCM as mobile phase to afford the title compound (450 mg, 49.12%, Light yellow sticky solid).
  • reaction mass was quenched with saturated Aq. ammonium chloride and extracted to ethylacetate.
  • the crude was purified by preparative HPLC purification method to get 7-(8-chloronaphthalen-l-yl)-4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin- l-yl)-2-(((R)-l-methylpyrrolidin-3-yl)methoxy)-5,6,7,8-tetrahydro-l,7-naphthyridine-3- carbonitrile (2.4 mg, 7.85%, Light yellow solid).
  • This example illustrates that exemplary compounds inhibit the growth of tumor cell lines that express KRas G12C.
  • the cellular inhibition of KRAs G12C by exemplary compounds was determined by measuring the amount of a downstream marker of KRas activity, phosphorylated ERK (“Phospho-ERK”).
  • Phospho-ERK phosphorylated ERK
  • H23 and Hl 373 cell lines were obtained from AddexBio. They were grown in a T-75 flask in RPMI Medium containing 10% fetal bovine serum and penicillin-streptomycin at 37 oC in a humidified, 5% CO2 incubator.
  • H23 or H1373 cells (100 pl, 2,500 cells/well) were plated in a 96-well plate and incubated overnight at 37oC in a humidified, 5% CO2 incubator. Next day, medium was replaced with 100 pl of fresh growth medium containing serially diluted test compounds in duplicate wells. After 72 hour incubation with the compound, cell viability was measured in a luminometer after the addition of 100 pL/well CellTiterGlo reagent (Promega) as recommended by the manufacturer.
  • Test compounds were serially diluted 5-fold in DMSO starting from 10 mM to 0.64 pM. These serially diluted compounds were diluted 100 fold in growth medium (2 pl to 200 pl) followed by another 10 fold dilution in growth medium (25 pl to 250 pl). Final concentration of compounds in the growth medium ranged between 10 pM to 0.64 nM.
  • Example 13 This example illustrates additional procedures in testing the compounds disclosed herein. Coupled Nucleotide Exchange Assay: Purified GDP-bound KRAS protein (aa 1- 169), containing both G12C and C118A amino acid substitutions and an N-terminal His-tag, was pre- incubated with a compound dose-response titration for 2 hours in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCh, and 0.01% Triton X-100). Following compound preincubation, purified SOS protein (aa 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional hour.
  • assay buffer 25 mM HEPES pH 7.4, 10 mM MgCh, and 0.01% Triton X-100
  • MIA PaCa-2 (ATCC® CRL-1420TM) and A549 (ATCC® CCL-185TM) cells were cultured in RPMI 1640 Medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and lx penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016).
  • MIA PaCa-2 or A549 cells were seeded in 96-well cell culture plates at a density of 25,000 cells/well and incubated at 37°C, 5% CO2.
  • a compound dose-response titration was diluted in growth media, added to appropriate wells of a cell culture plate, and then incubated at 37°C, 5% CO2 for 4 hours. Following compound treatment, cells were stimulated with 10 ng/mL EGF (Roche 11376454001) for 10 min, washed with ice-cold Dulbecco's phosphate-buffered saline, no Ca 2+ or Mg 2+ (ThermoFisher Scientific 14190144), and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001).

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Abstract

A novel class of compounds as KRas G12C inhibitors. Also disclosed are pharmaceutical compositions of the KRas G12C inhibitors and methods of treating KRas G12C associated diseases.

Description

NOVEL HETEROCYCLIC COMPOUNDS
TECHNICAL FIELD
[0001] Disclosed herein is a novel class of heterocyclic compounds as KRas G12C inhibitors.
BACKGROUND
[0002] The well-known role of KRAs in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractable target of the pharmaceutical industry for cancer therapy. Notwithstanding thirty years of large scale discovery efforts to develop inhibitors of KRas for treating cancer, progress has been very limited in developing safe and efficacious KRas inhibitors.
[0003] Despite many failed efforts to target KRas, compounds that inhibit KRas activity are still highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors. Clearly there remains a continued interest and effort to develop inhibitors of KRas, particularly inhibitors of activating KRas mutants, including KRas G12C.
[0004] Thus, there is a need to develop new KRas G12C inhibitors that demonstrate sufficient efficacy, stability and/or safety for treating KRas G12C-mediated cancer.
SUMMARY
[0005] An aspect of the patent document provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure imgf000002_0001
Formula I Wherein A is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R6;
B is a bond, O, S or NRa;
R1 is C(O)CRb=CRcRd, SO2(O)CRb=CRcRd, C(O)CHCRC, or SO2(O)CHCRC;
R2 is seleted from hydrogen, C(O)ORm, C(O)N(Rm)2, C(O) Ci-ealkyl, haloalkyl, Ci-ealkyl, hydroxyCi-ealkyl, dihydroxyCi-ioalkyl, cycloalkyl, heterocycloalkyl, Ci-ealkylene-cycloalkyl, Ci- ealkylene-heterocycloalkyl, Ci-ealkylene-aryl, Ci-ealkylene-heteroaryl, Ci-6alkylene-N(Rm)2, Ci- 6alkylene-N(Rm)(CORm), Ci-6alkylene-N(Rm)(Ci-6alkylene-aryl), Ci-ealkylene-N(Rm)(Ci- ealkylene-heteroaryl), Ci-6alkylene-N(Rm)(C(O)Ci-6alkylene-aryl), Ci-ealkylene-N(Rm)(C(O)Ci- ealkylene-heteroaryl), spirocyclic ring, and bridged ring, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moiety of these substituents is optionally substituted with one or more of halogen, acyl, CN, haloalkyl, hydroxyl, oxo, Ci-ealkyl, OCi-ealkyl, hydroxyCi- ealkyl, Ci-6alkylene-N(Rm)2, Ci-6alkylene-N(Rm)(CORm), N(Rm)2, cycloalkyl, heterocycloalkyl, Ci-ealkylene-heterocycloalkyl, Ci-ealkylene-aryl, and Ci-ealkylene-heteroaryl;
R3 in each instance is independently Ci-ealkyl, Ci-ealkylene-CN, oxo, haloalkyl, hydroxyl or halogen;
L is a bond, --C(O)--, or Ci-salkylene;
R4 hydrogen, cycloalkyl, heterocyclyl, aryl, Ci-ealkylene-aryl, Ci-ealkylene-heteroaryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl moiety of these substituents is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-ealkyl, OCi-ealkyl, hydroxyCi-ealkyl, Ci-6alkylene-N(Rm)2, Ci- 6alkylene-N(Rm)(CORm), CN, CFs, OH, N(Rm )2, haloCi-ealkyl, and cycloalkyl;
R5 is selected from the group consisting of H, cyano, ORm, C(O)ORm, C(O)N(Rm)2, C(O) Ci- ealkyl, and haloalkyl (e.g. CFs),
R6 is oxo, Ci-ealkyl, OCi-ealkyl, hydroxylCi-ealkyl, Ci-ealkylene-CN, Ci-ealkylene OCi-ealkyl, C2-C4 alkynyl, haloalkyl, heteroalkyl, cyano, C(O)ORm, C(0)N(Rm)2, N(Rm)2, , Ci-ealkylene- N(Rm)2, Ci-ealkylene-aryl, Ci-ealkylene-heteroaryl; C(O)OCi-ealkyl, C(0)N(Rm)2, C(O)Ci- ealkyl;
Ra hydrogen, Ci-ealkyl, heteroalkyl, C(O)Ci-ealkyl, C(O)Rm or C(0)N(Rm)2, Rb is selected from the group consisting of hydrogen, deuterium, halogen, Ci-ealkyl, OCi-ealkyl, hydroxyl-Ci-ealkyl, halo-Ci-ealkyl, N(Rm)(C(O) Ci-ealkyl), Ci-ealkylene-OCi-ealkyl, Ci-ealkylene- heteroaryl, and Ci-ealkylene-aryl,
Rc and Rd are independently selected from the group consisting of hydrogen, deuterium, CN, halogen, Ci-ealkyl, halo-Ci-ealkyl, hydroxyl-Ci-ealkyl, Ci-ealkylene-OCi-ealkyl, Ci-ealkylene- N(Ci-6alkyl)(halo-Ci-6alkyl), , Ci-6alkylene-N(Rm )2, Ci-6alkylene-N(Rm)(CORm), CON(Rm)2, cycloalkyl, heterocycloalkyl, heteroCi-ealkyl, heteroaryl, aryl, Ci-ealkylene-heteroaryl, Ci- ealkylene-aryl, Ci-ealkylene-cycloalkyl, and Ci-ealkylene-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl, or aryl moiety of these is optionally substituted with one or more of halogen, Ci-ealkyl, OCi-ealkyl, CN... .
Ra and Rd optionally link up to form a 5 to 8 membered, partially unsaturated ring, wherein the ring is optionally substituted with oxo or Ci-ealkyl;
Rm in each instance is independently hydrogen or Ci-ealkyl, acyl, heteroalkyl, hydroxyl-Ci-ealkyl or halo-Ci-ealkyl. m is 0, 1 or 2; n is 0, 1 or 2; and p is 0, 1 or 2.
[0006] Also provided are pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (I) disclosed herein or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0007] Another aspect provides a method for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of Formula (I) disclosed herein or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
[0008] Another aspect provides a method for treating cancer comprising administering to a subject having cancer a therapeutically effective amount of a compound of Formula (I) disclosed herein or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
DESCRIPTION OF THE DRAWINGS
[0009] Figure 1 shows the synethesis of an example compound of Formula I.
[0010] Figure 2 shows the synethesis of an example compound of Formula I. [0011] Figure 3 shows the synethesis of an example compound of Formula I.
[0012] Figure 4 shows two example compounds and their activities.
DETAILED DESCRIPTION
[0013] This patent document discloses a novel class of KRas G12C inhibitors. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12C.
[0014] While the following text may reference or exemplify specific embodiments of a compound, substituent, use thereof, it is not intended to limit the scope of the compound, substituent or its use to such particular reference or examples. Various modifications may be made by those skilled in the art, in view of scientific and practical considerations, such as replacement of the substituent and treatment of different diseases.
[0015] The articles "a" and "an" as used herein refer to "one or more" or "at least one," unless otherwise indicated. That is, reference to any element or component of an embodiment by the indefinite article "a" or "an" does not exclude the possibility that more than one element or component is present.
[0016] The term "acyl” refers to -C(O)CH3, -C(O)CH2CH3, -C(O)CH2CH2CH3, or - C(O)CH2CH2CH2CH3.
[0017] The term "alkyl" refers to a hydrocarbon or a hydrocarbon chain which may be either straight-chained or branched. The term "Ci-6 alkyl" refers to alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. Non-limiting examples include groups such as CH3, (CH2)2CH3, CH2CH(CH3)CH3, and the like. Similarly, the term "C2-5 alkyl" refers to alkyl groups having 2, 3, 4 or 5 carbon atoms.
[0018] The term "alkylene" refers to a methylene or a hydrocarbon chain which may be either straight-chained or branched. Different from alkyl which has only one point of bonding with other groups or atoms, alkylene has two points of bonding. Non-limiting examples include groups such as CH2, (CH2)2, CH2CH(CH3), and the like. A Ci-ealkylene has 1, 2, 3, 4, 5 or 6 carbons.
[0019] The term "C2-io alkenyl" refers to a hydrocarbon chain, straight-chained or branched with one or more double bonds in the chain. As is generally known in the art, a double bond requires two adjacent sp2 hybridized carbons. A C2-10 alkeny, for example, may have any number of carbons from 2 to 10. Nonlimiting examples include CH2CH=CHCH3 and CH2CH=CHCH2CH3.
[0020] The term "alkelene” refers to a hydrocarbon chain, straight-chained or branched, with one or two double bonds in the chain. Different from alkenyl which has only one point of bonding with other groups or atoms, alkelene has two points of bonding. A C2-10 alkenlene, for example, has from 2 to 10 carbon atoms. Nonlimiting examples include CH=CH and CH2CH=CHCH2CH2.
[0021] The term "alkylene-CN” referes to an alkyl chain having a CN group. Examples include CH2CH2CN and CH2CN.
[0022] The term "cycloalkyl" refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 ring carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
[0023] The term "aryl" group refers to a Ce-14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted. Examples of aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.
[0024] The term "arylene" group refers to a Ce-14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted. Different from aryl, arylene has two points of bonding with other groups or atoms. Examples of aryl groups include, without limitation, phenylene, naphthylene, anthracenylene, fluorenylene, and dihydrobenzofuranylene.
[0025] The term “haloalkyl” refers to a Ci-ioalkyl chain, straight or branched, in which one or more hydrogen has been replaced by a halogen. Non-limiting examples of haloalkyls include CHF2, CFH2, CF3, CH2CF2, CH2CF3, and CH2CH2F. In some embodiments, the alkyl in haloalkyl has 1, 2, 3 or 4 carbons.
[0026] The term “heteroalky 1” refers to a Ci-ioalkyl group, straight or branched, wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from the group consisting of O, S, N andNRm. In some embodiments, the alkyl in heteroalkyl has 1 to 10 carbons. In some embodiments, the alkyl in heteroalkyl has 2, 3, 4 or more than 2 carbons.
[0027] The term “hydroxyalkyl” refers to to a Ci-ioalkyl chain, straight or branched, wherein a carbon is substituted with a hydroxyl group. The carbon the hydroxyl is attached to is a primary carbon or secondary carbon. In some embodiments, the alkyl in hydroxylalkyl has 2, 3, 4 or more than 2 carbons.
[0028] The term “dihydroxy alkyl” refers to to a C2-ioalkyl chain, straight or branched, wherein two carbons are each substituted with a hydroxyl group. In some embodiments, the alkyl in dihydroxylalkyl has 2, 3, 4 or more than 2 carbons.
[0029] The term “heterocyclyl” or “heterocyclic” group is a ring structure having from about 3 to about 12 atoms, for example 4 to 8 atoms (4, 5, 6, 7 or 8 membered ring), wherein one or more atoms are selected from the group consisting of N, O, and S, the remainder of the ring atoms being carbon. The heterocyclyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, oxazepanyl, azabicyclohexanes, azabi cycloheptanes and oxa azabiocycloheptanes. Specifically excluded from the scope of this term are compounds having adjacent annular O and/or S atoms. In some embodiments, the heterocyclic ring or moiety is 4-8 or 4-6 membered.
[0030] The term “heteroaryl” refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 n electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5- thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
[0031] The term “biologically active agent” refers to any agent capable of eliciting a response in a biological system such as, for example, living cell(s), tissue(s), organ(s), and being(s). Biologically active agents can include natural and/or synthetic agents. Thus, a biologically active agent is intended to be inclusive of any substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or in the enhancement of desirable physical or mental development and conditions in a subject.
[0032] The term “halogen” refers to F, Cl, Br or I.
[0033] The term “subject” refers to humans or animals including for example sheep, horses, cattle, pigs, dogs, cats, rats, mice, birds, and reptiles. Preferably, the subject is a human or other mammal.
[0034] The term “KRas G12C-associated disease or disorder” as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12C mutation. A nonlimiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.
[0035] The term “effective amount” or “therapeutically effective amount” of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
[0036] The term “pharmaceutically acceptable” refers 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, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
[0037] The term “pharmaceutically acceptable carrier” refers to a chemical compound that facilitates the delivery or incorporation of a compound or therapeutic agent into cells or tissues. [0038] The term “pharmaceutically acceptable salts” means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Non-limiting examples of such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy- 2-ene- 1 -carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene- 1 -carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, and trimethylacetic acid. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Non-limiting examples of acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylgl ucamine. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).
[0039] The term “pharmaceutical composition” refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or additional carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a pharmaceutical composition exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. In some embodiments, pharmaceutically acceptable salts of the compounds disclosed herein are provided. [0040] The term "treating" or "treatment" of any disease or condition refers, in some embodiments, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In some embodiments "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In some embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In some embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder, or even preventing the same. “Prophylactic treatment” is to be construed as any mode of treatment that is used to prevent progression of the disease or is used for precautionary purpose for persons at risk of developing the condition.
[0041 ] An aspect of the disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof,
Figure imgf000010_0001
Formula I
Wherein:
A is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R6;
B is a bond, O, S, Cmalkylene, Ci-salkyleneO or NRa;
R1 is C(O)CRb=CRcRd, SO2CRb=CRcRd, C(O)CHCRC, or SO2CHCRC;
R2 is selected from hydrogen, C(O)ORm, C(O)N(Rm)2, C(O) Ci-ealkyl, haloalkyl, Ci-ealkyl, hydroxyCi-ealkyl, dihydroxyCi-ioalkyl, cycloalkyl, heterocycloalkyl, Ci-ealkylene-cycloalkyl, Ci- ealkylene-heterocycloalkyl, Ci-ealkylene-aryl, Ci-ealkylene-heteroaryl, Ci-6alkylene-N(Rm)2, Ci- 6alkylene-N(Rm)(CORm), Ci-6alkylene-N(Rm)(Ci-6alkylene-aryl), Ci-6alkylene-N(Rm)(Ci- ealkylene-heteroaryl), Ci-6alkylene-N(Rm)(C(O)Ci-6alkylene-aryl), Ci-6alkylene-N(Rm)(C(O)Ci- ealkylene-heteroaryl), spirocyclic ring, and bridged ring, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moiety of these substituents is optionally substituted with one or more of halogen, acyl, CN, haloalkyl, hydroxyl, oxo, Ci-ealkyl, OCi-ealkyl, hydroxyCi- ealkyl, Ci-6alkylene-N(Rm)2, Ci-6alkylene-N(Rm)(CORm), N(Rm)2, cycloalkyl, heterocycloalkyl, Ci-ealkylene-heterocycloalkyl, Ci-ealkylene-aryl, and Ci-ealkylene-heteroaryl, provided that the combination or bonding between B and R2 complies with valency rule;
R3 is independently Ci-ealkyl, Ci-ealkylene-CN, oxo, haloalkyl, hydroxyl or halogen;
R4 is selected from the group consisitng of hydrogen, cycloalkyl, heterocyclyl, aryl, Ci- ealkylene-aryl, Ci-ealkylene-heteroaryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, aryl, or heteroaryl moiety of these substituents is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-ealkyl, hydroxyCi-ealkyl, dihydroxyalkyl, Ci-6alkylene-N(Rm )2, Ci-6alkylene-N(Rm)(CORm), CN, CF3, OH, N(Rm )2, haloCi-ealkyl, and cycloalkyl;
R5 is selected from the group consisitng of hydrogen, cyano, ORm, C(O)ORm, C(O)N(Rm)2, C(O) Ci-ealkyl, halo Ci-salkyl, and CFs;
R6 is oxo, Ci-ealkyl, OCi-ealkyl, hydroxylCi-ealkyl, Ci-ealkylene-CN, Ci-ealkylene OCi-ealkyl, C2-C4 alkynyl, haloalkyl, heteroalkyl, cyano, C(O)ORm, C(O)N(Rm)2, N(Rm)2, Ci-ealkylene- N(Rm)2, Ci-ealkylene-aryl, Ci-ealkylene-heteroaryl; C(O)OCi-ealkyl, C(O)N(Rm)2, C(O)Ci- ealkyl;
Ra is selected from the group consisitng of hydrogen, Ci-ealkyl, heteroalkyl, C(O)Ci-ealkyl, C(O)Rm and C(O)N(Rm)2,
Rb is selected from the group consisting of hydrogen, deuterium, halogen, Ci-ealkyl, OCi-ealkyl, hydroxyl-Ci-ealkyl, halo-Ci-ealkyl, N(Rm)(C(O) Ci-ealkyl), Ci-ealkylene-OCi-ealkyl, Ci-ealkylene- heteroaryl, and Ci-ealkylene-aryl,
Rc and Rd are independently selected from the group consisting of hydrogen, deuterium, CN, halogen, Ci-ealkyl, halo-Ci-ealkyl, hydroxyl-Ci-ealkyl, Ci-ealkylene-OCi-ealkyl, Ci-ealkylene- N(Ci-6alkyl)(halo-Ci-6alkyl), , Ci-6alkylene-N(Rm )2, Ci-6alkylene-N(Rm)(CORm), CON(Rm)2, cycloalkyl, heterocycloalkyl, heteroCi-ealkyl, heteroaryl, aryl, Ci-ealkylene-heteroaryl, Ci- ealkylene-aryl, Ci-ealkylene-cycloalkyl, and Ci-ealkylene-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl, or aryl moiety of these is optionally substituted with one or more of halogen, Ci-ealkyl, OCi-ealkyl, CN, and halo-Ci-ealkyl; Ra and Rd optionally link up to form a 5 to 8 membered, partially unsaturated ring, wherein the ring is optionally substituted with oxo or Ci-ealkyl;
Rm in each instance is independently hydrogen, Ci-ealkyl, acyl, heteroalkyl, hydroxyl-Ci-ealkyl or halo-Ci-ealkyl, wherein optionally two Rm together with the nitrogen they are attached to link up to form a heterocyclic ring; m is 0, 1 or 2; n is 0, 1 or 2; and p is 0, 1 or 2.
[0042] In various embodiments, a subsitutent designator may be present in multiple moieties of a compound. Unless noted otherwise, the subsitutent designator can be same or different. For instance, the Rm of Ci-6alkylene-N(Rm for R2 is independent from the Rm of Ci- 6alkylene-N(Rm)2 for R4 and they can be same or different. Likewise, the two Rms in N(Rm)2 for R6 can be same or different.
[0043] In some embodiments, Ra is hydrogen, or Ci-ealkyl.
[0044] In some embodiments, Rb is selected from hydrogen, deuterium, halogen, Ci-ealkyl, halo-Ci-ealkyl, hydroxyl-Ci-ealkyl, and N(Rm)(C(O)Ci-6alkyl). In some embodiments, R1 is C(O)CRb=CRcRd. In some embodiments, Rb is H, deuterium or F. In some embodiments, one or both of Rc and Rd are selected from the group consisting of hydrogen, deuterium, halogen, CN, Ci-ealkyl, halo-Ci-ealkyl, hydroxyl-Ci-ealkyl, CON(Rm)2, Ci-ealkylene-OCi-ealkyl, Ci-ealkylene- N(Rm)2, Ci-6alkylene-N(Rm)(CORm), heterocycloalkyl, heteroaryl, aryl, Ci-ealkylene- heterocycloalkyl, Ci-ealkylene-heteroaryl, Ci-ealkylene-aryl, wherein the heterocycloalkyl, heteroaryl, or aryl moiety of these substituents (heteroaryl, aryl, Ci-ealkylene-heterocycloalkyl, Ci- ealkylene-heteroaryl, Ci-ealkylene-aryl) is optionally substituted with one or more of halogen, Ci- ealkyl, or OCi-ealkyl.
[0045] In some embodiments, only one of Rc and Rd is hydrogen or deuterium and the other is not hydrogen or deuterium. In some embodiments, Rc and Rd are both H. In some embodiments, Rb is fluorine.
[0046] In some embodiments, one of Rc and Rd is Ci-salkylene-heterocycloalkyl, Ci- lalkylene-cycloalkyl. heteroaryl or Ci-salkylene-heteroaryl, each of which is optionally substituted with one or more of halogen, CN, haloalkyl, hydroxyl, oxo, Ci-ealkyl, OCi-ealkyl, hydroxyCi- ealkyl, cycloalkyl, or heterocycloalkyl. In some embodiments, one of Rc and Rd is Cl-3alkylene- heterocycloalkyl, wherein the heterocycloalkyl is 5 or 6 membered and is optionally substituted with one or more of halogen, Cl-6alkyl, OCl-6alkyl or cycloalkyl.
[0047] In some embodiments, R1 is C(O)CRb=CRcRd or SO2CRb=CRcRd. The alkene moiety in C(O)CRb=C RcRd or SO2CRb=C RcRd may be in E or Z configuration. In some embodiments, Ra is F, Rc and Rd are hydrogen.
[0048] In some emodiments, A is a 5 or 6 membered cyclic ring. In some embodiments, A is a spirocyclic ring system. Non-limiting examples of spirocyclic ring systems with attached R1 include:
Figure imgf000013_0001
[0049] In some embodiments, R2 is selected from the group consisting of heteroaryl, Ci- salkylene-heterocycloalkyl, Ci-salkylene-cycloalkyl, and Ci-salkylene-heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, haloalkyl, hydroxyl, oxo, Ci-ealkyl, OCi-ealkyl, hydroxyCi-ealkyl, cycloalkyl, or heterocycloalkyl. In some embodiments, R2 is Ci-salkylene-heterocycloalkyl, wherein the heterocycloalkyl is 5 or 6 membered and is optionally substituted with one or more of halogen, Ci-ealkyl, OCi-ealkyl or cycloalkyl. In some embodiments, R2 is Ci-6alkylene-N(Rm)2. In some embodiments, B is O or S. In some embodiments, R2 is heterocycloalkyl, and B is a bond.
[0050] In some embodiments, B is O, and R2 is optionally substituted Ci-ealkylene- heterocycloalkyl. In some embodiments, B is a bond, and R2 is selected from the group consisting of cyano, C(O)ORm, C(O)N(Rm)2, C(O) Ci-ealkyl, haloalkyl, heterocycloalkyl, spirocyclic ring, and bridged ring, wherein the heterocycloalkyl, spirocyclic ring, and bridged ring are optionally substituted. In some embodiments, B is O, and R2 is selected from the group consisting of C(O)ORm, C(O)N(Rm)2, C(O) Ci-ealkyl, haloalkyl, heterocycloalkyl, spirocyclic ring, and bridged ring, wherein the heterocycloalkyl, spirocyclic ring, and bridged ring are optionally substituted.
[0051] In some embodiments, B is O, and R2 is optionally substituted heterocycloalkyl or optionally substituted Ci-ealkylene-heterocycloalkyl, wherein the heterocycloalkyl is a fused bicylic ring. Nonlimiting examples of fused bicylic rings include the following, where any ring atom of the bicyclic system can be attached to B directly or via a Ci-ealkylene chain.
Figure imgf000014_0002
[0053] In some embodiments, B is O, R2 is one of the following, wherein the nitrogen of the heterocyclic rings is optionally substituted with a Ci-ealkyl and each of the chiral centers can be R, or S. The compound can be an individual enantiomer, a racemi mixture and or a mixture of diasteromers. Rm is as defined above. In some embodiments, Rm is H or Ci-ealkyl (e.g. methyl, ethyl or propyl).
Figure imgf000014_0001
[0054] In some embodiments, B is a bond, and R2 is a spirocyclic ring system or a bridged ring system. The spirocyclic ring system or a bridged ring system can be optionally substituted with Re. The spirocyclic ring or bridged ring is attached to the core aryl group through its ring nitrogen. The optional sustituent may be on any ring atoms. In some embodiments, the optional sustituent is attached to the second nitrogen of the spirocyclic ring or bridged ring. Nonlimiting examples of bridged ring systems include diazabi cycloheptanes and diazabi cyclooctanes. In some embodiments, the bridged ring system is diazabicyclo [3.2.1]octan-8-yl or diazabicyclo [3.2.1]octan-3-yl.
[0055] Nonlimiting examples of spirocyclic ring system include the following:
Figure imgf000015_0001
[0056] Re is selected from Ci-ealkyl, Ci-ealkylene-CN, haloalkyl, Ci-ealkylene-OCi-ealkyl, C(O)ORm, C(O)N(Rm)2, Ci-6alkylene-N(Rm)2 heteroaiyl, C(O)Ci-6alkyl, C(O)Rm and C(O)N(Rm)2.
[0057] In some embodiments, R2 is heterocycloalkyl, and B is a bond.
[0058] In some embodiments, B is a NH or NRa, R2 can be any of the above desribed heterocycloalkyls.
[0059] Nonlimiting examples of optionally substituted R2 heterocyclyls include azetidinyl,
Ci-salkylene -substituted azetidinyl (e.g., methylazetidinyl), halo-substituted azetidinyl (e.g., difluoroazetidinyl), tetrahydropyran, pyrrolidinyl, Ci-salkylene-substituted pyrrolidinyl (e.g., methylpyrrolidinyl, dimethylpyrrolidinyl, and isopropylpyrrolidinyl), cycloalkylene-Ci-salkylene- pyrrolidinyl, hydroxypyrrolindinyl, halo-substituted pyrrolidinyl (e.g., fluoropyrrolidinyl and difluoropyrrolidinyl), methoxyethylpyrrolidinyl, (N-methyl)methoxypyrrolidinyl, piperazinyl, dimethylaminylpyrrolidinyl, morpholinyl, methylmorpholinyl, 1,4-oxazepanyl, piperdinyl, C1-C3 alkyl-substituted piperidinyl (e.g., methylpiperidinyl), acylpiperdinyl, cyanopiperdinyl, cycloalkylpiperdinyl, halopiperdinyl (e.g., fluoropiperdinyl), dihalopiperdinyl (e.g., difluoropiperdinyl), alkoxy piperdinyl, pyrrolidonyl, piperidonyl, thiomorpholinyl-l,l-dioxide, 3- azabicyclo[3.1.0]hexanyl, oxa-5-azabicyclo[2.2.1]heptan-5-yl, and azabicyclo[2.2.1]heptan-2-yl.
[0060] In some embodiments, B is O or NH. In some embodiments, p is 1. In some embodiments, m is 0.
[0061] In some embodiments, R4 is aryl or heteroaryl, wherein each of aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, Ci-ealkyl, OCi-ealkyl, hydroxyCi-ealkyl, dihydroxyalkyl, CN, CFs, N(Rm )2, haloCi-ealkyl, and cycloalkyl. In some embodiments, R4 is optionally substituted naphthalyl, indoyl, indazolyl, quinolinyl, isoquinolinyl, pyridinyl or benzo[d]thiazolyl optionally substituted with one or more of halogen, Ci-ealkyl, hydroxyCi-ealkyl, CN, CF3, N(Rm)2, haloCi-ealkyl, and cycloalkyl. In some embodiments, L is a bond.
[0062] Nonlimiting examples of R4 include the following. Any carbon of the rings can be substituted with one or more of halogen, Ci-ealkyl, hydroxyCi-ealkyl, CN, CF3, N(Rm)2, haloCi- ealkyl, and cycloalkyl. The wilggly line is merely an example point of attachment and any atom ring can be attached to L as long as it is chemically feasible in compliance with valency rule. In some embodiments, L is a bond and the ring is substituted with one or more halogens.
Figure imgf000016_0001
[0063] In some embodiments, R5 is selected from the group consisting of hydrogen, CN, ORm, C(O) Ci-ealkyl, and CF3. In some embodiments, R5 is selected from the group consisting of CN, C(O) Ci-ealkyl, and CFs. In some embodiments, R5 is CN.
[0064] In some embodiments, A is an optionally substituted 4, 5, or 6-membered ring. In some embodiments, A is a 6-membered ring.
Figure imgf000016_0002
[0065] In some embodiments, A is \ — f optionally substituted with Ci-salkylene-
CN (e.g. CH2CN), Ci-ealkylene OCi-ealkyl, C2-C4 alkynyl, or haloalkyl.
[0066] In some embodiments, R6 is oxo, Ci-ealkyl, Ci-ealkylene-CN, Ci-ealkylene OCi- ealkyl, C2-C4 alkynyl, haloalkyl, cyano, C(O)ORm, C(O)N(Rm)2, Ci-6alkylene-N(Rm)2, Ci- ealkylene-aryl, Ci-ealkylene-heteroaryl; C(O)OCi-ealkyl, C(O)N(Rm)2, C(O)Ci-ealkyl. In some embodiments, R6 is selected from the group consisting of oxo, Ci-ealkyl, Ci-ealkylene-CN (e.g. CH2CN), C2-C4 alkynyl, haloalkyl, cyano, and C(O)ORm; and wherein n is 1. In some embodiments, R6 is Ci-ealkylene-CN and n is 1. In cases where A is substituted with R6, each of the one or more chiral centers may independently be an R or S configuration. In some embodiments, n is 1 and the chiral center in A has an R configuration.
[0067] In some embodiments, Formula I is one of the following compounds. In case of a molecule having one or more chiral centers, each of the chiral centers may have a R or S configuration. For compounds that have two chiral centers, their stereochemistry may be RR, RS, SR, or SS.
Figure imgf000017_0001
Figure imgf000018_0001
[0068] Further examples of substituents and compounds of Formula I are shown below. In some embodiments, R5 is CN, C(O) Ci-ealkyl, C(O)N(Rm)2, or CFs. In some embodiments, R5 is CN.
Figure imgf000018_0002
bond, B=O or NH
Figure imgf000018_0003
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
[0069] The synthesis of the compounds of Formula I can be accomplished by various approaches using known synthetic techniques. For example, Intermediate V can be readily prepared as illustrated below. Coupling reaction between X (halogen) and A ring leads to Intermediate IV. Further coupling reaction between X of Intermediate IV and R’ leads to Intermediate III. P1 (e.g. Cbz or benzyl) and P2 (E.g. Boc) are protecting groups which can be selectively removed. After selective removal of P1, substituent R” can be introduced via a coupling reaction to provide intermediate II. Subsequent removal of P2 followed by acylation or sulfonylation and other steps if necessary affords compound I. Various modifications of this approach are certainly feasiable. For instance, the A ring may be first acylated or sulfonylated before being coupled to Intermediate IV. The R group in the intermediates can be different from the R in Formula I and may undergo additional chemistry conversions if necessary. The R’ and R” may contain additional removable protecting groups.
Figure imgf000022_0001
[0070] Pharmaceutical Composition and Kit
[0071] Another aspect of the patent document provides a pharmaceutical composition comprising a KRas G12C inhibitor of the compound of Formula I disclosed herein and a pharmaceutically acceptable carrier, excipient, or diluent. Compounds of this patent document may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
[0072] Nonlimiting examples of pharmaceutically acceptable carriers include physiologically acceptable surface active agents, glidants, plasticizers, diluents, excipients, smoothing agents, suspension agents, film forming substances, and coating assistants. Preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents, and the like may be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used. In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents. Suitable exemplary binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like. Suitable exemplary disintegrants include starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethylstarch, and the like. Suitable exemplary solvents or dispersion media include water, alcohol (for example, ethanol), polyol (for example, glycerol, propylene glycol, and polyethylene glycol, sesame oil, com oil, and the like), and suitable mixtures thereof that are physiologically compatible. Suitable exemplary solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzylbenzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like. Suitable exemplary suspending agents include surfactants such as stearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, coconut oil, olive oil, sesame oil, peanut oil, soya and the like; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxy ethylcellulose, hydroxypropylcellulose, and the like. Suitable exemplary isotonic agent includes sodium chloride, glycerin, D-mannose, and the like. Suitable exemplary buffer agents include buffer solutions of salts, such as phosphate, acetates, carbonates, and citrates. Suitable exemplary soothing agents include benzyl alcohol, and the like. Suitable exemplary antiseptic substances include para-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Suitable exemplary antioxidants include sulfite salts, ascorbic acid, and the like. Suitable exemplary sealers include, but are not limited to HPMC (or hypromellose), HPC, PEG and combinations thereof. Suitable exemplary lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, hardened oil and the like.
[0073] In further exemplary embodiments for solid preparations, carriers or excipients include diluents, lubricants, binders, and disintegrants. In exemplary embodiments for liquid preparations, carriers include solvents, solubilizing agents, suspending agents, isotonic agents, buffer agents, soothing agents, and the like. Acceptable additional carriers or diluents for therapeutic use and the general procedures for the preparation of pharmaceutical compositions are well known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety.
[0074] The compound of Formula I may also be in its pharmaceutically acceptable salt form. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt, wherein the counterion include, for example, chloride, bromide, iodide, — O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
[0075] A related aspect provides a kit, which includes a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and an instruction for treating or preventing diseases associated with KRas G12C. In some embodiments, the kit further includes an additional agent such as anti-cancer agent.
[0076] Non-limiting examples of the additional anti-cancer agent include alkylating agents: Busulfan, dacarbazine, ifosfamide, hexamethylmelamine, thiotepa, dacarbazine, lomustine, chlorambucil, procarbazine, altretamine, estramustine phosphate, mechlorethamine, streptozocin, temozolomide, Semustine cyclophosphamide; platinum agents: spiroplatin, tetraplatin, ormaplatin, iproplatin, ZD-0473 (AnorMED), oxaliplatin carboplatin, lobaplatin (Aetema), satraplatin (Johnson Matthey), BBR-3464 (Hoffmann-La Roche), SM-11355 (Sumitomo), AP-5280 (Access), cisplatin, arboplatin, cisplatin, satraplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, temozolomide, procarbazin; antimetabolites: azacytidine, Floxuridine, 2-chlorodeoxy adenosine, 6-mercaptopurine, 6- thioguanine, cytarabine, 2-fluorodeoxy cytidine, methotrexate, tomudex, fludarabine, raltitrexed, trimetrexate, deoxycoformycin, pentostatin, hydroxyurea, decitabine (SuperGen), clofarabine (Bioenvision), irofulven (MGI Pharma), DMDC (Hoffmann-La Roche), ethynylcytidine (Taiho) gemcitabine, capecitabine; topoisomerase inhibitors: amsacrine, epirubicin, etoposide, teniposide or mitoxantrone, 7-ethyl- 10-hydroxy-camptothecin, dexrazoxanet (TopoTarget), pixantrone (Novuspharma), rebeccamycin analogue (Exelixis), BBR-3576 (Novuspharma), rubitecan (SuperGen), irinotecan (CPT-11), topotecan; antitumor antibiotics: valrubicin, therarubicin, idarubicin, rubidazone, plicamycin, porfiromycin mitoxantrone (novantrone), amonafide, azonafide, anthrapyrazole, oxantrazole, losoxantrone, MEN-10755 (Menarini), GPX-100 (Gem Pharmaceuticals), Epirubicin, mitoxantrone, doxorubicin; antimitotic agents: colchicine, vinblastine, vindesine, dolastatin 10 (NCI), rhizoxin (Fujisawa), mivobulin (Warner-Lambert), cemadotin (BASF), RPR 109881A (Aventis), TXD 258 (Aventis), epothilone B (Novartis), T 900607 (Tularik), T 138067 (Tularik), cryptophy cin 52 (Eh Lilly), vinflunine (Fabre), auristatin PE (Teikoku Hormone), BMS 247550 (BMS), BMS 184476 (BMS), BMS 188797 (BMS), taxoprexin (Protarga), SB 408075 (GlaxoSmithKline), Vinorelbine, Trichostatin A, E7010 (Abbott), PG-TXL (Cell Therapeutics), IDN 5109 (Bayer), A 105972 (Abbott), A 204197 (Abbott), LU 223651 (BASF), D 24851 (ASTAMedica), ER-86526 (Eisai), combretastatin A4 (BMS), isohomohalichondrin-B (PharmaMar), ZD 6126 (AstraZeneca), AZ 10992 (Asahi), IDN-5109 (Indena), AVLB (Prescient NeuroPharma), azaepothilone B (BMS), BNP-7787 (BioNumerik), CA-4 prodrug (OXiGENE), dolastatin- 10 (NIH), CA-4 (OXiGENE), docetaxel, vincristine, paclitaxel; aromatase inhibitors: aminoglutethimide, atamestane (BioMedicines), letrozole, anastrazole, YM- 511 (Yamanouchi), formestane, exemestane; thymidylate synthase inhibitors: pemetrexed (Eh Lilly), ZD-9331 (BTG), nolatrexed (Eximias), CoFactor™ (BioKeys); dna antagonists: trabectedin (PharmaMar) ; glufosfamide (Baxter International), albumin + 32P (Isotope Solutions), thymectacin (NewBiotics), edotreotide (Novartis), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), 06 benzyl guanine (Paligent); famesyltransferase inhibitors: arglabin (NuOncology Labs), lonafamib (Schering-Plough), BAY- 43-9006 (Bayer), tipifamib (Johnson & Johnson), perilly 1 alcohol (DOR BioPharma); pump inhibitors: CBT-1 (CBA Pharma), tariquidar (Xenova), MS-209 (Schering AG), zosuquidar trihydrochloride (Eh Lilly), biricodar di citrate (Vertex); histone acetyltransferase inhibitors: tacedinaline (Pfizer), SAHA (Aton Pharma), MS-275 (Schering AG), pivaloyloxymethyl butyrate (Titan), depsipeptide (Fujisawa); metalloproteinase inhibitors: Neovastat (Aetema Laboratories), marimastat (British Biotech), CMT-3 (CollaGenex), BMS-275291 (Celltech); ribonucleoside reductase inhibitors: gallium maltolate (Titan), triapine (Vion), tezacitabine (Aventis), didox (Molecules for Health); tnf alpha agonists/antagonists: virulizin (Lorus Therapeutics), CDC-394 (Celgene), revimid (Celgene); endothelin a receptor antagonist: atrasentan (Abbott), ZD-4054 (AstraZeneca), YM-598 (Yamanouchi); retinoic acid receptor agonists: fenretinide (Johnson & Johnson), LGD-1550 (Ligand), alitretinoin (Ligand); immuno-modulators: Pembrolizumab (formerly lambrolizumab, brand name Keytruda); interferon, oncophage (Antigenics), GMK (Progenies), adenocarcinoma, vaccine (Biomira), CTP-37 (AVI BioPharma), IRX-2 (Immuno-Rx), PEP-005 (Peplin Biotech), synchrovax vaccines (CTL Immuno), melanoma vaccine (CTL Immuno), p21 RAS vaccine (GemVax) , MAGE- A3 (GSK), nivolumab (BMS), abatacept (BMS), dexosome therapy (Anosys), pentrix (Australian Cancer Technology), ISF-154 (Tragen), cancer vaccine (Intercell), norelin (Biostar), BLP-25 (Biomira), MGV (Progenies), B-alethine (Dovetail), CLL therapy (Vasogen), Ipilimumab (BMS), CM-10 (cCam Biotherapeutics), MPDL3280A (Genentech); hormonal and antihormonal agents: estrogens, conjugated estrogens, ethinyl estradiol, chlortrianisen, idenestrol, hydroxyprogesterone caproate, medroxyprogesterone, testosterone, testosterone propionate, fluoxymesterone, methyltestosterone, diethylstilbestrol, megestrol, bicalutamide, flutamide, nilutamide, dexamethasone, prednisone, methylprednisolone, prednisolone, aminoglutethimide, leuprolide, octreotide, mitotane, P-04 (Novogen), 2- methoxyestradiol (EntreMed), arzoxifene (Eh Lilly), tamoxifen, toremofine, goserelin, Leuporelin, bicalutamide; photodynamic agents: talaporfin (Light Sciences), Theralux (Theratechnologies), motexafin gadolinium (Pharmacy dies), Pd-bacteriopheophorbide (Yeda), lutetium texaphyrin (Pharmacyclics), hypericin; and kinase inhibitors: afatinib, osimertinib, poziotinib (Spedrum), imatinib (Novartis), leflunomide (Sugen/Pharmada), ZD1839 (AstraZeneca), erlotinib (Oncogene Sdence), canertinib (Pfizer), squalamine (Genaera), SU5416 (Pharmada), SU6668 (Pharmada), ZD4190 (AstraZeneca), ZD6474 (AstraZeneca), vatalanib (Novartis), PKI166 (Novartis), GW2016 (GlaxoSmithKline), EKB-509 (Wyeth), trastuzumab (Genentech), OSI-774 (Tarceva™), CI-1033 (Pfizer), SU11248 (Pharmacia), RH3 (York Medical), Genistein, Radicinol, Met-MAb (Roche), EKB-569 (Wyeth), kahalide F (PharmaMar), CEP-701 (Cephalon), CEP-751 (Cephalon), MLN518 (Millenium), PKC412 (Novartis), Phenoxodiol (Novogen), C225 (ImClone), rhu-Mab (Genentech), MDX- H210 (Medarex), 2C4 (Genentech), MDX-447 (Medarex), ABX-EGF (Abgenix), IMC-1C11 (ImClone), Tyrphostins, Gefitinib (Iressa), PTK787 (Novartis), EMD 72000 (Merck), Emodin, Radicinol, Vemurafenib (B-Raf enzyme inhibitor, Daiichi Sankyo), SR-27897 (CCK A inhibitor, Sanofi-Synthelabo), tocladesine (cyclic AMP agonist, Ribapharm), alvocidib (CDK inhibitor, Aventis), CV-247 (COX-2 inhibitor, Ivy Medical), P54 (COX-2 inhibitor, Phytopharm), CapCell™ (CYP450 stimulant, Bavarian Nordic), GCS-100 (gal3 antagonist, GlycoGenesys), G17DT immunogen (gastrin inhibitor, Aphton), efaproxiral (oxygenator, Alios Therapeutics), PI- 88 (heparanase inhibitor, Progen), tesmilifene (histamine antagonist, YM BioSciences), histamine (histamine H2 receptor agonist, Maxim), tiazofurin (IMPDH inhibitor, Ribapharm), cilengitide (integrin antagonist, Merck KGaA), SR-31747 (IL-1 antagonist, Sanofi-Synthelabo), CCI-779 (mTOR kinase inhibitor, Wyeth), exisulind (PDE V inhibitor, Cell Pathways), CP-461 (PDE V inhibitor, Cell Pathways), AG-2037 (GART inhibitor, Pfizer), WX-UK1 (plasminogen activator inhibitor, Wilex), PBI-1402 (PMN stimulant, ProMetic LifeSciences), bortezomib (proteasome inhibitor, Millennium), SRL-172 (T cell stimulant, SR Pharma), TLK-286 (glutathione S transferase inhibitor, Telik), PT-100 (growth factor agonist, Point Therapeutics), midostaurin (PKC inhibitor, Novartis), bryostatin-1 (PKC stimulant, GPC Biotech), CDA-II (apoptosis promotor, Everlife), SDX-101 (apoptosis promotor, Salmedix), rituximab (CD20 antibody, Genentech, carmustine, Mitoxantrone, Bleomycin, Absinthin, Chrysophanic acid, Cesium oxides, BRAF inhibitors, PDL1 inhibitors, MEK inhibitors, bevacizumab, angiogenesis inhibitors, dabrafenib, ceflatonin (apoptosis promotor, ChemGenex); BCX-1777 (PNP inhibitor, BioCryst), ranpimase (ribonuclease stimulant, Alfacell), galarubicin (RNA synthesis inhibitor, Dong-A), tirapazamine (reducing agent, SRI International), N, acetylcysteine (reducing agent, Zambon), R- flurbiprofen (NF-kappaB inhibitor, Encore), 3CPA (NF-kappaB inhibitor, Active Biotech), seocalcitol (vitamin D receptor agonist, Leo), 131-I-TM-601 (DNA antagonist, TransMolecular), eflomithine (ODC inhibitor , ILEX Oncology), minodronic acid (osteoclast inhibitor, Yamanouchi), indisulam (p53 stimulant, Eisai), aplidine (PPT inhibitor, PharmaMar), gemtuzumab (CD33 antibody, Wyeth Ayerst), PG2 (hematopoiesis enhancer, Pharmagenesis), Immunol™ (tri closan oral rinse, Endo), triacetyluridine (uridine prodrug , Wellstat), SN-4071 (sarcoma agent, Signature BioScience), TransMID- 107™ (immunotoxin, KS Biomedix), PCK- 3145 (apoptosis promotor, Procyon), doranidazole (apoptosis promotor, Pola), CHS-828 (cytotoxic agent, Leo), trans-retinoic acid (differentiator, NIH), MX6 (apoptosis promotor, MAXIA), apomine (apoptosis promotor, ILEX Oncology), urocidin (apoptosis promotor, Bioniche), Ro-31-7453 (apoptosis promotor, La Roche), brostallicin (apoptosis promotor, Pharmacia), [3-lapachone, gelonin, cafestol, kahweol, caffeic acid, Tyrphostin AG , PD-1 inhibitors, CTLA-4 inhibitors, sorafenib, BRAF inhibitors, mTOR inhibitors (e.g. Vistusertib, everolimus/Afinitor, rapamycin, dactolisib, BGT226, SF1126, PKI-587, NVPBE235) and Pan- HER inhibitor (e.g. afatinib, neratinb, AC480).
[0077] In some embodiments, the additional anti-cancer agent is selected from bevacizumab, bortezomib, capecitabine, cetuximab, fluorouracil, imatinib, irinotecan, leucovorin, oxaliplatin, panitumumab, pemetrexed, temozolomide, cisplatin, paclitaxel, erlotinib, sunitinib, lapatinib, sorafenib, carboplatin, doxorubicin, docetaxel, gemcitabine, etoposide, gefitinib, PD153035, cetuximab, bevacizumab, panitumumab, trastuzumab, anti-c-Met antibodies, gefitinib, ZD6474, EMD-72000, pariitumab, ICR-62, CI-1033, lapatinib, AEE788, EKB-569, EXEL 7647/EXEL 0999, erlotinib, imatinib, sorafinib, sunitinib, dasatinib, vandetinib, temsirolimus, PTK787, pazopanib, AZD2171, everolimus, seliciclib, AMG 706, axitinib, PD0325901, PKC-412, CEP701, XL880, bosutinib, BIBF1120, BIBF1120, nilotinib, AZD6244, HKI-272, MS-275, BI2536, GX15-070, AZD0530, enzastaurin, MLN-518, ARQ197, CM101, IFN-. alpha., IL-12, platelet factor-4, suramin, SU5416, thrombospondin, VEGFR antagonists, angiostatic steroids plus heparin, Cartilage-Derived Angiogenesis Inhibitory Factor, matrix metalloproteinase inhibitors, batimastat, marimastat, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, thrombospondin, . alpha. V.beta.3 inhibitors, linomide, and ADH-1, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine, streptozocin, carboplatin, cisplatin, satraplatin, oxaliplatin, altretamine, ET-743, XL119, dacarbazine, chlormethine, bendamustine, trofosfamide, uramustine, fotemustine, nimustine, prednimustine, ranimustine, semustine, nedaplatin, triplatin tetranitrate, mannosulfan, treosulfan, temozolomide, carboquone, triaziquone, triethylenemelamine, procarbazin, doxorubicin, daunorubicin, epirubicin, idarubicin, anthracenedione, mitoxantrone, mitomycin C, bleomycin, dactinomycin, plicatomycin, irinotecan, camptothecin, rubitecan, belotecan, etoposide, teniposide, topotecan, paclitaxel, taxol, docetaxel, BMS-275183, xyotax, tocosal, vinorlebine, vincristine, vinblastine, vindesine, vinzolidine, etoposide, teniposide, ixabepilone, larotaxel, ortataxel, tesetaxel, ispinesib, fluorouracil, floxuridine, methotrexate, xeloda, arranon, leucovorin, hydroxyurea, thioguanine, mercaptopurine, cytarabine, pentostatin, fludarabine phosphate, cladribine, asparaginase, gemcitabine, pemetrexed, bortezomib, aminopterin, raltitrexed, clofarabine, enocitabine, sapacitabine, azacitidine.
[0078] Further examples of the secondary anticancer agent include SHP2 inhibitors (e.g. RMC-4550 and RMC-4630), phosphatase inhibitors (e.g. Tautomycin), CDK 4/6 inhibitors (abemaciclib (Lilly), palbociclib (Pfizer)) and protein-protein interaction disruptors (BI 1701963).
[0079] Method of Inhibiting KRas G12C Activity or Treating Cancer
[0080] Another aspect of the patent document provides for methods for inhibiting KRas G12C activity in a cell. The method inludes contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of Formula I, pharmaceutically acceptable salt thereof or pharmaceutical composition containing the compound or pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo.
[0081] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a KRas G12C with a compound provided herein includes the administration of a compound provided herein to an subject, such as a human, having KRas G12C, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12C.
[0082] By negatively modulating the activity of KRas G12C, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12C activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12C. The degree of covalent modification of KRas G12C may be monitored in vitro using well known methods, including those described in Example A below. In addition, the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12C activity of the amount of phosphylated ERK, including those described in Example B below, to assess the effectiveness of treatment and dosages may be adjusted accordingly by the attending medical practitioner.
[0083] Another aspect of the patent document provides a method of treating cancer in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of a compound of Formula I, pharmaceutically acceptable salt thereof or pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof.
[0084] The composition, kit and method provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bihary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.
[0085] In some embodiments, the suject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer having a KRas G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA- approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a KRas G12C mutation (e.g., as determined using a regulatory agency-approved assay or kit). The subject can be a subject with a tumor(s) that is positive for a KRas G12C mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a KRas G12C mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a KRas G12C gene-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a KRas G12C mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
[0086] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether the suject has KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a suject (e.g., a suject suspected of having a KRas G12C-associated cancer, a patient having one or more symptoms of a KRas G12C-associated cancer, and/or a suject that has an increased risk of developing a KRas G12C-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof.
[0087] In some embodiments, the method further includes administering to the subject an additional anti-cancer agent. Examples of the additional anti-cancer agents are as described above.
[0088] Administration Regimen
[0089] The compound of Formula I, or a pharmaceutically acceptable salt thereof or a pharmaceutically composition thereof for the methods or kit described herein described herein may be administered to the subject by any suitable means. Non-limiting examples of methods of administration include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through non-oral pathways such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraauricular, which administration includes administration as an aqueous suspension, an oily preparation or the like or as a drip, spray, suppository, salve, ointment or the like; (c) administration via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, intrastemally, or the like, including infusion pump delivery; as well as (d) administration topically; as deemed appropriate by those of skill in the art for bringing the active compound into contact with living tissue.
[0090] Advantageously, the compound of Formula I, or a pharmaceutically acceptable salt thereof or a pharmaceutically composition thereof for administrations described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.
[0091] In exemplary embodiments of the pharmaceutical composition of the compound of Formula I, or a pharmaceutically acceptable salt thereof for oral administration, the composition can be a tablet, coated tablet, capsule, caplet, cachet, lozenges, gel capsule, hard gelatin capsule, soft gelatin capsule, troche, dragee, dispersion, powder, granule, pill, liquid, an aqueous or nonaqueous liquid suspension, an oil-in-liquid or oil-in-water emulsion, including sustained release formulations that are known in the art. For pediatric and geriatric applications, suspensions, syrups and chewable tablets are especially suitable.
[0092] The therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof required as a dose will depend on the route of administration, the type of subject, including human, being treated, and the physical characteristics of the specific subject under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
[0093] In non-human animal studies, applications of potential products are commenced at higher dosage levels, with dosage being decreased until the desired effect is no longer achieved adverse side effects disappear. The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Typically, dosages may be about 10 microgram/kg to about 100 mg/kg body weight, preferably about 100 microgram/kg to about 10 mg/kg body weight. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art.
[0094] The exact formulation, route of administration and dosage for the pharmaceutical compositions can be chosen by the individual physician in view of the patient’s condition, (see e.g, Fingl et al. 1975, in “The Pharmacological Basis of Therapeutics”, which is hereby incorporated herein by reference in its entirety, with particular reference to Ch. 1, p. 1). In some embodiments, the dose range of the compound of Formula I, or a pharmaceutically acceptable salt thereof administered to the subject or patient can be from about 0.5 to about 1000 mg/kg of the patient’s body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. In instances where human dosages for compounds have been established for at least some conditions, those same dosages, or dosages that are about 0.1% to about 500%, more preferably about 25% to about 250% of the established human dosage may be used.
[0095] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
[0096] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of about 0.1 mg to 2000 mg of the active ingredient, preferably about 1 mg to about 500 mg, e.g. 5 to 200 mg. In other embodiments, an intravenous, subcutaneous, or intramuscular dose of the active ingredient of about 0.01 mg to about 100 mg, preferably about 0.1 mg to about 60 mg, e.g. about 1 to about 40 mg is used. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free acid. In some embodiments, the composition is administered 1 to 4 times per day. Alternatively the compound of Formula I, or a pharmaceutically acceptable salt thereof may be administered by continuous intravenous infusion, preferably at a dose of up to about 1000 mg per day. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compound of Formula I, or a pharmaceutically acceptable salt thereof disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
[0097] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is formulated into a dosage form for release for a period of 1 to 12, typically 3 to 12 hours, more typically 6-12 hours after administration. In some embodiments, the oral pharmaceutical compositions described herein may be administered in single or divided doses, from one to four times a day. The oral dosage forms may be conveniently presented in unit dosage forms and prepared by any methods well known in the art of pharmacy.
[0098] The compound of Formula I or a pharmaceutically acceptable salt thereof can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of the compound may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for nearly every class of condition. Similarly, acceptable animal models may be used to establish efficacy of chemicals to treat such conditions. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, and route of administration, and regime. Of course, human clinical trials can also be used to determine the efficacy of the compound of Formula I, or a pharmaceutically acceptable salt thereof in humans.
[0099] The compound of Formula I or a pharmaceutically acceptable salt thereof may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
[0100] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-cancer agents, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
[0101] Examples
[0102] The following examples do not limit the scope of available synthesis routes and the structural variation of the compounds. Likewise, each of the synthetic intermediates can also be prepared by various approaches. [0103] Example 1
[0104] To a solution of l-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester hydrochloride (30 g, 100.74 mmol) in ethanol (600 mL) was added ammonium acetate (77.65 g, 1000.7 mmol) and the mixture was stirred for 1 h at roomtemperature. After the consumption of starting material, the solvent was removed in vacuo and the resulting residue was partitioned between ethyl acetate and 1 N NaOH. The aqueous layer was further extracted with dichloromethane and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a crude product ethyl 5-amino-l -benzyl- 1, 2,3,6- tetrahydropyridine-4-carboxylate (28 g, Crude, Light yellow sticky mass).
Figure imgf000036_0001
[0105] To a solution of ethyl 5-amino-l -benzyl-1, 2, 3, 6-tetrahydropyridine-4-carboxylate (28.0 g, 107.55 mmol) in DCM (280 mL) was added methyl 3-chloro-3-oxopropanoate (22.02 g, 161.32 mmol) dropwise at 00C. Then it was stirred for 16 hours at room temperature. The reaction mass was quenched with Saturated sodium bicarbonate in water 0 0C and extracted with DCM. The organic layer was dried over sodium sulfate and was evaporated to get crude ethyl 1-benzyl- 5-(3-methoxy-3-oxopropanamido)-l,2,3,6-tetrahydropyridine-4-carboxylate (35.0 g, crude- Yellow sticky solid).
Figure imgf000036_0002
[0106] To a solution of ethyl l-benzyl-5-(3-methoxy-3-oxopropanamido)-l, 2,3,6- tetrahydropyridine-4-carboxylate (30.0g, 83.238 mmol) in methanol (300 mL) was added 25% Sodiummethoxide in methanol (35.97 g, 166.48 mmol) and the mixture was refluxed for 2 hours. After the consumption of starting material, the solvent was removed in vacuo and the resulting residue was dissolved in water. It was extracted with ethylacetate. The aqueous layer was acidified with 1 N hydrochloric acid around pH = 6 at 0°C and precipitated light brown solid was filtered, washed with excess diethyl ether and suck dried to get product methyl 7-benzyl-2,4-dihydroxy- 5,6,7,8-tetrahydro-l,7-naphthyridine-3-carboxylate (14 g, 53.55% - Light brown solid).
Figure imgf000037_0001
[0107] To a flask was charged with 7-benzyl-N-cyclohexyl-2,4-dihydroxy-5,6,7,8- tetrahydro-l,7-naphthyridine-3-carboxamide (1.0 g, 2.621 mmol) was added Phosphorus oxychloride (16.0 mL) drop wise at 0 0C. Then 1.0 mL of dimethyl formamide was added drop wise. The resulting mixture was heated to 115 0C for 24 hours. The reaction mixture was concentrated in vacuo to yield a residue The crude residue was carefully treated with saturated sodium bicarbonate solution at 0 °C and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by combi flash using 12 g silica gel column as standard phase and 20-30% ethyl acetate : hexane as mobile phase to get 7-benzyl-2,4-dichloro- 5,6,7,8-tetrahydro-l,7-naphthyridine-3-carbonitrile (180 mg, 21.58% - Yellow solid) and 8-10% methanol : DCM as mobile phase to get 7-benzyl-4-chl oro-2 -hydroxy-5, 6,7, 8-tetrahydro-l, 7- naphthyridine-3-carbonitrile (200 mg, 25.47% - Light brown solid).
Figure imgf000037_0002
[0108] To a solution, stirred under nitrogen gas, of compound 7-benzyl-4-chloro-2- hydroxy-5, 6, 7, 8-tetrahydro-l, 7-naphthyridine-3-carbonitrile (20 mg, 0.066 mmol) in dimethylformamide (1 mL ) were added diisopropyl ethylamine (17 mg, 0.133 mmol) and tertbutyl piperazine- 1 -carboxylate (19 mg, 0.099 mmol). The reaction mixture was stirred at roomtemperature for 16 h. The precipitated solid was filtered and the solid was washed with ethylacetate (2.0 mL), followed by diethyl ether (2.0 mL) to get the required compound tert-butyl 4-(7-benzyl-3-cyano-2-hydroxy-5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)piperazine-l- carboxylate (9 mg, 31.03% - Off white solid).
Figure imgf000037_0003
[0109] To a solution, stirred under nitrogen gas, of compound 7-benzyl-2,4-dichloro-
5,6,7,8-tetrahydro-l,7-naphthyridine-3-carbonitrile (180 mg, 0.566 mmol) in dimethylformamide (2 mL ) were added diisopropyl ethylamine (109 mg, 0.848 mmol) and tert-butyl piperazine-1- carboxylate (116 mg, 0.622 mmol). The reaction mixture was stirred at roomtemperature for 16 h. The reaction mixture was then quenched with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution. The organic layer was dried over sodium sulfate and was evaporated to give a crude product. The crude was purified by combi flash using 12 g silica gel column as standard phase and 40 - 50% ethyl acetate : hexane as mobile phase to get the tert-butyl 4-(7-benzyl-2-chloro-3-cyano-5,6,7,8- tetrahydro-l,7-naphthyridin-4-yl)piperazine-l -carboxylate (140 mg, 53.03%, Light yellow solid)
Figure imgf000038_0001
[0110] To a Seal tube solution of methyl 7-benzyl-2,4-dihydroxy-5,6,7,8-tetrahydro-l,7- naphthyridine-3-carboxylate (5.0 g, 15.906 mmol) in toluene (40.0 mL) and Cyclohexanamine (3.16 g, 31.813 mmol) was added, then vessel was sealed and reaction carried out at 100°C for 4 hours. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution. The organic layer was dried over sodium sulfate and was evaporated to give a crude product. The crude was purified by combi flash using 24 g silica gel column as standard phase and 2-8% methanol in dichloromethane as mobile phase to get 7-benzyl-N-cyclohexyl-2,4-dihydroxy-5,6,7,8-tetrahydro- l,7-naphthyridine-3 -carboxamide (5.20 g, 85.80% - Off white solid).
Figure imgf000038_0002
[0111] To a solution, stirred under nitrogen gas, of compound tert-butyl 4-(7-benzyl-3- cyano-2-hydroxy-5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)piperazine-l-carboxylate (20 mg, 0.0444 mmol) in DCM (2 mL ) were added Triethylamine (14 mg, 0.1334 mmol) followed by Methanesulfonyl chloride (6 mg, 0.0533 mmol) at 00C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then quenched in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution. The organic layer was dried over sodium sulfate and was evaporated to give a crude product. The crude was purified by combi flash using 4 g silica gel column as standard phase and 40 - 50% ethyl acetate : hexane as mobile phase to get the tert-butyl 4-(7-benzyl-3-cyano-2-((methylsulfonyl)oxy)-5,6,7,8- tetrahydro-l,7-naphthyridin-4-yl)piperazine-l -carboxylate (15 mg, 63.91%, Light yellow solid)
Figure imgf000039_0001
[0112] To a Seal tube tert-butyl 4-(7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-l,7- naphthyridin-4-yl)piperazine-l -carboxylate (100 mg, 0.214 mmol) in toluene (10 mL), 1- (dimethylamino)propan-2-ol (44 mg, 0.427 mmol) and Cesium carbonate (174 mg, 0.534 mmol) were added and bubbled with argon for 15 minutes, then 2,2'-bis(diphenylphosphaneyl)-l,l'- binaphthalene (26 mg, 0.043 mmol) and diacetoxypalladium (7 mg, 0.032 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 90°C for 4 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to the crude material. The crude was purified by combi flash using 4 g silica gel column as standard phase and 1.5-2% methanol in dichloromethane as mobile phase. Further this material was purified by prep TLC method (3% methanol in dichloromethane as mobile phase) to get tert-butyl 4-(7-benzyl-3-cyano-2-((l-(dimethylamino)propan-2-yl)oxy)- 5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)piperazine-l-carboxylate (50 mg, 43.85%, light yellow sticky mass).
Figure imgf000039_0002
[0113] To a Seal tube tert-butyl 4-(7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-l,7- naphthyridin-4-yl)piperazine-l -carboxylate (600 mg, 1.282 mmol) in toluene (40 mL), 1- methylpiperidin-4-amine (293 mg, 2.564 mmol) and Cesium carbonate (1.04 g, 3.205 mmol) were added and bubbled with argon for 15 minutes, then 2,2'-bis(diphenylphosphaneyl)-l,l'- binaphthalene (159 mg, 0.256 mmol) and diacetoxypalladium (43 mg, 0.192 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 90°C for 4 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure . The crude was purified by combi flash using 12 g silica gel column as standard phase and 1-2% methanol in Dichloromethane as mobile phase to get tert-butyl 4-(7- benzyl-3-cyano-2-((l-methylpiperidin-4-yl)amino)-5,6,7,8-tetrahydro-l,7-naphthyridin-4- yl)piperazine-l -carboxylate (900 mg, 64.74%, light yellow sticky solid).
Figure imgf000040_0001
[0114] To a solution of tert-butyl 4-(7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-l,7- naphthyridin-4-yl)piperazine-l -carboxylate (200 mg, 0.427 mmol) in 10.0 mL of DCM was added benzyl Chloroformate (182 mg 1.068 mmol) drop wise at 00C, warmed to rt and stirred for 24 hours at rt. The reaction mass was quenched with Saturated sodium bicarbonate in water 0 0C and extracted with DCM. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by combi flash using 12 g silica gel column as standard phase and 30-35% ethyl acetate in hexane as mobile phase to get benzyl 4-(4- (tert-butoxycarbonyl)piperazin-l-yl)-2-chloro-3-cyano-5,8-dihydro-l,7-naphthyridine-7(6H)- carboxylate (200 mg, 91.74% - Light yellow sticky solid).
Figure imgf000040_0002
[0115] To a Seal tube benzyl 4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-2-chloro-3-cyano- 5,8-dihydro-l,7-naphthyridine-7(6H)-carboxylate (150 mg, 0.419mmol) in toluene (4 mL), 1- (dimethylamino)propan-2-ol (87 mg, 0.839 mmol) and Cesium carbonate (239 mg, 0.732 mmol) were added and bubbled with argon for 15 minutes, then 2,2'-bis(diphenylphosphaneyl)-l,l'- binaphthalene (36 mg, 0.058 mmol) and diacetoxypalladium (10 mg, 0.043 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 90°C for 20 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to the crude material. The crude was mixed with IN7015-088-P1 and purified by combi flash using 12 g silica gel column as standard phase and 1.5-2% methanol in di chloromethane as mobile phase to get benzyl4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-3-cyano- 2-((l-(dimethylamino)propan-2-yl)oxy)-5,8-dihydro-l,7-naphthyridine-7(6H)-carboxylate (80 mg, 35.39%, light yellow sticky solid).
Figure imgf000041_0001
[0116] To a solution of tert-butyl 4-(7-benzyl-3-cyano-2-((l-methylpiperidin-4- yl)amino)-5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)piperazine-l-carboxylate (10 mg, 0.018 mmol) in cyclohexene (2.0 mL) was heated to 800C and stirred for 24 hours at 800C. The reaction mixture was filtered through celite bed, the celite bed was washed with excess 10 % methanol in DCM. The filtrate was concentrated under reduced pressure.
Figure imgf000041_0002
[0117] To a solution of tert-butyl 4-(7-benzyl-3-cyano-2-((l-methylpiperidin-4- yl)amino)-5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)piperazine-l-carboxylate (100 mg, 0.183 mmol) in 5.0 mL of DCM was added benzyl Chloroformate (109 mg 0.642 mmol) drop wise at 00C, warmed to rt and stirred for 48 hours at rt. The reaction mass was quenched with Saturated sodium bicarbonate in water 0 0C and extracted with DCM. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by combi flash using 4 g silica gel column as standard phase and 0.5-1% methanol in di chloromethane as mobile phase to get benzyl 4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-3-cyano-2-((l- methylpiperidin-4-yl)amino)-5,8-dihydro-l,7-naphthyridine-7(6H)-carboxylate (40 mg, 37.04% - Light yellow sticky solid).
Figure imgf000041_0003
[0118] To a solution of benzyl 4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-3-cyano-2-((l- methylpiperidin-4-yl)amino)-5,8-dihydro-l,7-naphthyridine-7(6H)-carboxylate (120 mg, 0.203 mmol) in THF/ethyl acetate (4.0 mL, 1:1) was added 10% Pd-C (80 mg), then the mixture was stirred at room temperature for 48 hours under hydrogen atmosphere. The reaction mixture was filtered through celite bed, the celite bed was washed with excess 10 % methanol in DCM. The filtrate was concentrated under reduced pressure. The crude material was triturated with 50% diethyl ether in hexane (5.0 mL) to get the tert-butyl 4- (3-cyano-2- ((l-methylpiperidin-4-yl) amino) -5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl) piperazine- 1 -carboxylate (60 mg, 65.22%, Light brown sticky solid).
Figure imgf000042_0001
[0119] To a solution of benzyl 4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-3-cyano-2-((l- (dimethylamino)propan-2-yl)oxy)-5,8-dihydro-l,7-naphthyridine-7(6H)-carboxylate (80 mg, 0.138 mmol) in THF/EtOAc (4.0 mL, 1:1) was added 10% Pd-C (40 mg), then the mixture was stirred at room temperature for 72 hours under hydrogen atmosphere. The reaction mixture was filtered through celite bed, the celite bed was washed with excess 10 % methanol in DCM. The filtrate was concentrated under reduced pressure to get the tert-butyl 4-(3-cyano-2-((l- (dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)piperazine-l- carboxylate (30 mg, crude, Light brown sticky solid).
Figure imgf000042_0002
[0120] To (2,2'-bis(diphenylphosphino)-l,l'-binaphthyl) (3 mg, 0.0043mmol) and Tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.0021 mmol) under argon was added toluene (4.0 ml) and the reaction bubbled with Argon for 10 minutes followed by heating to 100°C for 10 minutes. The reaction was cooled to room temperature tert-butyl 4-(3-cyano-2-((l- methylpiperidin-4-yl)amino)-5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)piperazine-l-carboxylate (50 mg, 0.109 mmol) and Sodium tert-butoxide (11 mg, 0.109 mmol) were added to the dark solution as solids. Finally, l-bromo-2-(methoxymethoxy)benzene (29 mg, 0.132 mmol) was added (as the oil) and the reaction heated to 100°C for 20 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was quenched with saturated ammonium chloride in water and extracted with 5% MeoH in DCM, the organics washed with brine. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude was purified by combi flash using 12 g silica gel column as standard phase and 0.5-1% methanol in dichloromethane as mobile phase to get tert-butyl 4-(3-cyano-7-(2-(methoxymethoxy)phenyl)-2- ((l-methylpiperidin-4-yl)amino)-5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)piperazine-l- carboxylate (13 mg, 20.32%, Light yellow sticky solid).
Figure imgf000043_0001
[0121] A solution of tert-butyl 4-(3-cyano-7-(2-(methoxymethoxy)phenyl)-2-((l- methylpiperidin-4-yl)amino)-5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)piperazine-l-carboxylate (5 mg, 0.084 mmol) in Trifluoroethanol:H2O (2 mL, 3:2) was stirred at 130 oC for 150 minutes in microwave condition. The reaction mixture was diluted with saturated sodiumbicarbonate in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced to give a crude 7-(2-(methoxymethoxy)phenyl)-2-((l-methylpiperi din-4-yl)amino)-4-(piperazin-l-yl)-5, 6,7,8- tetrahydro-l,7-naphthyridine-3-carbonitrile (6 mg, crude, Light yellow ticky mass) .
Figure imgf000043_0002
[0122] A solution of tert-butyl 4-(3-cyano-2-((l-(dimethylamino)propan-2-yl)oxy)-7-(2- (methoxymethoxy)phenyl)-5 ,6,7, 8-tetrahydro- 1 ,7-naphthyridin-4-yl)piperazine- 1 -carboxylate (120 mg, 0.206 mmol) in toluene (10 mL) was added silica gel (1 g) and stirred at 120 oC for 5 hours. The reaction mass was cooled to room temperature, filtered and the filtrate was discarded.To the silica gel given excess 10% methanol in DCM wash. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to get 2-((l-(dimethylamino)propan-2- yl)oxy)-7-(2-(methoxy methoxy) phenyl)-4-(piperazin-l-yl)-5,6,7,8-tetrahydro-l,7-naphthyridine- 3 -carbonitrile ( 90 mg, Crude, yellow sticky solid).
Figure imgf000043_0003
[0123] To a stirred solution of 7-(2-(methoxymethoxy)phenyl)-2-((l-methylpiperidin-4- yl)amino)-4-(piperazin-l-yl)-5,6,7,8-tetrahydro-l,7-naphthyridine-3-carbonitrile (10 mg, 0.020 mmol ) in DCM (2 mL) was added tri ethylamine (3 mg, 0.031 mmol) and then acryloyl chloride (2 mg, 0.024 mmol) diluted in DCM (1 mL) was added at -15 °C. The resulting mixture was allowed to 0 °C an stirred at 0 °C for 2 hours. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure to get crude 4-(4-acryloylpiperazin-l-yl)-7-(2-(methoxymethoxy)phenyl)-2-((l- methylpiperidin-4-yl)amino)-5,6,7,8-tetrahydro-l,7-naphthyridine-3-carbonitrile (10 mg, Light yellow sticky mass).
Figure imgf000044_0001
[0124] To a stirred solution of 4-(4-acryloylpiperazin-l-yl)-7-(2- (methoxymethoxy)phenyl)-2-((l-methylpiperidin-4-yl)amino)-5,6,7,8-tetrahydro-l,7- naphthyridine-3 -carbonitrile (10 mg, 0.018 mmol) in DCM (0.2 mL) and trifluoroacetic acid (0.10 mL) was added drop wise at 0 0C. The mixture was stirred at room temperature for 8 hours, then the reaction mass was concentrated to dryness. The residue was quenched with sat. sodium bicarbonate at 0 0C and extracted in 5% methanol in DCM. The organic layer was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to get crude 4-(4- acryloylpiperazin-l-yl)-7-(2-hydroxyphenyl)-2-((l-methylpiperidin-4-yl)amino)-5,6,7,8- tetrahydro-l,7-naphthyridine-3-carbonitrile (8 mg, Crude, Off white sticky solid).
Figure imgf000044_0002
[0125] Example 2 [0126] To (2,2'-bis(diphenylphosphino)-l,T-binaphthyl) (4 mg, 0.006 mmol) and Tris(dibenzylideneacetone)dipalladium(O) (3 mg, 0.003 mmol) under argon was added toluene (2.0 ml) and the reaction bubbled with Argon for 10 minutes followed by heating to 100°C for 10 minutes. The reaction was cooled to room temperature tert-butyl 4-(3-cyano-2-((l- (dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)piperazine-l- carboxylate (30 mg, 0.067 mmol) and Sodium tert-butoxide (8 mg, 0.081 mmol) were added to the dark solution as solids. Finally, l-bromo-2-(methoxymethoxy)benzene (18 mg, 0.081 mmol) was added (as the oil) and the reaction heated to 100°C for 20 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was quenched with saturated ammonium chloride in water and extracted with 5% MeoH in DCM, the organics washed with brine. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was purified prep TLC method (3% methanol in di chloromethane as mobile phase) to get tert-butyl 4- (3-cyano-2-((l-(dimethylamino)propan-2-yl)oxy)-7-(2-(methoxymethoxy)phenyl)-5,6,7,8- tetrahydro-l,7-naphthyridin-4-yl)piperazine-l -carboxylate (8 mg, 20.51%, Light yellow sticky solid).
Figure imgf000045_0001
[0127] To a stirred solution of 4-(4-acryloylpiperazin-l-yl)-2-((l-(dimethylamino)propan- 2-yl)oxy)-7-(2-(methoxymethoxy) phenyl)-5,6,7,8-tetrahydro-l,7-naphthyridine-3-carbonitrile (55 mg, 0.103 mmol) in DCM (0.5 mL) and trifluoroacetic acid (1.0 mL) was added drop wise at 0 °C. The mixture was stirred at room temperature for 3 hours, then the reaction mass was concentrated to dryness. The residue was quenched with sat. sodium bicarbonate at 0 0C and extracted in 5% methanol in DCM. The organic layer was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure. The crude material was purified by prep HPLC method to get 4-(4-acryloylpiperazin-l-yl)-2-((l-(dimethylamino)propan-2-yl) oxy)-7-(2- hydroxyphenyl)-5,6,7,8-tetrahydro-l,7-naphthyridine-3-carbonitrile (15 mg, 30%, White solid).
Figure imgf000046_0001
[0128] Example 3
[0129] To (2,2'-bis(diphenylphosphino)-l,T-binaphthyl) (11 mg, 0.011 mmol) and
Tris(dihenzylideneacetone)dipalladium(0) (5 mg, 0.006 mmol) under argon was added toluene (4.0 ml) and the reaction bubbled with Argon for 10 minutes followed by heating to 100°C for 10 minutes. The reaction was cooled to room temperature tert-butyl 4-(3-cyano-2-((l- (dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)piperazine-l- carboxylate (50 mg, 0.112 mmol) and Sodium tert-butoxide (13 mg, 0.134 mmol) were added to the dark solution as solids. Finally, , 4-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole (44 mg, 0.134 mmol) was added (as the oil) and the reaction heated to 100 °C for 16 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was quenched with saturated ammonium chloride in water and extracted with 5% MeoH in DCM, the organics washed with brine. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude was purified by combi flash using 4 g silica gel column as standard phase and 0.2% methanol in dichloromethane as mobile phase to get tert-butyl 4-(3-cyano-2-((l- (dimethylamino)propan-2-yl)oxy)-7-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-4-yl)- 5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)piperazine-l-carboxylate (25 mg, 32.46%, Light yellow sticky solid).
Figure imgf000046_0002
[0130] A solution of tert-butyl 4-(3-cyano-2-((l-(dimethylamino)propan-2-yl)oxy)-7-(l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-4-yl)-5,6,7,8-tetrahydro-l,7-naphthyridin-4- yl)piperazine-l -carboxylate (30 mg, 0.043 mmol) in toluene (5 mL) was added silica gel (500 mg) and stirred at 110 oC for 5 hours. The reaction mass was cooled to room temperature, filtered and the filtrate was discarded.To the silica gel given excess 10% methanol in DCM wash. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to get 2- ((l-(dimethylamino)propan-2-yl)oxy)-4-(piperazin-l-yl)-7-(l-((2-(trimethylsilyl)ethoxy)methyl)- lH-indazol-4-yl)-5,6,7,8-tetrahydro-l,7-naphthyridine-3-carbonitrile ( 20 mg, Crude, yellow sticky mass).
Figure imgf000047_0001
[0131] A solution of tert-butyl 4-(3-cyano-2-((l-methylpiperidin-4-yl)amino)-7-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazol-4-yl)-5,6,7,8-tetrahydro-l,7-naphthyridin-4- yl)piperazine-l -carboxylate (5 mg, 0.007 mmol) in Trifluoroethanol :H2O (0.9 mL, 2: 1) was stirred at 130 oC for 4 hours in micro wave condition. The reaction mixture was diluted with saturated sodiumbicarbonate in water and extracted to 5% methanol in dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced to give a crude 2-((l-methylpiperidin-4-yl)amino)-4-(piperazin- l-yl)-7-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-4-yl)-5,6,7,8-tetrahydro-l,7- naphthyridine-3-carbonitrile (4 mg, crude, Light yellow ticky mass) .
Figure imgf000047_0002
[0132] To a stirred solution of 2-((l-(dimethylamino)propan-2-yl)oxy)-4-(piperazin-l-yl)-
7-(l-((2-(trimethylsilyl)ethoxy) methyl) -lH-indazol-4-yl)-5,6,7,8-tetrahydro-l,7-naphthyridine- 3 -carbonitrile (20 mg, 0.034 mmol ) in DCM (2 mL) was added triethylamine (5 mg, 0.050 mmol) and then acryloyl chloride (3 mg, 0.04 mmol) diluted in DCM (1 mL) was added at -40 °C. The resulting mixture was stirred at -40 °C for 30 minutes. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by prep TLC method (3% methanol in di chloromethane as mobile phase) to get 4-(4-acryloylpiperazin-l-yl)-2-((l- (dimethylamino)propan-2-yl)oxy)-7-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-4-yl)-
5,6,7,8-tetrahydro-l,7-naphthyridine-3-carbonitrile (10 mg, 47.61% - Light yellow sticky solid).
Figure imgf000048_0001
[0133] To a stirred solution of 4-(4-acryloylpiperazin-l-yl)-2-((l-(dimethylamino)propan- 2-yl)oxy)-7-(l-((2-(trimethylsilyl) ethoxy)methyl)-lH-indazol-4-yl)-5,6,7,8-tetrahydro-l,7- naphthyridine-3 -carbonitrile (5 mg, 0.008 mmol) in DCM (0.2 mL) and trifluoroacetic acid (0.20 mL) was added drop wise at 0 0C. The mixture was stirred at room temperature for 2 hours, then the reaction mass was concentrated to dryness. The residue was quenched with sat. sodium bicarbonate at 0 0C and extracted in 10% methanol in DCM. The organic layer was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to get crude 4-(4- acryloylpiperazin-1 -yl)-2-((l-(dimethylamino)propan-2-yl)oxy)-7-(lH-indazol-4-yl)-5, 6,7,8- tetrahydro-l,7-naphthyridine-3-carbonitrile (3 mg, Crude, light yellow sticky solid).]
Figure imgf000048_0002
[0134] Example 4
[0135] To a solution of 1 -benzyl 4-(tert-butyl) (R)-2-
(((methylsulfonyl)oxy)methyl)piperazine-l,4- dicarboxylate (13.0 g, 30.338 mmol) in N,N- dimethyl acetamide (130.0 mL) was added sodium cyanide (2.97 g, 60.677 mmol) and heated at
55°C for 2 days. The reaction mass was quenched with brine (600 mL )solution.The mixture was partitioned between EtOAc/brine, and the organic layer was washed with brine (3x 150 mL), dried over sodium sulfate, concentrated under reduced pressure to give a yellow liquid. The residue was purified by combi flash using 80 g silica gel column as standard phase and 20-30% ethyl acetate : hexane as mobile phase to afford the title compound (5.50 g, 50.45%, Light yellow sticky liquid). Aqueous layers were basified and dis- posed of in cyanide waste stream.
Figure imgf000049_0001
[0136] To a solution of benzyl (S)-4-(7-benzyl-3-cyano-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5, 6, 7, 8-tetrahydro-l,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-l -carboxylate (30 mg, 0.048 mmol) in DCM (2.0 mL) were added triethyl amine (1 drops) and 1- Chloroethylchloroformate (21 mg 0.150 mmol) drop wise at 0°C, warmed to rt and stirred for 16 hours at rt. Then DCM was removed using vaccum, and vaccum was released under nitrogen, the resulting residue was dissolved in Methanol (1.0 mL) and stirred for 6 hours at 60 °C. The reaction mixture was concentrated to dryness and neutralized with an aqueous saturated solution of sodium bicarbonate and extracted with 10% methanol in di chloromethane (5 mL X3) times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum to get the crude material.
Figure imgf000049_0002
[0137] Example s
[0138] To a solution, stirred under nitrogen gas, of compound benzyl (S)-2-
(cyanomethyl)piperazine-l -carboxylate hydrochloride (1.90 g, 6.425 mmol) in dimethylformamide (10 mL ) were added diisopropyl ethylamine (2.25 g, 17.442 mmol) and 7- benzyl-2,4-dichloro-5,6,7,8-tetrahydro-l,7-naphthyridine-3-carbonitrile (1.85 g, 5.841 mmol). The reaction mixture was stirred at 90 °C for 7 h. The reaction mixture was then quenched with saturated ammonium chloride in water and filtered the precipitated brown solid. The brown solid was purified by combi flash using 12 g silica gel column as standard phase and 30-35% ethyl acetate as mobile phase to afford the title compound (1.20 g, 38.22%, Light yellow sticky solid).
Figure imgf000049_0003
[0139] To a Seal tube benzyl (S)-4-(7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-l,7- naphthyridin-4-yl)-2-(cy anomethyl) piperazine- 1 -carboxylate (600 mg, 1.109 mmol) in dioxane (12 mL), (S)-(l-methylpyrrolidin-2-yl) methanol (383 mg, 3.327 mmol) and Cesium carbonate (1.08 g, 3.327 mmol) were added and bubbled with argon for 15 minutes, then Ruphos-Pd-G3 (93 mg, 0.110 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 100 °C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The brown solid was purified by combi flash using 12 g silica gel column as standard phase and 2-3% methanol in DCM as mobile phase to afford the title compound (450 mg, 65.50%, Light yellow sticky solid).
Figure imgf000050_0001
[0140] To a flask was charged with 7-benzyl-N-cyclohexyl-2,4-dihydroxy-5,6,7,8- tetrahydro-l,7-naphthyridine-3-carboxamide (11 g, 28.835 mmol) was added 11 mL of dimethyl formamide. Then Phosphorus oxychloride (60 mL) was added drop wise at 0 °C. The resulting mixture was heated to 115 °C for 20 hours. The reaction mixture was concentrated in vacuo to yield a residue, the resulting black residue was co-distilled with toluene (150 mL X 3) times. The crude residue was diluted dichloromethane and then carefully treated with ice cooled water at 0 °C, separated the di chloromethane. One more time extracted with di chloromethane. The combained organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to get the first fraction. The aqueous layer was carefully treated with saturated sodium bicarbonate solution at 0 °C and extracted to dichloromethane. The organic layer was separated, dried over sodium sulphate, filtered and concentrated under reduced pressure to get second fraction. The crude material was mixed and purified by combi flash using 80 g silica gel column as standard phase and 20-30% ethyl acetate : hexane as mobile phase to get 7-benzyl-2,4-dichloro-5,6,7,8- tetrahydro-l,7-naphthyridine-3-carbonitrile (3.70 g, 40.34% - Light yellow solid).
Figure imgf000051_0001
[0141] To a Seal tube benzyl (S)-4-(3-cyano-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate (10 mg, 0.019 mmol) in toluene (1 mL), l-bromo-8-chloro naphthalene (6 mg, 0.023 mmol) and Sodium tert-butoxide (3 mg, 0.028 mmol) were added and bubbled with argon for 15 minutes, then 2,2'- bis(diphenyl phosphaneyl)-l,l'-binaphthalene (1.2 mg, 0.002 mmol) and Tris (dibenzylidene acetone) dipalladium(O) (1 mg, 0.001 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 100 °C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give a crude title compound (20 mg, crude, brown thick mass).
Figure imgf000051_0002
[0142] To a Seal tube benzyl (S)-4-(3-cyano-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate (130 mg, 0.245 mmol) in toluene (8 mL), l-bromo-8-chloro naphthalene (77 mg, 0.319 mmol) and Cesium carbonate (199 mg, 0.614 mmol) were added and bubbled with argon for 15 minutes, then Ruphos (23 mg, 0.049 mmol) and Tris (dibenzylidene acetone) dipalladium(O) (45 mg, 0.049 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 100 °C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. . The brown solid was purified by combi flash using 12 g silica gel column as standard phase and 2-3% methanol in DCM as mobile phase to afford the title compound (85 mg, 50.29%, Light yellow sticky solid).
Figure imgf000052_0001
[0143] To a solution of benzyl (S)-4-(7-(8-chloronaphthalen-l-yl)-3-cyano-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)-2-
(cyanomethyl)piperazine-l -carboxylate (5 mg, 0.007 mmol) in 1 mL THF: Ethylacetate (1: 1) was added 10% Pd-C (2 mg). Then the mixture was stirred at room temperature for 6 hours under hydrogen bladder pressure. The reaction mixture was filtered through celite bed, the celite bed was washed with excess 10 % methanol in DCM. The filtrate was concentrated under reduced pressure (4 mg, brown sticky mass).
Figure imgf000052_0002
[0144] To a stirred solution of 2-fluoroacrylic acid (1 mg, 0.011 mmol) in di chloromethane (1 mL), Diisopropyl ethylamine (2 mg, 0.018 mmol) was added and cooled to 0 °C. Then HATU (3 mg, 0.009 mmol) was added. After stirring for 30 min at 0 °C, 7-(8-chloronaphthalen-l-yl)-4- ((S)-3-(cyanomethyl)piperazin-l-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5, 6,7,8- tetrahydro-l,7-naphthyridine-3-carbonitrile (4 mg, 0.0072 mmol) was added and stirred for 16 hours at room temperature. The reaction mass was quenched with saturated Aq. ammonium chloride and extracted to ethylacetate. The organic layer was separated, washed with water, brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude material (5 mg, crude - Light yellowish brown solid).
Figure imgf000052_0003
[0145] Example 6
[0146] To a stirred solution of 7-(8-chloronaphthalen-l-yl)-4-((S)-3- (cyanomethyl)piperazin-l-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-l,7- naphthyridine-3-carbonitrile (35 mg, 0.063 mmol ) in DCM (4 mL) was added triethylamine (10 mg, 0.094 mmol) and then acryloyl chloride (7 mg, 0.075 mmol) diluted in DCM (0.5 mL) was added drop wise at -40 °C. The resulting mixture was stirred at -40 °C for 30 minutes. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by preparative HPLC purification method to get 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-l-yl)-7-(8- chloronaphthalen-1 -yl)-2-(((S)- 1 -methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro- 1,7- naphthyridine-3-carbonitrile (25 mg, 65.78% - Light yellow solid).
Figure imgf000053_0001
[0147] Example 7
[0148] To a Seal tube benzyl (S)-4-(7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-l,7- naphthyridin-4-yl)-2-(cyanomethyl)piperazine-l -carboxylate (800 mg, 1.478 mmol) in toluene (12 mL), (R)-(l-methylpyrrolidin-3-yl)methanol (681 mg, 5.914 mmol) and Cesium carbonate (1.20 g, 3.696 mmol) were added and bubbled with argon for 15 minutes, then Ruphos (137 mg, 0.295 mmol) and Tris (dibenzylidene acetone) dipalladium(O) (271 mg, 0.295 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 100 °C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. . The brown solid was purified by combi flash using 12 g silica gel column as standard phase and 2-3% methanol in DCM as mobile phase to afford the title compound (450 mg, 49.12%, Light yellow sticky solid).
Figure imgf000054_0001
[0149] To a solution of benzyl (S)-4-(7-benzyl-3-cyano-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5, 6, 7, 8-tetrahydro-l,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-l -carboxylate (450 mg, 0.726 mmol) in dichloroethane (5.0 mL) was added 1 -Chloroethylchloroformate (311 mg, 2.178 mmol) drop wise at rt, heated to 85 °C and stirred for 3 hours at rt. Then di chloroethane was removed using vaccum, and vaccum was released under nitrogen, the resulting residue was dissolved in Methanol (5.0 mL) and stirred for 1 hour at 70 °C. The reaction mixture was concentrated to dryness and neutralized with an aqueous saturated solution of sodium bicarbonate and extracted with 10% methanol in di chloromethane (5 mL X3) times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The brown solid was purified by combi flash using 12 g neutral alumina packed column as standard phase and 6- 20% methanol in DCM as mobile phase to afford the title compound (300 mg, 78.12%, Light yellow sticky solid).
Figure imgf000054_0002
[0150] To a Seal tube benzyl (S)-4-(3-cyano-2-(((R)-l-methylpyrrolidin-3-yl)methoxy)- 5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate (20 mg, 0.038 mmol) in toluene (1 mL), l-bromo-8-chloro naphthalene (12 mg, 0.049 mmol) and Cesium carbonate (31 mg, 0.094 mmol) were added and bubbled with argon for 15 minutes, then Ruphos (3 mg, 0.006 mmol) and Tris (dibenzylidene acetone) dipalladium(O) (3 mg, 0.003 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 85 °C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The crude was purified by prep TLC plate using 3% methanol in DCM as amobile phase to give a title compound (7 mg, 26.92%, light yellow solid).
Figure imgf000055_0001
[0151] To a solution of benzyl (S)-4-(7-(8-chloronaphthalen-l-yl)-3-cyano-2-(((R)-l- methylpyrrolidin-3-yl)methoxy)-5,6,7,8-tetrahydro-l,7-naphthyridin-4-yl)-2-
(cyanomethyl)piperazine-l -carboxylate (35 mg, 0.051 mmol) in 3 mL THF was added 10% Pd-C (40mg). Then the mixture was stirred at room temperature for 48 hours under hydrogen bladder pressure. The reaction mixture was filtered through celite bed, the celite bed was washed with excess 10 % methanol in DCM. The filtrate was concentrated under reduced pressure to give a title compound (25 mg, Crude, Light yellow brown mass).
Figure imgf000055_0002
[0152] To a stirred solution of 2-fluoroacrylic acid (6 mg, 0.067 mmol) in di chloromethane
(2 mL), Diisopropyl ethylamine (15 mg, 0.112 mmol) was added and cooled to 0 °C. Then HATU (21 mg, 0.054 mmol) was added. After stirring for 30 min at 0 °C, 7-(8-chloronaphthalen-l-yl)-4- ((S)-3-(cyanomethyl)piperazin-l-yl)-2-(((R)-l-methylpyrrolidin-3-yl)methoxy)-5, 6,7,8- tetrahydro-l,7-naphthyridine-3-carbonitrile (25 mg, 0.044mmol) was added and stirred for 16 hours at room temperature. The reaction mass was quenched with saturated Aq. ammonium chloride and extracted to ethylacetate. The crude was purified by preparative HPLC purification method to get 7-(8-chloronaphthalen-l-yl)-4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin- l-yl)-2-(((R)-l-methylpyrrolidin-3-yl)methoxy)-5,6,7,8-tetrahydro-l,7-naphthyridine-3- carbonitrile (2.4 mg, 7.85%, Light yellow solid).
Figure imgf000056_0001
[0153] Example 8
[0154] Inhibition of KRas G12C-dependent Cell Growth
[0155] This example illustrates that exemplary compounds inhibit the growth of tumor cell lines that express KRas G12C. The cellular inhibition of KRAs G12C by exemplary compounds was determined by measuring the amount of a downstream marker of KRas activity, phosphorylated ERK (“Phospho-ERK”).
[0156] Cell Lines and Culture conditions: H23 and Hl 373 cell lines were obtained from AddexBio. They were grown in a T-75 flask in RPMI Medium containing 10% fetal bovine serum and penicillin-streptomycin at 37 oC in a humidified, 5% CO2 incubator.
[0157] Proliferation assay: H23 or H1373 cells (100 pl, 2,500 cells/well) were plated in a 96-well plate and incubated overnight at 37oC in a humidified, 5% CO2 incubator. Next day, medium was replaced with 100 pl of fresh growth medium containing serially diluted test compounds in duplicate wells. After 72 hour incubation with the compound, cell viability was measured in a luminometer after the addition of 100 pL/well CellTiterGlo reagent (Promega) as recommended by the manufacturer.
[0158] Serial dilutions of test compounds: Test compounds were serially diluted 5-fold in DMSO starting from 10 mM to 0.64 pM. These serially diluted compounds were diluted 100 fold in growth medium (2 pl to 200 pl) followed by another 10 fold dilution in growth medium (25 pl to 250 pl). Final concentration of compounds in the growth medium ranged between 10 pM to 0.64 nM.
[0159] Quantitative analysis of phospho-ERK protein levels in H23 and H1373 cell lines: Similar to proliferation assay, a 8-point dose response curve will be generated in duplicate. In cell western will be done using phosphor-ERK and total-ERK antibodies. Detection will be done using anti-rabbit and anti-mouse secondary antibodies. Imaging and quantification will be on LICOR.
[0160] Example 13 [0161] This example illustrates additional procedures in testing the compounds disclosed herein. Coupled Nucleotide Exchange Assay: Purified GDP-bound KRAS protein (aa 1- 169), containing both G12C and C118A amino acid substitutions and an N-terminal His-tag, was pre- incubated with a compound dose-response titration for 2 hours in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCh, and 0.01% Triton X-100). Following compound preincubation, purified SOS protein (aa 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional hour. To determine the extent of inhibition of SOS-mediated nucleotide exchange, purified GST-tagged cRAF (aa 1-149), nickel chelate AlphaLISA acceptor beads (PerkinElmer AL108R), and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were added to the assay wells and incubated for 10 minutes. The assay plates were then read on a PerkinElmer EnVision Multilabel Reader, using AlphaScreen® technology, and data were analyzed using a 4- parameter logistic model to calculate IC50 values. [0162] Phospho-ERKl/2 MSD Assay: MIA PaCa-2 (ATCC® CRL-1420™) and A549 (ATCC® CCL-185™) cells were cultured in RPMI 1640 Medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and lx penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). Sixteen hours prior to compound treatment, MIA PaCa-2 or A549 cells were seeded in 96-well cell culture plates at a density of 25,000 cells/well and incubated at 37°C, 5% CO2. A compound dose-response titration was diluted in growth media, added to appropriate wells of a cell culture plate, and then incubated at 37°C, 5% CO2 for 4 hours. Following compound treatment, cells were stimulated with 10 ng/mL EGF (Roche 11376454001) for 10 min, washed with ice-cold Dulbecco's phosphate-buffered saline, no Ca2+ or Mg2+ (ThermoFisher Scientific 14190144), and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001). Cell lysates were stored frozen at -80°C overnight. Phosphorylation of ERK1/2 in compound-treated lysates was assayed using Phospho-ERKl/2 Whole Cell Lysate kits (Meso Scale Discovery K151DWD) according to the manufacturer's protocol. Assay plates were read on a Meso Scale Discovery Sector Imager 6000, and data were analyzed using a 4-parameter logistic model to calculate IC50 values. [0163] [0164] It will be appreciated by persons skilled in the art that the invention described herein is not limited to what has been particularly shown and described. Rather, the scope of the invention is defined by the claims which follow. It should further be understood that the above description is only representative of illustrative examples of embodiments. The description has not attempted to exhaustively enumerate all possible variations. The alternate embodiments may not have been presented for a specific substituent of the compound, or a step of the method, and may result from a different combination of described substituent or step, or that other undescribed alternate embodiments may be available for a compound or method, is not to be considered a disclaimer of those alternate embodiments. It will be appreciated that many of those un-described embodiments are within the literal scope of the following claims, and others are equivalent.

Claims

CLAIMS 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, saturated or partially saturated monocyclic, bridged or
Figure imgf000059_0001
spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R6; B is a bond, O, S or NRa; R1 is C(O)CRb=CRcRd, SO2CRb=CRcRd, C(O)CΞCRc, or SO2CΞCRc; R2 is selected from the group consisting of hydrogen, C(O)ORm, C(O)N(Rm)2, C(O) C1-6alkyl, haloalkyl, C1-6alkyl, hydroxyC1-6alkyl, dihydroxyC1-10alkyl, cycloalkyl, heterocycloalkyl, C1- 6alkylene-cycloalkyl, C1-6alkylene-heterocycloalkyl, C1-6alkylene-aryl, C1-6alkylene-heteroaryl, C1-6alkylene-N(Rm)2, C1-6alkylene-N(Rm)(CORm), C1-6alkylene-N(Rm)(C1-6alkylene-aryl), C1- 6alkylene-N(Rm)(C1-6alkylene-heteroaryl), C1-6alkylene-N(Rm)(C(O)C1-6alkylene-aryl), C1- 6alkylene-N(Rm)(C(O)C1-6alkylene-heteroaryl), spirocyclic ring, and bridged ring, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moiety of these substituents is optionally substituted with one or more of halogen, acyl, CN, haloalkyl, hydroxyl, oxo, C1-6alkyl, OC1- 6alkyl, hydroxyC1-6alkyl, C1-6alkylene-N(Rm)2, C1-6alkylene-N(Rm)(CORm), N(Rm)2, cycloalkyl, heterocycloalkyl, C1-6alkylene-heterocycloalkyl, C1-6alkylene-aryl, and C1-6alkylene-heteroaryl; R3 is independently C1-6alkyl, C1-6alkylene-CN, oxo, haloalkyl, hydroxyl or halogen; L is a bond, -C(O)-, or C1-3alkylene; R4 is a substituent selected from the group consisting of hydrogen, cycloalkyl, heterocyclyl, aryl, C1-6alkylene-aryl, C1-6alkylene-heteroaryl, and heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl moiety of the substituent is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-6alkyl, OC1-6alkyl, hydroxyCi-ealkyl, Ci-6alkylene-N(Rm )2, Ci-6alkylene-N(Rm)(CORm), CN, CF3, OH, N(Rm )2, haloCi-ealkyl, and cycloalkyl;
R5 is selected from the group consisitng of hydrogen, cyano, ORm, C(O)ORm, C(O)N(Rm)2, C(O) Ci-ealkyl, and CF3,
R6 is selected from the group consisitng of oxo, Ci-ealkyl, OCi-ealkyl, hydroxylCi-ealkyl, Ci- ealkylene-CN, Ci-ealkylene OCi-ealkyl, C2-4 alkynyl, haloalkyl, cyano, C(O)ORm, C(O)N(Rm)2, N(Rm)2, , Ci-ealkylene-N(Rm)2, Ci-ealkylene-aryl, Ci-ealkylene-heteroaryl; C(O)OCi-ealkyl, C(O)N(Rm)2, and C(O)Ci-6alkyl;
Ra is selected from the group consisting of hydrogen, Ci-ealkyl, C(O)Ci-ealkyl, C(O)Rm and C(O)N(Rm)2;
Rb is selected from the group consisting of hydrogen, deuterium, halogen, Ci-ealkyl, OCi-ealkyl, hydroxyl-Ci-ealkyl, halo-Ci-ealkyl, N(Rm)(C(O) Ci-ealkyl), Ci-ealkylene-OCi-ealkyl, Ci-ealkylene- heteroaryl, and Ci-ealkylene-aryl,
Rc and Rd are independently selected from the group consisting of hydrogen, deuterium, CN, halogen, Ci-ealkyl, halo-Ci-ealkyl, hydroxyl-Ci-ealkyl, Ci-ealkylene-OCi-ealkyl, Ci-ealkylene- N(Ci-ealkyl)(halo-Ci-ealkyl), , Ci-ealkylene-N(Rm )2, Ci-ealkylene-N(Rm)(CORm), CON(Rm)2, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, Ci-ealkylene-heteroaryl, Ci-ealkylene-aryl, Ci- ealkylene-cycloalkyl, and Ci-ealkylene-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl, or aryl moiety of Rc and Rd is optionally substituted with one or more of halogen, haloalkyl, Ci-ealkyl, OCi-ealkyl, and CN;
Ra and Rd optionally link up to form a 5 to 8 membered, partially unsaturated ring, wherein the ring is optionally substituted with oxo or Ci-ealkyl;
Rm in each instance is independently hydrogen or Ci-ealkyl, acyl, heteroalkyl, hydroxyl-Ci-ealkyl or halo-Ci-ealkyl, wherein optionally two Rm together with the nitrogen they are attached to link up to form a heterocyclic ring; m is 0, 1 or 2; n is 0, 1 or 2; and p is 0, 1 or 2.
2. The compound or the pharmaceutically acceptable salt thereof of claim 1, wherein R1 is C(O)CRb=CRcRd, Rb is selected from the group consisting of hydrogen, deuterium, halogen, Ci- ealkyl, halo-Ci-ealkyl, hydroxyl-Ci-ealkyl, and N(Rm)(C(O)Ci-ealkyl).
59
3. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-2, wherein one of Rc and Rd is selected from the group consisting of hydrogen, deuterium, halogen, CN, Ci-ealkyl, halo-Ci-ealkyl, hydroxyl-Ci-ealkyl, CON(Rm)2, Ci-ealkylene-OCi-ealkyl, Ci- 6alkylene-N(Rm )2, Ci-6alkylene-N(Rm)(CORm), heterocycloalkyl, heteroaryl, aryl, Ci-ealkylene- heterocycloalkyl, Ci-ealkylene-heteroaryl, and Ci-ealkylene-aryl, wherein the heterocycloalkyl, heteroaryl, or aryl moiety of these is optionally substituted with one or more of halogen, Ci- ealkyl, and OCi-ealkyl; and wherein the other of Rc and Rd is hydrogen or deuterium.
4. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-3, wherein the alkene in C(O)CRb=CRcRd for R1 is a trans configuration
5. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-4, wherein one of Rc and Rd is Ci-salkylene-heterocy cloalkyl, Ci-salkylene-cy cloalkyl, or Ci- salkylene-heteroaryl. wherein the heterocycloalkyl, cloalkyl or heteroaryl moiety of these substituents is optionally substituted with one or more of halogen, CN, haloalky 1, hydroxyl, oxo, Ci-ealkyl, OCi-ealkyl, hydroxyCi-ealkyl, cycloalkyl, and heterocycloalkyl.
6. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-5, wherein one of Rc and Rd is Ci-salkylene-heterocy cloalkyl, wherein the heterocycloalkyl is 5 or 6 membered and is optionally substituted with one or more of halogen, Ci-ealkyl, OCi-ealkyl and cycloalkyl.
7. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-6, wherein B is O or NH.
8. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-7, wherein R2 is heterocycloalkyl, Ci-ealkylene-heterocy cloalkyl, Ci-ealkylene-heteroaryl, or Ci- 6alkylene-N(Rm)2.
9. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-8, wherein p is 1.
10. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-9, wherein B is a bond and R2 is an optionally substituted bridged ring.
11. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-10, wherein R4 is aryl or heteroaryl, wherein each of the aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-ealkyl, hydroxyCi-ealkyl, CN, CFs, N(Rm )2, haloCi-ealkyl, and cycloalkyl.
12. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-11, wherein L is a bond.
60
13. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-12, wherein R5 is selected from the group consisting of CN, Ci-ealkylene-CN, C(O)Ci-6alkyl, and CFs.
14. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-13, wherein R5 is CN.
15. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-14, wherein A is a 6-membered ring.
16. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-15, wherein R6 is selected from the group consisting of oxo, Ci-ealkyl, Ci-ealkylene-CN, Ci-ealkylene OCi-ealkyl, C2-C4 alkynyl, haloalkyl, cyano, C(O)ORm, C(O)N(Rm)2, Ci-6alkylene-N(Rm)2, Ci- ealkylene-aryl, Ci-ealkylene-heteroaryl, C(O)OCi-ealkyl, C(O)N(Rm)2, and C(O)Ci-ealkyl.
17. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-16, wherein R6 is selected from the group consisting of oxo, Ci-ealkyl, Ci-ealkylene-CN, C2-C4 alkynyl, haloalkyl, cyano, and C(O)ORm; and wherein n is 1.
18. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula (I) according to any one of claims 1-17 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
19. A method for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of Formula (I) according to any one of claims 1-17 or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
20. A method for treating cancer comprising administering to a subject having cancer a therapeutically effective amount of a compound of Formula (I) according to any one of claims 1- 17 or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
21. The method of claim 20, wherein the cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous
61 adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bihary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial ‘carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.
22. The method of any one of claims 20-21, wherein the cancer is a KRas G12C-associated cancer.
23. The method of any one of claims 20-22, wherein the cancer is non-small cell lung cancer.
24. The method of any one of claims 20-22, wherein the cancer is colon cancer.
25. The method of any one of claims 20-22, wherein the cancer is pancratic cancer.
26. The method of any one of claims 20-25, further comprising administering to the subject an additional anti-cancer agent.
62
27. The method of claim 26, wherein the additional anti-cancer agent is selecte from the group cosnsiting of alkylating agent, platinum agent, antimetabolite, topoisomerase inhibitor, antitumor antibiotics, antimitotic agent, aromatase inhibitor, thymidylate synthase inhibitor, dna antagonist, famesyltransferase inhibitor, pump inhibitor, histone acetyltransferase inhibitor, metalloproteinase inhibitor, ribonucleoside reductase inhibitor, tnf alpha agonist/antagonist, endothelin receptor antagonist, retinoic acid receptor agonist, immuno-modulator, hormonal and antihormonal agent, photodynamic agent, SHP2 inhibitors, CDK 4/6 inhibitors, protein-protein interaction distruptors, phosphatase inhibitors and kinase inhibitor.
28. The method of claim 26, wherein the additional anti-cancer agent is selecte from the group cosnsiting of poziotinib, bevacizumab, bortezomib, capecitabine, cetuximab, fluorouracil, imatinib, irinotecan, leucovorin, oxaliplatin, panitumumab, pemetrexed, temozolomide, cisplatin, paclitaxel, erlotinib, sunitinib, lapatinib, sorafenib, carboplatin, doxorubicin, docetaxel, gemcitabine, etoposide, gefitinib, PD153035, cetuximab, bevacizumab, panitumumab, trastuzumab, anti-c-Met antibodies, gefitinib, ZD6474, EMD-72000, pariitumab, ICR-62, CI- 1033, lapatinib, AEE788, EKB-569, EXEL 7647/EXEL 0999, erlotinib, imatinib, sorafinib, sunitinib, dasatinib, vandetinib, temsirolimus, PTK787, pazopanib, AZD2171, everolimus, seliciclib, AMG 706, axitinib, PD0325901, PKC-412, CEP701, XL880, bosutinib, BIBF1120, BIBF1120, nilotinib, AZD6244, HKI-272, MS-275, BI2536, GX15-070, AZD0530, enzastaurin, MLN-518, ARQ197, CM101, IFN-.alpha., IL-12, platelet factor-4, suramin, SU5416, thrombospondin, VEGFR antagonists, angiostatic steroids plus heparin, Cartilage-Derived Angiogenesis Inhibitory Factor, matrix metalloproteinase inhibitors, batimastat, marimastat, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, thrombospondin, .alpha.V.beta.3 inhibitors, linomide, and ADH-1, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine, streptozocin, carboplatin, cisplatin, satraplatin, oxaliplatin, altretamine, ET-743, XL119, dacarbazine, chlormethine, bendamustine, trofosfamide, uramustine, fotemustine, nimustine, prednimustine, ranimustine, semustine, nedaplatin, triplatin tetranitrate, mannosulfan, treosulfan, temozolomide, carboquone, triaziquone, triethylenemelamine, procarbazin, doxorubicin, daunorubicin, epirubicin, idarubicin, anthracenedione, mitoxantrone, mitomycin C, bleomycin, dactinomycin, plicatomycin, irinotecan, camptothecin, rubitecan, belotecan, etoposide, teniposide, topotecan, paclitaxel, taxol, docetaxel, BMS-275183, xyotax, tocosal, vinorlebine, vincristine, vinblastine, vindesine, vinzolidine, etoposide, teniposide, ixabepilone, larotaxel, ortataxel, tesetaxel, ispinesib, fluorouracil, floxuridine, methotrexate, xeloda, arranon, leucovorin, hydroxyurea, thioguanine, mercaptopurine, cytarabine, pentostatin, fludarabine phosphate, cladribine, asparaginase, gemcitabine, pemetrexed, bortezomib, aminopterin, raltitrexed, clofarabine, enocitabine, sapacitabine, and azacitidine.
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