KRAS G12C inhibitors

Abstract

The present invention relates to compounds that inhibit KRas G12C. Specifically, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions containing the compounds, and methods of use thereof.

Description

[Technical field]

[0001] The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds, and methods of use thereof. [Background technology]

[0002] Kirsten rat sarcoma 2 viral oncogene homolog ("KRas") is a small GTPase and a member of the Ras family of oncogenes. KRas serves as a molecular switch that shuttles between inactive (GDP-bound) and active (GTP-bound) states to transmit upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 3:394-401).

[0003] The role of activated KRas in malignancy was observed more than 30 years ago (see, e.g., Santos et al., (1984) Science 223:661-664). Aberrant expression of KRas accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25-30% of lung adenocarcinomas. (See, e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428). Single nucleotide substitutions resulting in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma, with the G12C transversion being the most common activating mutation (see, e.g., Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177 doi:10.1158 / 1078-0432. CCR-11-3265, published online September 26, 2012).

[0004] The well-known role of KRAs in malignancy and the discovery of these frequent mutations of KRas in various tumor types have made KRas a highly attractive target for cancer therapy by the pharmaceutical industry.

[0005] Although many attempts to target KRas have failed, compounds that inhibit KRas activity, including those that interfere with effectors such as guanine nucleotide exchange factors (see, for example, Sun et al., (2012) Agnew Chem Int Ed Engl. 51 (25): 6140-6143 doi: 10.1002 / anie201201358) and also target KRas G12C (see, for example, Ostrem et al., (2013) Nature 503: 548-551), are still highly desirable and under investigation. Clearly, there is still ongoing interest and attempts to develop inhibitors of KRas, particularly inhibitors of activated KRas mutants, including KRas G12C.

[0006] Thus, there is a need to develop novel KRas G12C inhibitors that exhibit sufficient efficacy, stability, and / or safety to treat KRas G12C-mediated cancers. The compounds and compositions of the present invention advantageously overcome one or more of the previous shortcomings by providing selective KRas G12C inhibitors. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Alamgeer et al.,(2013)Current Opin Pharmcol.3:394-401 [Non-Patent Document 2] Santos et al.,(1984)Science 223:661-664 [Non-Patent Document 3] Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428 [Non-Patent Document 4] Dogan et al.,(2012)Clin Cancer Res.18(22):6169-6177 doi:10.1158 / 1078-0432.CCR-11-3265 [Non-Patent Document 5] Sun et al.,(2012)Agnew Chem Int Ed Engl.51(25):6140-6143 doi:10.1002 / anie201201358 [Non-Patent Document 6] Ostrem et al.,(2013)Nature 503:548-551 Summary of the Invention

[0008] In one aspect of the present invention, compounds are provided that inhibit KRas G12C activity. In certain embodiments, the compounds are represented by formula (I) or: [ka] or a pharma- ceutically acceptable salt thereof, X is a 4-12 membered saturated or partially saturated monocyclic ring, bridged ring, spirocyclic ring, or fused bicyclic ring, and the saturated or partially saturated monocyclic ring is 8 is optionally replaced by Y is a bond, O, S, or NR 5 and R 1 But -C(O)C(R A ) [ka] C(R B ) p OR -SO 2 C(R A ) [ka] C(R B ) p and R 2 is hydrogen, alkyl, alkoxy, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR 5 SO 2 C1-C3 alkyl, haloalkyl, -Z-NR 5 R 10 , cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl, and each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be selected from one or more R 9 may be optionally substituted with Z is C1-C4 alkylene; R 3 are independently hydrogen, halogen, C1-C3 alkyl, oxo, CN, -O-haloalkyl, or -OR 5 and L is a bond, -C(O)-, or C1-C3 alkylene; R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl, and each of the cycloalkyl, heterocyclyl, aryl, aralkyl, and heteroaryl is independently R 6 , R 7 , or R 9 may be optionally substituted with one or more substituents selected from Each R 5 is independently hydrogen or C1-C3 alkyl; R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, each of which is selected from one or more R 7 may be optionally substituted with Each R 7 are independently halogen, hydroxyl, C1-C6 alkyl, C2-C4 alkynyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, or Q-haloalkyl, where Q is O or S; Each R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 , -C(O)N(R 5 ) 2 , -N(R 5 ) 2 or haloC1-C3 alkyl, wherein C1-C3 alkyl is cyano, halogen, -OR 5 , -N(R 5 ) 2 or heteroaryl, Each R 9 are independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, -N(R 5 ) 2, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein C1-C6 alkyl can be optionally substituted with cycloalkyl; Each R 10 is independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl, or hydroxyalkyl; R A is absent, hydrogen, deuterium, cyano, halogen, C1-C-3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 ) 2 or hydroxyalkyl, Each R B are independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 (In the formula, R 11 is haloalkyl), -C(O)N(R 5 ) 2 , -NHC(O)C1-C3 alkyl, -CH 2 NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, where the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and the heteroaryl portion of the heteroaryl or heteroarylalkyl is substituted with one or more R 7 is optionally replaced by p is 1 or 2; [ka] If is a triple bond, R A But it doesn't exist, R B exists and p is equal to 1 or or [ka] If is a double bond, R A But there exists R B exists and p is equal to 2 or R A , R B and the carbon atom to which they are attached may be one or more R 7 forming a 5-8 membered partially saturated cycloalkyl optionally substituted with

[0009] Also included are compounds of formula I having formula IA: [ka]

[0010] In the formula, R 1 , R 3 , R 4 , R 8 and L are as defined for formula I; R 2 is one or more R 9 and the piperazinyl ring is optionally substituted with one or more R 8 Optionally substituted with R 8 is as defined for formula I.

[0011] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0012] In yet another aspect of the invention, there is provided a method for inhibiting KRas G12C activity in a cell, the method comprising contacting the cell with a compound of formula I and formula IA. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0013] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula I and Formula IA, as defined herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0014] Also provided is a method for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the invention, or a pharma- ceutically acceptable salt thereof.

[0015] Also provided herein is a method of treating a KRas G12C-associated disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I and Formula IA, or a pharma- ceutically acceptable salt or solvate thereof, as defined herein, or a pharmaceutical composition thereof.

[0016] Also provided herein are compounds of Formula I and Formula IA, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in therapy.

[0017] Also provided herein are compounds of Formula I and Formula IA, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in the treatment of cancer.

[0018] Also provided herein are compounds of Formula I and Formula IA, or pharma- ceutically acceptable salts or solvates thereof, for use in inhibiting KRas G12C.

[0019] Also provided herein are compounds of Formula I and Formula IA, or pharma- ceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, as de?ned herein, for use in the treatment of a KRas G12C-associated disease or disorder.

[0020] Also provided herein is the use of a compound of Formula I and Formula IA, or a pharma- ceutically acceptable salt or solvate thereof, as de?ned herein, in the manufacture of a medicament for the treatment of cancer.

[0021] Also provided herein is the use of a compound of Formula I and Formula IA, or a pharma- ceutically acceptable salt or solvate thereof, as de?ned herein, in the manufacture of a medicament for the inhibition of the activity of KRas G12C.

[0022] Also provided herein is the use of a compound of Formula I and Formula IA, or a pharma- ceutically acceptable salt or solvate thereof, as de?ned herein, in the manufacture of a medicament for the treatment of a KRas G12C-associated disease or disorder.

[0023] Also provided herein is a method for treating cancer in a patient in need of such treatment, comprising: (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula I or Formula IA, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0024] Also provided herein are processes for preparing compounds of formula I and formula IA, or a pharma- ceutically acceptable salt or solvate thereof.

[0025] Also provided herein are compounds of Formula I and Formula IA, or pharma- ceutically acceptable salts thereof, obtained by the process for preparing the compounds as defined herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] The present invention relates to inhibitors of KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising a therapeutically effective amount of the compounds, and methods of use thereof.

[0027] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications referenced herein are incorporated herein by reference.

[0028] As used herein, "KRas G12C" refers to a mutant mammalian KRas protein containing a glycine to cysteine ​​amino acid substitution at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by Uniprot KB / Swissprot P01116: variant p.Gly12Cys.

[0029] As used herein, "KRas G12C inhibitor" refers to the compounds of the present invention represented by formula (I) as described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12C. The KRas G12C inhibitors of the present invention interact with KRas G12C and irreversibly bind thereto by forming a covalent adduct with the sulfhydryl side chain of the cysteine ​​residue at position 12, thereby inhibiting the enzymatic activity of KRas G12C.

[0030] As used herein, "KRas G12C-associated disease or disorder" refers to a disease or disorder that is associated with, mediated by, or has KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is KRas G12C-associated cancer.

[0031] As used herein, the terms "subject", "individual", or "patient" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with a KRas G12C mutation (e.g., determined using a regulatory approved, e.g., FDA approved, assay or kit). In some embodiments, the subject has a tumor that is positive for the KRas G12C mutation (e.g., determined using a regulatory approved, e.g., FDA approved, assay or kit). The subject may be a subject with a tumor that is positive for the KRas G12C mutation (e.g., identified as positive using a regulatory approved, e.g., FDA approved, assay or kit). The subject may be a subject whose tumor has a KRas G12C mutation (e.g., where the tumor is identified as such using a regulatory 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 clinical records indicating that the subject has a tumor with a KRas G12C mutation (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0032] The term "pediatric patient" as used herein refers to a patient who is under 16 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subpopulations, including neonates (birth to 1 month), infants (1 month to 2 years), children (2 to 12 years), and adolescents (12 to 21 years (until their 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0033] In some embodiments of any of the methods or uses described herein, the assays used to determine whether a patient has a KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12C-associated cancer, a patient having one or more symptoms of a KRas G12C-associated cancer, and / or a patient at high risk of developing a KRas G12C-associated cancer) may 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 using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0034] The term "regulatory authority" refers to a national agency that approves pharmaceutical products for medical use in that country. For example, a non-limiting example of a regulatory authority is the US Food and Drug Administration (FDA).

[0035] The term "amino" means -NH 2 Refers to...

[0036] The term "acyl" means -C(O)CH 3 Refers to...

[0037] The term "alkyl" as used herein refers to straight- and branched-chain aliphatic groups having 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms, optionally substituted with 1, 2, or 3 substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0038] The term "haloalkyl" refers to an alkyl chain as defined herein above in which one or more hydrogens have been replaced by halogen. Examples of haloalkyl are trifluoromethyl, difluoromethyl, and fluoromethyl.

[0039] The term "haloalkyloxy" refers to -O-haloalkyl.

[0040] An "alkylene" group is an alkyl group, as defined herein above, that is positioned between and serves to link two other chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0041] The term "alkoxy" refers to -OC1-C6 alkyl.

[0042] The term "cycloalkyl" as used herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example, 3 to 8 carbons, and further examples, 3 to 6 carbons, which cycloalkyl groups are further optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0043] The term "heteroalkyl" refers to an alkyl group, as defined herein above, in which one or more carbon atoms in the chain is replaced by a heteroatom selected from the group consisting of O, S, and N.

[0044] As used herein, the term "hydroxyalkyl" refers to an alkyl chain, as defined herein above, in which one hydrogen atom has been replaced with a hydroxyl group.

[0045] The term "dihydroxyalkyl" refers to an alkyl group, as defined herein, in which two carbon atoms are each substituted with a hydroxyl group.

[0046] The term "alkylaminyl" means -NR x -alkyl, R x is hydrogen.

[0047] The term “dialkylaminyl” refers to —N(R y ) 2 Each R y is independently C1-C3 alkyl.

[0048] The term "alkylaminylalkyl" means -alkyl-NR x -alkyl, R x is hydrogen.

[0049] The term “dialkylaminylalkyl” refers to -alkyl-N(Ry ) 2 Each R y is independently C1-C4 alkyl, -alkyl-N(R y ) 2 where alkyl is an alkyl group as defined herein above, and may be optionally substituted with hydroxy or hydroxyalkyl.

[0050] An "aryl" group is a C aryl group containing 1 to 3 aromatic rings, which are optionally substituted. 6 -C 14 In one embodiment, the aryl group is 6 -C 10 It is an aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. An "aryl" group may optionally contain one aromatic ring fused to a heterocyclyl.

[0051] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently linked to an alkyl group as defined herein above, either of which may be independently optionally substituted or unsubstituted. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl, and naphthylmethyl (C 1 -C 6 )Alkyl(C 6 -C 10 ) aryl. An example of a substituted aralkyl is one in which an alkyl group is substituted with a hydroxyalkyl.

[0052] A "heterocyclyl" or "heterocycle" group is a ring structure having from about 3 to about 12 atoms, e.g., 4 to 8 atoms, in which one or more atoms are selected from the group consisting of N, O, and S, and the remainder of the ring atoms are carbon. A heterocyclyl may be a monocyclic, bicyclic, spirocyclic, or bridged ring system. A heterocycle group has R on a carbon or nitrogen at one or more positions. 7 Optionally substituted with R 7is as defined for formula I. Heterocyclic groups are also independently optionally substituted on the nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl. Examples of heterocyclic groups include 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, hexahydrofuro[3.2-b]furanyl, (3 R,3aR,6R,6aR)-hydroxyhexahydrofuro[3.2-b]furanyl, morpholinyl, oxazepanyl, azabicyclohexane, azabicycloheptane, and oxazabicycloheptane (including diazabicyclo[3.2.0]heptan-6-yl, diazabicyclo[3.2.0]heptan-2-yl, diazabicyclo[3.2.1]octan-8-yl, or diazabicyclo[3.2.1]octan-3-yl). Specifically excluded from the scope of this term are compounds having adjacent cyclic O and / or S atoms.

[0053] The term "heterocyclylalkyl" refers to a heterocyclyl group, as defined herein, covalently bonded to an alkyl group, as defined herein above, where the radical is located on the alkyl group, and the alkyl group of the heterocyclylalkyl can be optionally substituted with hydroxy or hydroxyalkyl.

[0054] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6, 10, or 14 pi electrons shared in a cyclic array, and having, in addition to carbon atoms, 1 to 3 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, and the like. phenyl, 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, tetrahydro Examples include isoquinolinyl, 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, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0055] A "heteroarylalkyl" group includes a heteroaryl group covalently bonded to an alkyl group, the radical being on the alkyl group, each of which is independently optionally substituted or unsubstituted. Examples of heteroarylalkyl groups include heteroaryl groups having 5, 6, 9, or 10 ring atoms bonded to a C1-C6 alkyl group. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl, quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl, isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent cyclic O and / or S atoms.

[0056] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of KRas G12C. Such an amount may be administered as a single dose or according to a dosing regimen, whereby the amount is effective.

[0057] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to alleviate or in some way reduce symptoms, or to halt or reverse the progression of a condition, or to negatively regulate or inhibit the activity of KRas G12C. Such an amount may be administered as a single dose or according to a dosing regimen, whereby the amount is effective.

[0058] As used herein, treatment refers to any manner in which the symptoms or pathology of a condition, disorder, or disease are alleviated or beneficially altered. Treatment also includes any pharmaceutical use of the compositions herein.

[0059] As used herein, alleviation of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, persistent or transient, that can result from or be associated with administration of the composition.

[0060] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., a dose of a KRAS inhibitor or a pharma- ceutically acceptable salt thereof detailed herein, or a length of treatment time described herein) means that the parameter may vary above or below the numerical value listed for that parameter by as much as 10%. For example, a dose of about 5 mg / kg may vary between 4.5 mg / kg and 5.5 mg / kg. "About" used at the beginning of a list of parameters means to modify the respective parameter. For example, about 0.5 mg, 0.75 mg, or 1.0 mg means about 0.5 mg, about 0.75 mg, or about 1.0 mg. Similarly, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, or about 25% or more.

[0061] compound In one aspect of the invention, a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, X is a 4-12 membered saturated or partially saturated monocyclic ring, bridged ring, spirocyclic ring, or fused bicyclic ring, and the saturated or partially saturated monocyclic ring is 8 is optionally replaced by Y is a bond, O, S, or NR 5 and R 1 But -C(O)C(R A ) [ka] C(R B )p OR -SO 2 C(R A ) [ka] C(R B ) p and R 2 is hydrogen, alkyl, alkoxy, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR 5 SO 2 C1-C3 alkyl, -Z-NR 5 R 10 , cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl, and each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be selected from one or more R 9 may be optionally substituted with Z is C1-C4 alkylene; Each R 3 are independently C1-C3 alkyl, halogen, CN, -O-haloalkyl, or -OR 5 and L is a bond, -C(O)-, or C1-C3 alkylene; R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl, and each of the cycloalkyl, heterocyclyl, aryl, aralkyl, and heteroaryl is independently R 6 , R 7 , or R 9 may be optionally substituted with one or more substituents selected from Each R 5 is independently hydrogen or C1-C3 alkyl; R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, each of which is selected from one or more R 7may be optionally substituted with Each R 7 are independently halogen, hydroxyl, C1-C6 alkyl, C2-C4 alkynyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, or Q-haloalkyl, where Q is O or S; Each R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 , -C(O)N(R 5 ) 2 , -N(R 5 ) 2 or haloC1-C3 alkyl, wherein C1-C3 alkyl is cyano, halogen, -OR 5 , -N(R 5 ) 2 or heteroaryl, Each R 9 are independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, -N(R 5 ) 2 , halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein C1-C6 alkyl can be optionally substituted with cycloalkyl; Each R 10 is independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl, or hydroxyalkyl; R A is absent, hydrogen, deuterium, cyano, halogen, C1-C-3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 ) 2 or hydroxyalkyl, Each R B are independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 (In the formula, R11 is haloalkyl), -C(O)N(R 5 ) 2 , -NHC(O)C1-C3 alkyl, -CH 2 NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, where the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and the heteroaryl portion of the heteroaryl or heteroarylalkyl is substituted with one or more R 7 is optionally replaced by p is 1 or 2; [ka] If is a triple bond, R A But it doesn't exist, R B exists and p is equal to 1 or or [ka] If is a double bond, R A But there exists R B exists and p is equal to 2 or R A , R B and the carbon atom to which they are attached may be one or more R 7 forming an optionally substituted 5-8 membered partially saturated cycloalkyl.

[0062] In certain embodiments, R 1 -X is [ka]

[0063] where R 1 is as defined for formula I, and the piperazinyl ring is selected from one or more R 8 Optionally substituted with R 8is as defined for formula I. In certain embodiments, R 8 is C1-C3 alkyl, alkyl being cyano or OR 5 , or -C(O)N(R 5 ) 2 and each R 5 is independently hydrogen or C-C alkyl. In certain embodiments, R 8 is heteroalkyl, C2-C4 alkynyl, or -OR 5 , cyano, or heteroaryl. In certain embodiments, R 8 is C-C alkyl optionally substituted with cyano. In certain embodiments, R 8 is cyano.

[0064] In one embodiment, R 1 -SO 2 C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and R A , R B and p are as defined for formula I.

[0065] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where R A , R B and p are as defined for formula I. In one embodiment, R 1 is -C(O)C(R A) [ka] C(R B ) p where: [ka] is a triple bond, and R A does not exist, p is 1, and R B is as defined for formula I. In one embodiment, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a triple bond, and R A does not exist, p is 1, and R B is hydroxyalkyl.

[0066] In one embodiment, R 1 is -C(O)C(R A ) [ka] C(R B ) p and [ka] is a double bond, p is 2, and R A , R B and p are as defined for formula I. In one embodiment, R 1 is -C(O)C(R A ) [ka] C(R B ) pand [ka] is a double bond, and R A is hydrogen or C1-C3 alkyl, p is 2, and at least one R B is deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 , -C(O)N(R 5 ) 2 , -NHC(O)C1-C3 alkyl, -CH 2 NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, where the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and the heteroaryl portion of the heteroaryl or heteroarylalkyl is substituted with one or more R 7 In one embodiment, [ka] is a double bond, the double bond is in the E configuration. In one embodiment, the double bond is in the Z configuration.

[0067] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one of R Bis independently a heterocyclylalkyl substituted with one or more substituents selected from halogen, hydroxyl, alkoxy, or C1-C3 alkyl, and the other R B is hydrogen. In one embodiment, the heterocyclyl moiety of the heterocyclylalkyl is azetidinyl substituted with a halogen. In certain embodiments, the halogen is fluorine. In one embodiment, the heterocyclyl moiety of the heterocyclylalkyl is pyrrolidinyl substituted with one or more halogens. In certain embodiments, the halogen-substituted pyrrolidinyl is fluoropyrrolidinyl or difluoropyrrolidinyl.

[0068] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one of R B is a halogen, and the other R B is hydrogen. In one embodiment, the halogen is chlorine.

[0069] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one of R B is haloalkyl, and the other R Bis hydrogen. In one embodiment, haloalkyl is chloromethyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0070] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one R B is heteroalkyl, and the other R B is hydrogen. In one embodiment, heteroalkyl is methoxymethyl.

[0071] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one R B is -ZNR 5 R 11 where Z is methylene and R 5 is methyl, R 11 is trifluoromethyl or 2,2,2-trifluoroethyl, and the other R B is hydrogen.

[0072] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one R B is hydroxyalkyl, and the other R B is hydrogen.

[0073] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one R B is one or more R 7 and the other R B In one embodiment, heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, each of which is selected from one or more R 7 has been replaced with.

[0074] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one R B is one or more R 7and the other R B In one embodiment, the heteroaryl portion of the heteroarylalkyl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, each of which is selected from one or more R 7 In one embodiment, one or more R 7 is C1-C3 alkyl.

[0075] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one R B is -C(O)N(R 5 ) 2 and the other R B is hydrogen. In one embodiment, each R 5 is hydrogen. In one embodiment, each R 5 is C1-C3 alkyl.

[0076] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one R B is -NHC(O)C1-C3 alkyl or -CH 2NHC(O)C1-C3 alkyl, and the other R B is hydrogen. In one embodiment, the C1-C3 alkyl is methyl.

[0077] In one embodiment, R 1 is -C(O)C(R A )=C(R B ) p where: [ka] is a double bond, and R A is deuterium, cyano, halogen, C1-C-3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 ) 2 or hydroxyalkyl, p is 2, and each R B is hydrogen. In one embodiment, R A is a halogen. In one embodiment, the halogen is fluorine or chlorine. In one embodiment, R A is haloalkyl. In one embodiment, haloalkyl is trifluoromethyl. In one embodiment, R A is cyano. In one embodiment, R A is heteroalkyl. In one embodiment, heteroalkyl is methoxy. In one embodiment, R A is hydroxyalkyl.

[0078] In one embodiment, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, and R A is deuterium, p is 2, and at least one R B is deuterium.

[0079] In one embodiment, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and R A is hydrogen, p is 2, and each R B is hydrogen.

[0080] In one embodiment, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one R B is hydrogen and R A and one R B and the carbon atom to which they are attached form a 5-8 membered partially saturated cycloalkyl substituted with oxo.

[0081] In one embodiment, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one R Bis hydrogen, and the second R B is dialkylaminylalkyl, R A is a halogen.

[0082] In one embodiment, Y is O or NR 5 and R 2 is alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, heterocyclyl, heterocyclylalkyl, -NR 5 SO 2 In one embodiment, Y is O and R 2 is hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, or dialkylaminylalkyl, and alkylaminylalkyl or dialkylaminylalkyl is selected from one or more R 9 In one embodiment, the optionally substituted alkylaminylalkyl or dialkylaminylalkyl is independently selected from methylaminylpropan-2-yl, dimethylaminylethyl, methylethylaminylethyl, dimethylaminylpropanyl, dimethylaminylpropan-2-yl, dimethylaminylbutanyl, dimethylaminylbutan-2-yl, 2-dimethylaminylpropanol, or diethylaminylethyl. In one embodiment, Y is O or NR 5 and R 2 is one or more R 9 R is heterocyclyl or heterocyclylalkyl optionally substituted with 2 is heterocyclyl or heterocyclylalkyl, one or more R 9 Non-limiting examples of R include C1-C3 alkyl, acyl, oxo, cyano, alkoxy, cycloalkyl, cycloalkylmethyl, halogen, and hydroxyl. 2 is heterocyclyl or heterocyclylalkyl, each of which is one or more R 9Non-limiting examples of heterocyclyl moieties, when optionally substituted with, independently, include azetidinyl, C1-C4 alkyl substituted azetidinyl (e.g., methylazetidinyl, ethylazetidinyl, isopropylazetidinyl, or tert-butylazetidinyl), halo substituted azetidinyl (e.g., difluoroazetidinyl), dimethylaminyl substituted azetidinyl, cycloalkyl substituted azetidinyl (e.g., cyclopropyl), C1-C4 alkyl disubstituted azetidinyl (e.g., dimethylazetidinyl), two C1-C4 alkyl and alkoxy groups. azetidinyl, oxetanyl, C1-C4 alkyl-substituted oxetanyl (e.g., methyloxetanyl), tetrahydropyran, pyrrolidinyl, C1-C3 alkyl-substituted pyrrolidinyl (e.g., methylpyrrolidinyl, dimethylpyrrolidinyl, and isopropylpyrrolidinyl), cycloalkylpyrrolidinyl (e.g., cyclopropylpyrrolidinyl and cyclobutylpyrrolidinyl), cycloalkylalkylpyrrolidinyl, hydroxypyrrolidinyl, halo-substituted pyrrolidinyl (e.g., fluoroethylpyrrolidinyl and difluoroethylpyrrolidinyl), pyrrolidinyl substituted with one or more substituents selected from halogen and C1-C6 alkyl (e.g., N-methyl-3,3-difluoropyrrolidinyl, N-methyl-3-fluoropyrrolidinyl, methoxyethylpyrrolidinyl, (N-methyl)methoxypyrrolidinyl, piperazinyl, dimethylaminylpyrrolidinyl, morpholinyl, methylmorpholinyl, 1,4-oxazepanyl, 1,4-oxazinyl, piperdinyl, C1-C3 alkyl substituted piperidinyl (e.g., methylpiperidinyl), acylpiperdinyl, cyanopiperazinyl, cycloalkylpiperdinyl, halopiperdinyl (e.g., fluoropiperdinyl), dihalopiperdinyl (e.g., difluoropiperdinyl), alkoxypiperdinyl, heterocyclyl-substituted piperdinyl (e.g., tertolahydropyranyl), piperidonyl, thiomorpholinyl-1,1-dioxide, hexahydrofuro[3.2-b]furanyl, (3R,3aR,6R,6aR)-hydroxyhexahydrofuro[3.2-b]furanyl, 3-azabicyclo[3.1.0]hexanyl (e.g., (1S,2S,5R)-azabicyclo[3.1.0]hexanyl, and (1R,2S,5S-azabicyclo[3.1.0]hexanyl), oxa-5-azabicyclo[2.2.1]heptan-5-yl, and 2-methyl-azabicyclo[2.2.1]heptan-2-yl, azabicyclo[2.2.1]heptan-2-yl.

[0083] In one embodiment, R 2 When is heterocyclyl or heterocyclylalkyl, the heterocyclyl moiety is one or more R 9 In one embodiment, the tetrahydropyrazinyl is tetrahydropyrazinyl optionally substituted with one R 9 where R 9 is halogen, hydroxyalkyl, or haloalkyl.

[0084] R 2 One or more R 9 In one embodiment of heterocyclylalkyl optionally substituted with, the alkyl portion of the heterocyclylalkyl is C1-C3 alkyl. In one embodiment, the alkyl portion is methylene. In one embodiment, the alkyl portion is ethylene. In one embodiment, the alkyl portion is propylene.

[0085] In one embodiment, Y is O and R 2 is one or more R 9 In one embodiment, the heteroaryl portion of the heteroarylalkyl is pyridinyl, imidazolyl, pyrazolyl, pyrrolopyrimdinyl, and tetrahydroisoquinolinyl, each of which is optionally substituted with one or more R 9 is optionally replaced by

[0086] In one embodiment, Y is O and R 2 is one or more R 9 In one embodiment, the aryl portion of the aralkyl is phenyl. In one embodiment, the phenyl is optionally substituted with a single R 9 is replaced by R 9is an amino.

[0087] In one embodiment, Y is O and R 2 -ZR 5 R 10 In one embodiment, R 5 is C1-C3 alkyl, R 10 is selected from acyl, independently hydroxyalkyl, or alkoxy.

[0088] In one embodiment, Y is O and R 2 -NR 5 SO 2 In one embodiment, R 5 is hydrogen and C1C3 alkyl is methyl.

[0089] In one embodiment, Y is O and R 2 is haloalkyl. In one embodiment, haloalkyl is 1,1,1-trifluoropropyl.

[0090] In one embodiment, Y is a bond and R 2 is hydrogen, alkyl, haloalkyl, alkoxy, cyclocyclyl, -NR 5 SO 2 C1-C3 alkyl, heterocyclyl, or aryl, wherein the heterocyclyl and aryl are each independently one or more R 9 is optionally replaced by

[0091] In one embodiment, Y is a bond and R 2 is hydrogen.

[0092] In one embodiment, Y is a bond and R 2 is alkyl. In one embodiment, alkyl is C1-C3 alkyl. In one embodiment, C1-C3 alkyl is methyl.

[0093] In one embodiment, Y is a bond and R 2is haloalkyl. In one embodiment, haloalkyl is trifluoromethyl.

[0094] In one embodiment, Y is a bond and R 2 is alkoxy. In one embodiment, alkoxy is methoxy.

[0095] In one embodiment, Y is a bond and R 2 is cycloalkyl. In one embodiment, cycloalkyl is cyclopropyl. In one embodiment, Y is a bond and R 2 is one or more R 9 In one embodiment, Y is a bond and R 2 R is heterocyclyl optionally substituted with methyl, halogen, or dimethylamino. 2 Non-limiting examples of heterocyclyl include azetidinyl, piperidinyl, piperazinyl, morpholinyl, and pyrrolidinyl.

[0096] In one embodiment, Y is a bond and R 2 is one or more R 9 In one embodiment, the aryl is phenyl substituted with heterocyclylalkyl.

[0097] In certain other embodiments, when X is a monocyclic ring, R 4 is aryl. In one embodiment, R 4 is selected from the group consisting of phenyl and naphthyl, and one or more R 6 , R 7 , or R 9 Optionally replaced by R 7Examples of substituents include halogen, hydroxyl, C1-C6 alkyl (e.g., C1-C3 alkyl), cycloalkyl, haloalkyl, Q-haloalkyl, amino, cyano, hydroxyalkyl, and alkoxy. In one embodiment, aryl is selected from one or more R independently selected from halogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. 7 In one embodiment, the aryl is phenyl substituted with one or more R groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl, and hydroxyl. 7 In one embodiment, the aryl is phenyl substituted with one or more R independently selected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl, trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl, and trifluoromethylthio. 7 In one embodiment, aryl is phenyl substituted with a phenyl group. In one embodiment, aryl is substituted with one to three R groups independently selected from amino, hydroxyl, cyclopropyl, fluorine, and chlorine. 7 In one embodiment, the aryl is a phenyl substituted with a group. In one embodiment, the aryl is a phenyl substituted with hydroxyl and C1-C3 alkyl or two C1-C3 alkyl. In one embodiment, the aryl is a phenyl substituted with chloro and cyclopropyl. In one embodiment, the aryl is a phenyl substituted with Q-haloalkyl and hydroxyl or fluorine. In one embodiment, the aryl is a phenyl substituted with amino, two chlorines and fluorines.

[0098] In one embodiment, R 4 is aryl, which is selected from one or more R 7 In one embodiment, the aryl is naphthyl optionally substituted with one or more R independently selected from halogen, hydroxyl, C1-C3 alkyl, C2-C4 alkynyl, haloalkyl, Q-haloalkyl, and alkoxy. 7In one embodiment, the aryl is naphthyl substituted with a group. In one embodiment, the aryl is substituted with one or more R groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl, and hydroxyl. 7 In one embodiment, R is a naphthyl substituted with a naphthyl group. 4 is one or more R independently selected from hydroxyl, halogen, C1-C3 alkyl, C2-C4 alkynyl, amino, and haloalkyl; 7 In one embodiment, R is naphthyl optionally substituted with a substituent. 4 is one to three R independently selected from difluoromethyl, methyl, hydroxyl, amino, ethynyl, 2-propynyl, fluoro, and chloro; 7 Naphthyl is optionally substituted with a substituent.

[0099] In one embodiment, the aryl is naphthyl optionally substituted with one or more halogens. In one embodiment, the aryl is naphthyl optionally substituted with chloro. In one embodiment, the aryl is naphthyl substituted with chloro and fluoro. In one embodiment, the aryl is naphthyl substituted with C1-C6 alkyl. In one embodiment, the aryl is naphthyl substituted with C2-C4 alkynyl. In one embodiment, the aryl is naphthyl substituted with hydroxyl. In one embodiment, the aryl is naphthyl substituted with hydroxyl and trifluoromethyl or C1-C3 alkyl. In one embodiment, the aryl is naphthyl substituted with hydroxyl. In one embodiment, the aryl is naphthyl unsubstituted.

[0100] In one embodiment, R 4 is one or more R 7 In one embodiment, R 4 is one or more R independently selected from halogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl, alkoxy, and amino; 7 In one embodiment, R 4is one or more R 7 In one embodiment, R is an indolyl, indazolyl, quinolinyl, isoquinolinyl, pyridinyl, or benzo[d]thiazolyl, optionally substituted with 4 is one or more R independently selected from halogen, hydroxyl, C1-C3 alkyl, C2-C4 alkynyl, haloalkyl, Q-haloalkyl, alkoxy, and amino; 7 and optionally substituted with -(indoyl, indazolyl, quinolinyl, isoquinolinyl, pyridinyl, or benzo[d]thiazolyl.

[0101] In yet another embodiment, R 4 is heteroaryl, optionally indolyl or indazolyl, each of which is selected from one or more R 7 In one embodiment, R 4 is one or more R independently selected from the group consisting of halogen, hydroxyl, C1-C3 alkyl, C2-C4 alkynyl, haloalkyl, Q-haloalkyl, and alkoxy. 7 In one embodiment, R is a heteroaryl optionally substituted with a substituent. 4 Heteroaryl is one or two R independently selected from alkoxy, haloalkyl, halogen, and C1-C6 alkyl. 7 In another embodiment, R 4 Heteroaryl is quinolinyl or isoquinolinyl, each of which is selected from one or more R 7 In one embodiment, R 4 Heteroaryl is quinolinyl or isoquinolinyl, each of which is independently one or more R selected from amino, hydroxyl, C1-C3 alkyl, halogen, and hydroxyl. 7 In one embodiment, R 4 Heteroaryl is quinolinyl or isoquinolinyl, each of which is independently selected from one or more R 7 In one embodiment, R4 Heteroaryl is quinolinyl or isoquinolinyl, each of which is optionally substituted with methyl or chlorine. In one embodiment, R 4 Heteroaryl is one or more R 7 In one embodiment, R 4 Heteroaryl is one or more R independently selected from C1-C3 alkyl, halogen, and haloalkyl. 7 In another embodiment, R 4 Heteroaryl is one or more R 1 , such as hydroxyl, one or two C1-C3 alkyl, or hydroxyl and one or two C1-C3 alkyl. 7 In one embodiment, R is benzo[d]thiazolyl optionally substituted with 4 Heteroaryl is one or more R 7 In one embodiment, R 4 Heteroaryl is a heteroaryl group consisting of one or two R independently selected from hydroxyl and C1-C3 alkyl. 7 is an indolyl optionally substituted with

[0102] In one embodiment, when X is a monocyclic ring, R 4 is aralkyl. In certain embodiments, the aralkyl is benzyl. In other embodiments, the alkyl of the benzyl group is optionally substituted with hydroxyalkyl.

[0103] In one embodiment, L is a bond.

[0104] In one embodiment, R 3 is C1-C3 alkyl. In one embodiment, the C1-C3 alkyl is methyl.

[0105] In one embodiment, R 3 is a halogen. In one embodiment, the halogen is fluorine or chlorine.

[0106] In one embodiment, R3 -OR 5 and R 5 is hydrogen.

[0107] In one embodiment, R 3 is -O-haloalkyl. In one embodiment, haloalkyl is 1,1,1-trifluoroethyl.

[0108] In one embodiment, R 8 is heteroalkyl, C2-C4 alkynyl, or -OR 5 , cyano, or heteroaryl. 8 is methyl, cyanomethyl, methoxymethyl, or hydroxymethyl. In one embodiment, R 8 is methyl. In one embodiment, R 8 is cyanomethyl. In one embodiment, R 8 is hydroxymethyl.

[0109] In one embodiment, formula I includes compounds having the formula IA: [ka] R 1 , R 3 , R 4 , R 9 and L are as defined for formula I; R 2 is one or more R 9 and the piperazinyl ring is optionally substituted with one or more R 8 Optionally substituted with R 8 is as defined for formula I. In one embodiment, R 2 The heterocyclyl moiety of is a monocyclic, bicyclic, or bridged ring system having 1 or 2 ring heteroatoms independently selected from N and O. In one embodiment, R 2Heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, 1,4-oxazepanyl, tetrahydropyrazinyl, thiomorpholinyl-1,1-dioxide, hexahydrofuro[3.2-b]furanyl, (3R,3aR,6R,6aR)-hydroxyhexahydrofuro[3.2-b]furanyl, 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, and azabicyclo[2.2.1]heptan-2-yl, with one or more R 9 In one embodiment, each R 9 is selected from acyl, oxo, halogen, cyano, C1-C3 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, aralkyl, and dialkylamidoalkyl. In one embodiment, L is a bond. In one embodiment, R 4 is aryl or heteroaryl, each of which is selected from one or more R 6 or R 7 In one embodiment, R 4 is aryl or heteroaryl, each of which is selected from one or more R 7 In one embodiment, each R 7 are independently selected from hydroxyl, amino, halogen, C1-C3 alkyl, C2-C4 alkynyl, haloalkyl, Q-haloalkyl, cycloalkyl, and alkoxy. In one embodiment, aryl is represented by one or more R independently selected from halogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. 7 In one embodiment, the aryl is phenyl substituted with one or more R groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl, and hydroxyl. 7In one embodiment, the aryl is phenyl substituted with one or more R independently selected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl, trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl, and trifluoromethylthio. 7 In one embodiment, aryl is phenyl substituted with one to three R groups independently selected from hydroxyl, fluorine, and chlorine. 7 In one embodiment, the aryl is phenyl substituted with a hydroxyl and a C1-C3 alkyl or two C1-C3 alkyl groups. In one embodiment, the aryl is phenyl substituted with a Q-haloalkyl and a hydroxyl or fluorine. In one embodiment, the aryl is substituted with one or more R groups independently selected from halogen, hydroxyl, C1-C3 alkyl, C2-C4 aralkyl, haloalkyl, Q-haloalkyl, and alkoxy. 7 In one embodiment, the aryl is naphthyl substituted with a group. In one embodiment, the aryl is substituted with one or more R groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl, and hydroxyl. 7 In one embodiment, R is a naphthyl substituted with a naphthyl group. 4 is one or more R independently selected from hydroxyl, halogen, C1-C3 alkyl, C2-C4 aralkyl, amino, and haloalkyl; 7 In one embodiment, R is naphthyl optionally substituted with a substituent. 4 is one to three R independently selected from difluoromethyl, methyl, hydroxyl, amino, fluoro, and chloro; 7 In one embodiment, the aryl is naphthyl optionally substituted with one or more halogens. In one embodiment, the aryl is naphthyl substituted with hydroxyl and trifluoromethyl or C1-C3 alkyl. In one embodiment, the aryl is naphthyl substituted with hydroxyl. In one embodiment, the aryl is naphthyl substituted with ethynyl or 2-propynyl. In one embodiment, R4 is heteroaryl, the heteroaryl being selected from one or two R 7 In one embodiment, R 4 is heteroaryl, heteroaryl is quinolinyl or isoquinolinyl, each of which is selected from one or more R 7 In one embodiment, R 4 is heteroaryl, where heteroaryl is quinolinyl or isoquinolinyl, each optionally substituted with one or more amino, C1-C3 alkyl, C2-C4 aralkyl, halogen, or hydroxyl. 4 Heteroaryl is one or more R 7 In one embodiment, R 4 Heteroaryl is one or more R independently selected from C1-C3 alkyl, halogen, and haloalkyl. 7 In one embodiment, R 4 Heteroaryl is one or more R 1 , such as hydroxyl, one or two C1-C3 alkyl, or hydroxyl and one or two C1-C3 alkyl. 7 In one embodiment, R is benzo[d]thiazolyl optionally substituted with 4 Heteroaryl is one or more R 7 In one embodiment, R 4 Heteroaryl is a heteroaryl group having one or two R independently selected from hydroxyl, halogen, and C1-C3 alkyl. 7 In one embodiment, R 11 is trifluoromethyl. In one embodiment, the piperidinyl ring is unsubstituted. In one embodiment, the piperidinyl ring is 8 In one embodiment, R 8 is C-C alkyl optionally substituted with cyano, hydroxyl, or methoxy. 8is methyl, cyanomethyl, hydroxymethyl, or methoxymethyl. In one embodiment, R 8 is cyano.

[0110] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p and R A , R B and p are as defined for formula I. In one embodiment, R 1 is -C(O)C(R A ) [ka] C(R B ) p and [ka] is a triple bond, and R A does not exist, p is 1, and R B is hydroxyalkyl.

[0111] In one embodiment, R 1 is -C(O)C(R A ) [ka] C(R B ) p and [ka] is a double bond, p is 2, and R A , R B and p are as defined for formula I. In one embodiment, R 1 is -C(O)C(R A ) [ka] C(R B ) p and [ka] is a double bond, and R A is hydrogen or C1-C3 alkyl, p is 2, and at least one R B is deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 , -C(O)N(R 5 ) 2 , -NHC(O)C1-C3 alkyl, -CH 2 NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, where the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and the heteroaryl portion of the heteroaryl or heteroarylalkyl is substituted with one or more R 7 In one embodiment, [ka] is a double bond, the double bond is in the E configuration. In one embodiment, the double bond is in the Z configuration.

[0112] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one of R Bis heterocyclylalkyl substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, or C1-C3 alkyl, and the other R B is hydrogen. In one embodiment, the heterocyclyl moiety of the heterocyclylalkyl is azetidinyl substituted with a halogen. In certain embodiments, the halogen is fluorine. In one embodiment, the heterocyclyl moiety of the heterocyclylalkyl is pyrrolidinyl substituted with one or more halogens. In certain embodiments, the halogen-substituted pyrrolidinyl is fluoropyrrolidinyl or difluoropyrrolidinyl.

[0113] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one of R B is a halogen, and the other R B is hydrogen. In one embodiment, the halogen is chlorine.

[0114] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one of R B is haloalkyl, and the other R Bis hydrogen. In one embodiment, haloalkyl is chloromethyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0115] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one R B is heteroalkyl, and the other R B is hydrogen. In one embodiment, heteroalkyl is methoxymethyl.

[0116] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one R B is -ZNR 5 R 11 where Z is methylene and R 5 is methyl, R 11 is trifluoromethyl or 2,2,2-trifluoroethyl, and the other R B is hydrogen.

[0117] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one of R B is hydroxyalkyl, and the other R B is hydrogen.

[0118] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one of R B is one or more R 7 and the other R B In one embodiment, heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, each of which is selected from one or more R 7 has been replaced with.

[0119] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one of R B is one or more R 7and the other R B In one embodiment, the heteroaryl portion of the heteroarylalkyl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, each of which is selected from one or more R 7 In one embodiment, one or more R 7 is C1-C3 alkyl.

[0120] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one of R B is -C(O)N(R 5 ) 2 and the other R B is hydrogen. In one embodiment, each R 5 is hydrogen. In one embodiment, each R 5 is C1-C3 alkyl.

[0121] In certain embodiments, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one of R B is -NHC(O)C1-C3 alkyl or -CH 2NHC(O)C1-C3 alkyl, and the other R B is hydrogen. In one embodiment, the C1-C3 alkyl is methyl.

[0122] In one embodiment of formula IA, R 1 is -C(O)C(R A )=C(R B ) p where R A is deuterium, cyano, halogen, C1-C-3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 ) 2 or hydroxyalkyl, p is 2, and each R B is hydrogen. In one embodiment, R A is a halogen. In one embodiment, the halogen is fluorine or chlorine. In one embodiment, R A is haloalkyl. In one embodiment, haloalkyl is trifluoromethyl. In one embodiment, R A is cyano. In one embodiment, R A is heteroalkyl. In one embodiment, heteroalkyl is methoxy. In one embodiment, R A is hydroxyalkyl.

[0123] In one embodiment of formula IA, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, and R A is deuterium, p is 2, and at least one R B is deuterium.

[0124] In one embodiment of formula IA, R 1 is -C(O)C(RA ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one R B is hydrogen and R A and one R B and the carbon atom to which they are attached form a 5-8 membered partially saturated cycloalkyl substituted with oxo.

[0125] In one embodiment of formula IA, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, p is 2, and one R B is hydrogen, and the second R B is dialkylaminylalkyl, R A is a halogen.

[0126] In one embodiment of Formula I, X is a saturated bridged ring system. Non-limiting examples of bridged ring systems include diazabicycloheptane and diazabicyclooctane. In certain embodiments, when X is a saturated bridged ring system, R 1 is -C(O)CH=CH 2 In one embodiment, the bridged ring system is independently R 8 and R 8is as defined for formula I. In one embodiment, the bridged ring system is unsubstituted. In one embodiment, the bridged ring system is diazabicyclo[3.2.0]heptan-6-yl, diazabicyclo[3.2.0]heptan-2-yl, diazabicyclo[3.2.1]octan-8-yl, or diazabicyclo[3.2.1]octan-3-yl.

[0127] In one embodiment of Formula I, R 1 -X is [ka]

[0128] wherein A and B are spiro ring systems, A and B are the same or different and independently represent a 4-6 membered saturated ring system, and the rings are independently selected from one or more R 8 Optionally substituted with R 8 is as defined for formula I. In certain embodiments, rings A and B are unsubstituted.

[0129] In certain embodiments, when A and B represent a spiro ring system, R 1 is -C(O)CH=CH 2 It is.

[0130] In one embodiment, when A and B represent a spiro ring system, R 1 is -C(O)C(R A ) [ka] C(R B ) p where: [ka] is a double bond, and R A is hydrogen or C1-C3 alkyl, p is 2, and at least one R Bis deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 , -C(O)N(R 5 ) 2 , -NHC(O)C1-C3 alkyl, -CH 2 NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, where the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and the heteroaryl portion of the heteroaryl or heteroarylalkyl is substituted with one or more R 7 In one embodiment, [ka] is a double bond, the double bond is in the E configuration. In one embodiment, the double bond is in the Z configuration.

[0131] In one embodiment, when A and B represent a spiro ring system, R 1 is -C(O)C(R A )=C(R B ) p where R A is deuterium, cyano, halogen, C1-C-3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 ) 2 or hydroxyalkyl, p is 2, and each R B is hydrogen. In one embodiment, R A is a halogen. In one embodiment, the halogen is fluorine or chlorine. In one embodiment, R A is haloalkyl. In one embodiment, haloalkyl is trifluoromethyl. In one embodiment, R A is cyano. In one embodiment, R A is heteroalkyl. In one embodiment, heteroalkyl is methoxy. In one embodiment, R Ais hydroxyalkyl.

[0132] In one embodiment, the spiro ring system is unsubstituted. Non-limiting examples of spiro ring systems include: [ka] Examples include:

[0133] In one embodiment of formula I, when A and B represent a spiro ring system, R 2 is selected from the group consisting of hydrogen (Y is a bond), hydroxyalkyl, dialkylaminylalkyl, heterocyclyl, and heterocyclylalkyl, each of the heterocyclyl or heterocyclylalkyl being selected from the group consisting of R 9 In another embodiment, R 2 is heterocyclyl and heterocyclylalkyl, each of the heterocyclyl or heterocyclylalkyl independently being selected from one or more R 9 In certain embodiments, R 2 is one or more R 9 Non-limiting examples include dimethylaminylethyl, dimethylaminylpropanyl, dimethylaminylpropan-2-yl, dimethylaminylbutanyl, dimethylaminylbutan-2-yl, 2-dimethylaminylpropanol, or diethylaminylethyl.

[0134] In one embodiment, when A and B represent a spiro ring system, Y is O and R 2 is hydroxyalkyl, dialkylaminylalkyl, heterocyclyl, heterocyclylalkyl, and -ZR 5 R 10 wherein R 5 and R 10 is as defined for formula I. In one embodiment, heterocyclyl is selected from one R 9 piperdinyl substituted with R 9 is heterocyclyl.

[0135] In one embodiment, when A and B represent a spiro ring system, Y is O and R 2 is selected from the group consisting of hydroxyalkyl, dialkylaminylalkyl, heterocyclyl, and heterocyclylalkyl, each of the heterocyclyl or heterocyclylalkyl being independently selected from R 9 In another embodiment, R 2 is heterocyclyl and heterocyclylalkyl, each of the heterocyclyl or heterocyclylalkyl independently being selected from one or more R 9 Optionally replaced by R 9 Non-limiting examples of include acyl, oxo, halogen, cyano, C1-C6 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, heterocyclyl, cycloalkyl, aralkyl, or dialkylamidoalkyl. In certain embodiments, R 2 is one or more R 9 Non-limiting examples include dimethylaminylethyl, dimethylaminylpropanyl, dimethylaminylpropan-2-yl, dimethylaminylbutanyl, dimethylaminylbutan-2-yl, 2-dimethylaminylpropanol, or diethylaminylethyl.

[0136] In one embodiment of formula I, when A and B represent a spiro ring system, R 4 is one or more R 6 or R 7 In one embodiment, R 4 is one or more R 6 or R 7 In one embodiment, R 4 is one or more R 7 In one embodiment, R 4 is one or more R independently selected from halogen, hydroxyl, C1-C3 alkyl, cycloalkyl, alkoxy, haloalkyl, or Q-haloalkyl;7 In one embodiment, R is a phenyl or naphthyl optionally substituted with a substituent, where Q is O or S. 4 is one or more R independently selected from methyl, trifluoromethyl, hydroxyl, trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl, and methylthio; 7 It is phenyl or naphthyl optionally substituted with a substituent.

[0137] In one embodiment, when A and B represent a spiro ring system, R 4 is isoquinolinyl, which is optionally substituted with amino, C1-C3 alkyl, or halogen. In one embodiment, R 4 is aralkyl. In certain embodiments, the aralkyl is benzyl. In one embodiment, the aralkyl is benzyl, and the alkyl portion is substituted with hydroxyl or hydroxyalkyl.

[0138] In one embodiment, X is a fused bicyclic ring system. 1 -X is [ka] It is.

[0139] Non-limiting examples of compounds of formula I and formula IA are: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and pharma- ceutically acceptable salts thereof.

[0140] Further non-limiting examples of compounds of formula I and formula IA are: [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0141] The compounds of formula (I) and formula IA may be formulated into pharmaceutical compositions.

[0142] Pharmaceutical Compositions In another embodiment, the present invention provides a pharmaceutical composition comprising the KRas G12C inhibitor according to the present invention and a pharma- ceutical acceptable carrier, excipient, or diluent.The compounds of the present invention can be formulated by any method known in the art and prepared for administration by any route, including but not limited to parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.In certain embodiments, the compounds of the present invention are administered intravenously in hospital.In one embodiment, administration can be by oral route.

[0143] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutical acceptable" refers to a non-toxic material that is compatible with a biological system, such as a cell, cell culture, tissue, or organism, and does not interfere with the effectiveness of the biological activity of the active ingredient. Thus, the composition according to the present invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutical acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0144] As used herein, the term pharma-ceutically acceptable salt refers to the salt that retains the desired biological activity of the compound identified above and exhibits minimal or no undesired toxicological effects.Examples of such salts include, but are not limited to, the acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and the 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 may also be administered as pharma- ceutically acceptable quaternary salts known to those of skill in the art, including, in particular, quaternary ammonium salts of the formula -NR+Z-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandelloate, benzylloate, and diphenylacetate).

[0145] The active compound is contained in a pharma- ceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing serious toxic effects to the patient being treated. In one embodiment, for all the above conditions, the dose of the active compound is in the range of about 0.01 to 300 mg / kg per day, e.g., 0.1 to 100 mg / kg per day, and as a further example, in the range of 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical local dosage is in the range of 0.01 to 3% weight / weight in a suitable carrier. The effective dosage range of the pharma- ceutically acceptable derivative may be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage may be estimated as above using the weight of the derivative or by other means known to those skilled in the art.

[0146] Pharmaceutical compositions containing the compounds of the invention can be used in the methods of use described herein.

[0147] How to use In yet another aspect, the present invention provides a method for inhibiting KRas G12C activity in a cell, comprising contacting a cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of formula I and formula IA, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharma- ceutically acceptable salt thereof.In one embodiment, the contact is in vitro.In one embodiment, the contact is in vivo.

[0148] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro or in vivo system. For example, "contacting" KRas G12C with a compound provided herein includes administering a compound provided herein to an individual or patient, such as a human, having KRas G12C, as well as introducing a compound provided herein into a sample containing, for example, a cell preparation or purified preparation containing KRas G12C.

[0149] In one embodiment, the cells in which inhibition of KRas G12C activity is desired are contacted with an effective amount of a compound of formula I and formula IA to negatively regulate KRas G12C activity. In other embodiments, a therapeutically effective amount of a pharma- ceutically acceptable salt or pharmaceutical composition containing a compound of formula I and formula IA may be used.

[0150] The methods described herein are designed to inhibit undesired cell proliferation resulting from enhanced KRas G12C activity in cells by negatively regulating the activity of KRas G12C. Cells can be contacted with a single dose or multiple doses according to a specific treatment regimen to achieve the desired negative regulation of KRas G12C. The degree of covalent modification of KRas G12C can be monitored in vitro using well-known methods, including those described in Example A below. Furthermore, the inhibitory activity of exemplary compounds in cells can be monitored by measuring the inhibition of KRas G12C activity of a certain amount of phosphorylated ERK, including those described in Example B below, to evaluate the effectiveness of treatment, and dosage can be adjusted by the attending physician accordingly.

[0151] In another aspect, a method of treating cancer in a patient in need of such treatment is provided comprising administering to the patient a therapeutically effective amount of a compound of Formula I or Formula IA, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharma- ceutically acceptable salt thereof.

[0152] The compositions and methods provided herein can be used to treat KRas G12C-associated cancer in patients who need KRas G12C-associated cancer, comprising administering to said patient a therapeutically effective amount of the compound of formula I and formula IA, their pharmaceutically acceptable salts, or the pharmaceutical composition comprising the compound or its pharmaceutically acceptable salts.In one embodiment, KRas G12C-associated cancer is lung cancer.

[0153] The compositions and methods provided herein may be used for the treatment of a wide variety of cancers, including, for example, tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that may be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, and thyroid cancer, as well as sarcoma. More specifically, these compounds are useful in treating heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), Pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' 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, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); Liver: Liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bile duct: Gallbladder cancer, 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 tumors chordoma, osteochondroma (osteochondroma exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Gynaecological: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); hematological: blood (myeloid leukemia) It can be used to treat: myeloproliferative disorders (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma; skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.

[0154] The concentration of the administered dose and the route of administration to the patient will vary depending on the cancer being treated. The compounds, their pharma- ceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts can also be co-administered with other anti-neoplastic compounds, such as chemotherapeutic agents, or used as pre- or post-operative adjuvants in combination with other treatments, such as radiation or surgical intervention.

[0155] Also provided herein are compounds of Formula I and Formula IA, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in therapy.

[0156] Also provided herein are compounds of Formula I and Formula IA, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in the treatment of cancer.

[0157] Also provided herein are compounds of Formula I and Formula IA, or pharma- ceutically acceptable salts or solvates thereof, for use in inhibiting KRas G12C.

[0158] Also provided herein are compounds of Formula I and Formula IA, or pharma- ceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, as de?ned herein, for use in the treatment of a KRas G12C-associated disease or disorder.

[0159] Also provided herein is the use of a compound of Formula I and Formula IA, or a pharma- ceutically acceptable salt or solvate thereof, as de?ned herein, in the manufacture of a medicament for the treatment of cancer.

[0160] Also provided herein is the use of a compound of Formula I and Formula IA, or a pharma- ceutically acceptable salt or solvate thereof, as de?ned herein, in the manufacture of a medicament for the inhibition of the activity of KRas G12C.

[0161] Also provided herein is the use of a compound of Formula I and Formula IA, or a pharma- ceutically acceptable salt or solvate thereof, as de?ned herein, in the manufacture of a medicament for the treatment of a KRas G12C-associated disease or disorder.

[0162] Also provided herein is a method for treating cancer in a patient in need of such treatment, comprising: (a) determining (e.g., using a regulatory approved, e.g., FDA approved, assay or kit) that the cancer is associated with a KRas G12C mutation (e.g., is a KRas G12C-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula I or Formula IA, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0163] Those skilled in the art will appreciate that both in vivo and in vitro tests using suitable known and generally accepted cellular and / or animal models predict the ability of a test compound to treat or prevent a given disorder.

[0164] One of ordinary skill in the art will appreciate that human clinical trials, including first-in-human studies, dose ranging studies, and efficacy studies in healthy patients and / or patients afflicted with a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0165] Reaction Schemes and Examples The compounds of the invention can be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those of skill in the art.

[0166] For example, compounds of the present invention can be prepared according to general reaction schemes I and II. General reaction scheme [ka]

[0167] L and Y are bonds, and R 2 Compounds of formula 1, where R is hydrogen, can be prepared according to Scheme 1. In step A, a suitably substituted compound 1 is reacted with a heterocycle, one of the nitrogen atoms being protected with a suitable nitrogen protecting group PG, such as a carboxybenzyl group. The reaction proceeds in a solvent, such as dichloromethane, in the presence of a base, such as diisopropylethylamine. In step B, R 4 The coupling of the R groups can be carried out in the presence of a palladium catalyst and a base such as potassium phosphate in a solvent such as dioxane by the addition of a suitably functionalized R 4 In step C, the protecting group is removed under standard conditions. For example, if the protecting group is a carboxybenzyl group, it can be removed upon treatment with hydrogen in the presence of a palladium catalyst and ammonia in a solvent such as methanol. 1 The group is introduced, for example, by treatment of intermediate 4 with an acid chloride in the presence of a base such as diisopropyl ether in a solvent such as dichloromethane.

[0168] Compounds (1), (2), (3), (4), and (5), as shown and described above with respect to Scheme 1, are useful as intermediates for preparing compounds of formula I and are provided as further aspects of the present invention. [ka]

[0169] Compounds of formula 1 where L is a bond can be prepared according to general scheme 2. In step A, a suitably substituted compound 5 is reacted with a heterocycle, one of the nitrogen atoms being protected with a suitable nitrogen protecting group PG, such as a carboxybenzyl group. The reaction proceeds in a solvent such as dichloromethane in the presence of a base such as diisopropylethylamine. In step B, YR 2 Addition of the group is accomplished by either transition metal mediated coupling or aromatic substitution. As an example, aromatic substitution can be achieved by reaction of HY-R in the presence of a base such as diisopropylethylamine in a solvent such as dioxane. 2 In step C, the mixture of R 4 The coupling of the R groups can be carried out by reacting a suitably functionalized R 4 In step D, the protecting group is removed under standard conditions. For example, if the protecting group is a carboxybenzyl group, it can be removed upon treatment with hydrogen in the presence of a palladium catalyst and ammonia in a solvent such as methanol. Finally, in step E, R 1 The group is introduced, for example, by treatment of intermediate 9 with an acid chloride in the presence of a base such as diisopropyl ether in a solvent such as dichloromethane.

[0170] Thus, there is provided a process for preparing a compound of formula I, comprising: (a) Y is a bond and R 2For compounds of formula I where is hydrogen, formula 5 [ka] (In the formula, X, R 3 , R 4 and L is as defined for formula I; -YR 2 is other than hydrogen) is a compound of the formula Cl-C(O)C(R A ) [ka] C(R B ) p or Cl-SO 2 C(R A ) [ka] C(R B ) p or an acid chloride having the formula C(R B ) p [ka] C(R A )C(O)OC(O)C(R A ) [ka] C(R B ) p (In the formula, R A , R B and p is as defined for formula I) in the presence of a base; and optionally forming a salt thereof.

[0171] Thus, there is provided a process for preparing a compound of formula I, comprising: (a) L is a bond and -YR 2 For compounds of formula I where is other than hydrogen, formula 5 [ka] (In the formula, X, R 3 , R 4 is as defined for formula I, L is a bond, -YR 2 is other than hydrogen) is a compound of the formula Cl-C(O)C(R A ) [ka] C(R B ) p or Cl-SO 2 C(R A ) [ka] C(R B ) p or an acid chloride having the formula C(R B ) p [ka] C(R A )C(O)OC(O)C(R A ) [ka] C(R B ) p (In the formula, R A , R B and p is as defined for formula I) in the presence of a base; and optionally forming a salt thereof.

[0172] The compounds of the present invention may have one or more chiral centers and may be synthesized as stereoisomeric mixtures or atropisomers, isomers that have the same configuration but differ in the spatial arrangement of their atoms. The compounds may be used as mixtures or the individual components / isomers may be separated using commercially available reagents and conventional methods for isolating stereoisomers and enantiomers well known to those skilled in the art, for example, using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic HPLC columns according to the manufacturer's instructions. Alternatively, the compounds of the present invention may be synthesized using optically pure chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise specified, whenever the specification, including the claims, refers to a compound of the present invention, the term "compound" should be understood to include all chiral (enantiomers and diastereomers) and racemic forms.

[0173] The following intermediates can be used to synthesize compounds of formula I and formula IA. [ka]

[0174] 3-Hydroxynaphthalen-1-yl trifluoromethanesulfonate (13.101 g, 44.831 mmol) was dissolved in dichloromethane (100 mL) and stirred at 0° C. To this solution was added chloro(methoxy)methane (3.7456 ml, 49.315 mmol) and Hunig's base (11.745 mL, 67.247 mmol). The reaction was stirred at 0° C. for 4 hours. The reaction was partitioned with 1M HCl and washed with saturated sodium bicarbonate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The concentrated material was loaded onto a 120 g RediSep® gold silica gel column with dichloromethane and purified by normal phase chromatography (CombiFlash®, 0% to 20% ethyl acetate / hexanes as eluent) to give 3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (11.785 g, 35.045 mmol, 78.171% yield). [ka]

[0175] To a solution of 7-bromonaphthalen-2-ol (2.0 g, 9.0 mmol) in dimethylacetamide (40 mL) was added chloro(methoxy)methane (1.4 g, 18 mmol) and cesium carbonate (5.8 g, 18 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was diluted with water and the aqueous layer was washed with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated under vacuum. The crude material was purified by normal phase chromatography using 5-50% ethyl acetate / hexane as the eluent to give 2-bromo-7-(methoxymethoxy)naphthalene (1.0 g, 3.7 mmol, 42% yield). [ka]

[0176] To a stirred solution of 2-bromo-3-fluorophenol (1422 mg, 7.445 mmol) in 22 mL of tetrahydrofuran at room temperature under nitrogen was added neat NaH (327.6 mg, 8.190 mmol) as a solid in portions. After 15 min, a solution formed. Chloro(methoxy)methane (678.6 μL, 8.934 mmol) was added via syringe. After stirring for 2 h, the reaction was quenched with saturated ammonium chloride solution and then partitioned between ethyl acetate (30 mL) and water (30 mL). The combined organic layers were isolated, washed with brine, and diluted with MgSO 4 The crude product in minimal dichloromethane was loaded onto a 40 gram RediSep® column pre-wetted with hexanes and eluted with an ethyl acetate / hexanes gradient (0% to 20% ethyl acetate). The product-containing fractions were combined and concentrated to give the product (1.45 g, 83%) as a clear oil. [ka]

[0177] To a stirred solution of 3-bromo-4-fluorophenol (327 mg, 1.71 mmol) in 5.1 mL of tetrahydrofuran at room temperature under nitrogen was added neat NaH (75.3 mg, 1.88 mmol) as a solid in portions. After 15 min, a solution formed. Chloro(methoxy)methane (156 μL, 2.05 mmol) was added via syringe. After stirring for 2 h, the reaction was quenched with saturated ammonium chloride solution and partitioned between ethyl acetate and water. The combined organic layers were washed with brine and diluted with MgSO 4 The crude product in minimal dichloromethane was loaded onto a 24 gram RediSep® column pre-wetted with hexanes and eluted with an ethyl acetate / hexanes gradient (0% to 20% ethyl acetate). The product-containing fractions were combined and concentrated to give the product (120 mg, 29.8%) as a clear oil. [ka]

[0178] To a solution of 4-bromo-5-methyl-1H-indazole (0.7 g, 3.3 mmol) in dimethylacetamide (30 mL) cooled to 0° C. was added NaH (0.19 g, 4.6 mmol) in portions and the reaction mixture was purged with nitrogen. The reaction was stirred for 20 min, then (2-(chloromethoxy)ethyl)trimethylsilane (0.83 g, 5.0 mmol) was added and the reaction was stirred for 2 h while allowing to warm to room temperature. The reaction was quenched by pouring into water and the aqueous layer was extracted into ethyl acetate. The combined organic layers were washed with water and brine and diluted with MgSO 4 After drying over rt and concentrating in vacuo, the crude material was purified by chromatography using 10-50% ethyl acetate / hexane as eluent to give 4-bromo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0.87 g, 79%). [ka]

[0179] In a sealed tube, R-(+)-propylene oxide (3.69 mL, 52.7 mmol) was cooled to -78°C and then sparged with anhydrous dimethylamine for several minutes. The reaction mixture was heated to 70°C for 16 hours. The reaction was cooled and concentrated in vacuo for 20 minutes to give (R)-1-(pyrrolidin-1-yl)propan-2-ol (5.35 g, 41.4 mmol, 98.2% yield). [ka]

[0180] In a sealed tube, R-(+)-propylene oxide (2.111 mL, 30.13 mmol) and morpholine (1.490 mL, 17.22 mmol) were heated to 70° C. for 20 h. The reaction was cooled and concentrated in vacuo to give (R)-1-morpholinopropan-2-ol (2.47 g, 17.01 mmol, 98.80% yield). [ka]

[0181] In a sealed tube, R-(+)-propylene oxide (4.00 g, 55.5 mmol) and dimethylamine (1.00 g, 22.2 mmol) were heated to 65 °C for 18 h. The reaction was cooled and concentrated in vacuo. The resulting residue was purified on silica gel (0-12% MeOH in DCM) to give (R)-1-(dimethylamino)butan-2-ol (1.38 g, 11.8 mmol, 53.1% yield). [ka]

[0182] In a sealed tube, R-(3)-methoxypyrrolidine hydrochloride (1.00 g, 7.27 mmol), TEA (2.03 mL, 14.5 mmol), and R-(+)-propylene oxide (1.27 mL, 18.2 mmol) were heated to 65 °C for 18 h. The reaction was cooled and concentrated in vacuo. The resulting residue was purified on silica gel (0-12% MeOH in DCM) to give (R)-1-((R)-3-methoxypyrrolidin-1-yl)propan-2-ol (775 mg, 4.87 mmol, 67.0% yield). [ka]

[0183] In a sealed tube, (S)-3-methoxypyrrolidine hydrochloride (1.00 g, 7.27 mmol), TEA (2.03 mL, 14.5 mmol), and R-(+)-propylene oxide (1.27 mL, 18.2 mmol) were heated to 65 °C for 18 h. The reaction was cooled and concentrated in vacuo. The resulting residue was purified on silica gel (0-12% MeOH in DCM) to give (R)-1-((S)-3-methoxypyrrolidin-1-yl)propan-2-ol (781 mg, 4.90 mmol, 67.5% yield). [ka]

[0184] In a sealed tube, R-(+)-propylene oxide (0.609 mL, 8.69 mmol) and (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine (1.00 g, 4.97 mmol) were heated to 70° C. for 20 h. The reaction was cooled and concentrated in vacuo to give (R)-1-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)propan-2-ol (1.29 g, 4.20 mmol, 84.6% yield). [ka]

[0185] To a suspension of lithium chloride (246 mg, 5.81 mmol) and lithium borohydride (126 mg, 5.81 mmol) in ethanol (9 mL) under nitrogen at 0° C. was added a solution of 1-(tert-butyl) 2-methyl 4-methylpiperazine-1,2-dicarboxylate (750 mg, 2.90 mmol) in dry THF (6 mL) dropwise. The reaction was stirred overnight and a white precipitate formed. The precipitate was filtered and washed with ethanol. The combined filtrate and organic extracts were concentrated to give a white residue, which was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (isocratic 10% MeOH + 0.2% NH in DCM). 4 OH) to give tert-butyl 2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate (104 mg, 0.452 mmol, 15.6% yield). [ka]

[0186] A mixture of (S)-2-methylpiperidine (100 mg, 1.01 mmol), 2-bromoethanol (78 μL, 139 mg, 1.11 mmol, 1.1 equiv), sodium iodide (151 mg, 1 equiv), potassium carbonate (418 mg, 3 equiv), and acetonitrile (1 mL) in a 4 mL vial was purged with nitrogen, sealed, and stirred at room temperature for 2 days. The reaction mixture was partitioned between diethyl ether (15 mL) and water (2 mL). The ether layer was washed with brine (2 mL), acidified with TFA, and then dried under high vacuum for 2 days. The residue was washed with ether (3 mL), diluted with water (0.5 mL), and basified with 10 M NaOH (0.2 mL). The layers were separated and the upper layer was carefully dried over NaOH. The ether solution was evaporated under nitrogen to give crude (S)-2-(2-methylpiperidin-1-yl)ethan-1-ol (100 mg, 0.698 mmol, 69.24% yield) as a colorless oil. [ka]

[0187] Synthesized following the method for Intermediate 13 using (R)-2-methylpiperidine (99 mg, 1 mmol) instead of (S)-2-methylpiperidine. [ka]

[0188] Synthesized following the method for Intermediate 13 using (S)-3-methoxypiperidine (173 mg, 1.50 mmol) instead of (S)-2-methylpiperidine. [ka]

[0189] Synthesized following the method for Intermediate 13 using R-3-methoxypiperidine (173 mg, 1.50 mmol) instead of (S)-2-methylpiperidine. [ka]

[0190] To a vial was added homomorpholine (0.250 g, 2.472 mmol), acetonitrile (4.943 mL, 2.472 mmol), and 3-bromo-1-propanol (0.2459 mL, 2.719 mmol). Potassium carbonate (0.6832 g, 4.943 mmol) was added and the mixture was warmed to 50 °C and stirred for 6 h. The mixture was cooled to ambient temperature, diluted with DCM, filtered, and the collected solid was washed with DCM. The filtrate was concentrated in vacuo and the crude oil was purified by column chromatography (Biotage Isolera, 12 g Isco RediSep Gold, 10-20% MeOH / DCM + 0.2% NH 4 OH) to give 3-(1,4-oxazepan-4-yl)propan-1-ol (0.272 g, 1.708 mmol) as a colorless oil. [ka]

[0191] Synthesized following the method for Intermediate 17 using (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (0.250 g, 2.522 mmol) instead of homomorpholine. [ka]

[0192] Synthesized following the method of Intermediate 13 using 4-methoxypiperidine (173 mg, 1.50 mmol) instead of (S)-2-methylpiperidine. [ka]

[0193] Synthesized following the method of Intermediate 13 using 4,4-difluoropiperidine hydrochloride (173 mg, 1.50 mmol) instead of (S)-2-methylpiperidine. [ka]

[0194] Synthesized following the method of Intermediate 13 using S-3-fluoropiperidine hydrochloride (209 mg, 1.50 mmol) instead of (S)-2-methylpiperidine. [ka]

[0195] Step A: 1-[4-[(2R)-2-hydroxypropyl]piperazin-1-yl]ethanone: (2R)-2-Methyloxirane (1.00 g, 17.2 mmol, 1.20 mL, 1.00 equiv.) and 1-piperazin-1-ylethanone (8.00 g, 62.4 mmol, 3.62 equiv.) were placed in a microwave tube. The sealed tube was heated under microwave at 150 °C for 1 h. The mixture was dissolved in DCM (80.0 mL) and (Boc) 2 O (3.62 equiv., 13.6 g) was added and stirred at 20° C. for 1 h. The residue was purified by column chromatography (DCM / MeOH=100 / 1 to 10 / 1) to give 1-[4-[(2R)-2-hydroxypropyl]piperazin-1-yl]ethanone (3.80 g, 13.5 mmol, 78.2% yield, 66.0% purity) as a yellow oil. [ka]

[0196] Step A: 1-Benzyloxy-3,5-dibromobenzene: 3,5-dibromophenol (1.50 g, 5.95 mmol, 1.00 equiv.) in MeCN (30.0 mL) and K 2 CO 3 (2.47 g, 17.9 mmol, 3.00 equiv.) was added benzyl bromide (1.07 g, 6.25 mmol, 742 μL, 1.05 equiv.) and the reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate=1:1) to give 1-benzyloxy-3,5-dibromobenzene (1.60 g, 4.68 mmol, 78.6% yield) as a colorless oil.

[0197] Step B: 1-Benzyloxy-3-bromo-5-cyclopropylbenzene: H 2 To a mixture of 1-benzyloxy-3,5-dibromobenzene (1.20 g, 3.51 mmol, 1.00 equiv.) and cyclopropylboronic acid (392 mg, 4.56 mmol, 1.30 equiv.) in 2H2O (4.00 mL) and dioxane (20.0 mL) was added Pd(dppf)Cl 2 (513 mg, 702 μmol, 0.20 equiv.) and Cs 2 CO 3 (2.29 g, 7.02 mmol, 2.00 equiv.) was added. The reaction mixture was diluted with N 2 The mixture was stirred at 90° C. for 12 hours under reduced pressure. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (2×15 mL). The combined organic layer was extracted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1:1) to give 1-benzyloxy-3-bromo-5-cyclopropyl-benzene (270 mg, 890 μmol, 25.4% yield) as a colorless oil. [ka]

[0198] 3-Bromo-4-fluorophenol (4.00 g, 20.9 mmol, 1.00 equiv) in ACN (80.0 mL) and K 2 CO 3To a solution of (8.68 g, 62.8 mmol, 3.00 equiv.), benzyl bromide (3.65 g, 21.4 mmol, 2.54 mL, 1.02 equiv.) was added and the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate; gradient 1:0 to 10:1) to give 4-benzyloxy-2-bromo-1-fluorobenzene (5.02 g, 17.0 mmol, 81.0% yield, 95% purity) as a white solid. [ka]

[0199] Step A: tert-Butyl 3-fluoropyrrolidine-1-carboxylate: To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (10.0 g, 53.4 mmol, 1.00 equiv) in DCM (150.00 mL) was added diethylaminosulfur trifluoride (DAST) (12.9 g, 80.1 mmol, 10.6 mL, 1.50 equiv) under nitrogen atmosphere at -40 °C. After stirring at -40 °C for 2 h, the mixture was warmed to 20 °C and stirred for 16 h. The mixture was poured into 5% aqueous sodium bicarbonate solution (200 mL) and extracted with dichloromethane (2 x 100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100:1 to 5:1). The desired fractions were collected and concentrated in vacuo to give tert-butyl 3-fluoropyrrolidine-1-carboxylate (4.30 g, 22.7 mmol, 42.6% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 5.27 (t, J = 3.6 Hz, 0.5H), 5.13 (t, J = 3.6 Hz, 0.5H), 3.77-3.38 (m, 4H), 2.26-2.15 (m, 1H), 2.08-1.85 (m, 1H), 1.46 (s, 9H).

[0200] Step B: 3-Fluoropyrrolidine: To a solution of tert-butyl 3-fluoropyrrolidine-1-carboxylate (4.30 g, 22.7 mmol, 1.00 equiv) in DCM (50.00 mL) was added HCl / dioxane (4 M, 35.0 mL, 6.16 equiv) dropwise at 0° C. The mixture was warmed to 20° C. and stirred for 1 h. The mixture was concentrated under vacuum. The residue was triturated with diisopropyl ether (20 mL) and the precipitate was filtered and dried under vacuum to give 3-fluoropyrrolidine (2.70 g, 21.5 mmol, 94.6% yield, HCl) as a white solid. 1 H NMR (400MHz, methanol-d 4 )δ=5.51(t,J=3.6Hz,0.5H),5.38(t,J=3.6Hz,1H),3.66-3.27(m,5H),2.45-2.12(m,2H).

[0201] Step C: Methyl 2-(3-fluoropyrrolidin-1-yl)acetate: A suspension of 3-fluoropyrrolidine (2.70 g, 21.5 mmol, 1.00 equiv, HCl) in DCM (27.00 mL) was cooled to 0° C. Triethylamine (5.44 g, 53.8 mmol, 7.45 mL, 2.50 equiv) and methyl 2-bromoacetate (3.62 g, 23.7 mmol, 2.23 mL, 1.10 equiv) were added and the reaction mixture was stirred at 20° C. for 16 h. The reaction mixture was cooled to CH 2 Cl 2 (100 mL) and water (50 mL). The organic layer was washed with 5% aqueous citric acid (1×50 mL). The aqueous layer was basified with saturated aqueous sodium carbonate (20 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give methyl 2-(3-fluoropyrrolidin-1-yl)acetate (2.20 g, 13.7 mmol, 63.5% yield). 1 H NMR (400 MHz, chloroform-d) δ = 5.22-5.02 (m, 1H), 3.66 (s, 3H), 3.35 (s, 2H), 3.07-2.93 (m, 1H), 2.91-2.77 (m, 2H), 2.67 (dt, J = 5.2, 8.4 Hz, 1H), 2.21-1.93 (m, 2H).

[0202] Step D: 2-(3-fluoropyrrolidin-1-yl)ethanol: LiAlH in THF (20 mL) 4 To a solution of (706 mg, 18.6 mmol, 1.50 equiv) was added dropwise a solution of methyl 2-(3-fluoropyrrolidin-1-yl)acetate (2.00 g, 12.4 mmol, 1.00 equiv) in THF (10 mL) at 0° C. The mixture was warmed to 20° C. and stirred for 3 h. The mixture was quenched with saturated aqueous sodium sulfate (1 mL). The mixture was filtered and the filtrate was concentrated under vacuum. The product was purified by silica gel chromatography using 5% MeOH in DMC. The desired fractions were collected and concentrated under vacuum to give 2-(3-fluoropyrrolidin-1-yl)ethanol (1.20 g, 9.01 mmol, 72.6% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 5.28-5.05 (m, 1H), 3.68-3.61 (m, 2H), 2.99-2.73 (m, 4H), 2.72-2.67 (m, 2H), 2.58-2.45 (m, 1H), 2.28-1.97 (m, 2H). [ka]

[0203] Step A: Methyl piperazine-2-carboxylate: To a mixture of 1-tert-butyl 2-methylpiperazine-1,2-dicarboxylate (5.0 g, 22.6 mmol, 1.00 equiv) in MeOH (50.0 mL) was added HCl / dioxane (4.0 M, 134 mL). The reaction mixture was degassed and purged with nitrogen three times, and the mixture was stirred under nitrogen atmosphere at 25° C. for 12 h. The reaction mixture was concentrated to dryness under reduced pressure to give methyl piperazine-2-carboxylate (4.89 g, 2HCl, crude) as a white solid, which was used directly in the next step without further purification.

[0204] Step B: 1-(tert-butyl) 3-methylpiperazine-1,3-dicarboxylate: To a solution of methylpiperazine-2-carboxylate (4.30 g, crude) and TEA (8.02 g, 79.2 mmol, 11.0 mL) in MeOH (50.0 mL) was added di-tert-butyl dicarbonate (4.32 g, 19.8 mmol, 4.55 mL). After stirring at 25 °C for 12 h, the reaction mixture was filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (SiO 2 , DCM / MeOH=1:0 to 20:1) to give 1-(tert-butyl) 3-methylpiperazine-1,3-dicarboxylate (4.80 g, 19.7 mmol, two steps, 99.0% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 4.10-3.85 (m, 1H), 3.73 (s, 3H), 3.71-3.65 (m, 1H), 3.47-3.38 (m, 1H), 3.10-2.98 (m, 2H), 2.78-2.66 (m, 1H), 2.17 (s, 1H), 1.46 (s, 9H). [ka]

[0205] Step A: 2,4-Dibromonaphthalen-1-amine: Br in AcOH (750 mL) 2 To a solution of (246 g, 1.54 mol, 79.3 mL, 2.18 equiv) was added a solution of naphthalene-1-amine (101 g, 705 mmol, 99.0 mL, 1.00 equiv) in AcOH (500 mL) at ambient temperature and the reaction was stirred at 70° C. for 1 h. The reaction mixture was cooled at room temperature and filtered. The filter cake was washed with AcOH (300 mL) and then added to 20% aqueous NaOH (1.2 L). The mixture was stirred for 20 min and filtered. The isolated solid was washed with water (1 L) and dried under vacuum to give 2,4-dibromonaphthalene-1-amine (200 g, 664 mmol, 94.2% yield) as a grey solid. ESI MS m / z 301.9 [M+H] + .

[0206] Step B: 4-Bromo-1-diazonio-naphthalene-2-oleate: To a solution of 2,4-dibromonaphthalene-1-amine (60.0 g, 199 mmol, 1.00 equiv) in AcOH (900 mL) and propionic acid (150 mL) was added NaNO 2 (16.5 g, 239 mmol, 13.0 mL, 1.20 equiv) was added in portions over 30 min at 5-8° C., and the reaction mixture was then stirred for 30 min at 5-8° C. The reaction mixture was poured into ice water (4000 mL) and the resulting solid was collected and washed with water (2×50 mL) to give 4-bromo-1-diazonio-naphthalen-2-olate (150 g, wet crude) as a grey solid, which was used directly in the next step. 1 H NMR (400 MHz, CDCl 3 )δ8.12-8.10(d,J=8.4Hz,1H),7.62-7.58(t,J=7.6Hz,1H),7.41-7.37(t,J=7.6Hz,1H),7.31-7.29(d,J=8.0Hz,1H),7.20(s,1H).

[0207] Step C: 4-Bromonaphthalen-2-ol: To a solution of 4-bromo-1-diazonio-naphthalen-2-olate (100 g, 402 mmol, 1.00 equiv) in EtOH (2.00 L), add NaBH 4 (30.4 g, 803 mmol, 2.00 equiv) was added in portions over 1 h at 13-15 °C and the reaction mixture was stirred at 15-18 °C for 3 h. The reaction was filtered and concentrated to dryness. The residue was dissolved in DCM (1000 mL) and washed with water (500 mL x 2). The organic phase was washed with Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated to dryness. The residue was purified by silica gel column chromatography and eluted with diethyl ether / ethyl acetate (60:1 to 10:1). The isolated product was further purified by reverse phase HPLC to give 4-bromonaphthalen-2-ol (40.0 g, 139 mmol, 17.3% yield, 77.4% purity) as a grey solid. 1 H NMR (400 MHz, CDCl 3)δ8.07-8.05(d,J=8.0Hz,1H),7.60-7.58(d,J=7.6Hz,1H),7.41-7.36(m,3H),7.07(s,1H).

[0208] Step D: 3-Benzyloxy-1-bromo-naphthalene: 4-Bromonaphthalen-2-ol (30.0 g, 134 mmol, 1.00 equiv.), benzyl bromide (25.3 g, 148 mmol, 17.6 mL, 1.10 equiv.), and K in MeCN (500 mL) were reacted. 2 CO 3 (55.7 g, 403 mmol, 3.00 equiv) was heated at 80 °C for 1 h. The reaction mixture was filtered and concentrated to dryness. The residue was purified by silica gel column chromatography eluting with diethyl ether / ethyl acetate (100:1 to 60:1) to give 3-benzyloxy-1-bromo-naphthalene (40.0 g, 128 mmol, 95% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ8.19-8.17(d,J=8.0Hz,1H),7.75-7.32(d,J=8.8Hz,1H),7.64-7.63(d, J=2.4Hz,1H),7.52-7.37(m,7H),7.23-7.21(d,J=2.0Hz,1H),5.2(s,2H). [ka]

[0209] Step A: 3-Methoxynaphthalen-1-ol: To a solution of naphthalene-1,3-diol (3.00 g, 18.7 mmol, 1.00 equiv) in MeOH (60.0 mL) was added HCl / MeOH (4 M, 60.0 mL, 12.8 equiv) at 0 °C. The mixture was stirred at 25 °C for 60 h. The solvent was removed under vacuum. The residue was purified by silica gel chromatography (diethyl ether:ethyl acetate = 10:1 to 5:1) to give 3-methoxynaphthalen-1-ol (2.10 g, 12.1 mmol, 64.4% yield) as a brown solid. 1 H NMR (400 MHz, CDCl 3 -d6 )δ=8.10-8.08(d,J=8.4Hz,1H).7.73-7.71(d,J=8.4Hz,1H),7.47-7.45(m,1H),7.38 -7.35(m,1H),6.80-6.79(d,J=2.0Hz,1H),6.56-6.55(d,J=2.4Hz,1H),3.92(s,3H).

[0210] Step B: (3-Methoxy-1-naphthyl)trifluoromethanesulfonate: To a solution of 3-methoxynaphthalen-1-ol (2.10 g, 12.0 mmol, 1.00 equiv) in DCM (40.0 mL) was added DIEA (7.79 g, 60.3 mmol, 10.5 mL, 5.00 equiv) and trifluoromethanesulfonic anhydride (5.10 g, 18.1 mmol, 2.98 mL, 1.50 equiv) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was diluted with DCM (30 mL) and water (10 mL) and extracted with DCM (20 mL). The combined organic layers were washed with brine (5 mL) and Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated in vacuo. The residue was purified by silica gel chromatography (diethyl ether:ethyl acetate=20:1 to 10:1) to give (3-methoxy-1-naphthyl)trifluoromethanesulfonate (3.00 g, 8.52 mmol, 70.7% yield, 87.0% purity) as a brown oil. ESI MS m / z 307.1 [M+H] + . [ka]

[0211] Step A: A mixture of 1-bromoisoquinolin-3-amine (400 mg, 1.79 mmol, 1.00 equiv) and tert-butoxycarbonyl tert-butyl carbonate (3.91 g, 17.9 mmol, 4.12 mL, 10.0 equiv) was stirred at 70° C. for 16 h. The residue was purified by column chromatography (SiO 2, diethyl ether / ethyl acetate=5:1) to give tert-butyl N-(1-bromo-3-isoquinolyl)carbamate (400 mg, 1.24 mmol, 69.2% yield) as a yellow solid. ESI MS m / z 322.1, 324.1 [M+H] + . [ka]

[0212] Step A: 3-Methoxynaphthalen-1-ol: To a solution of naphthalene-1,3-diol (40.0 g, 250 mmol, 1.00 equiv.) in MeOH (800 mL) was added HCl (4 M, 750 mL, 12.0 equiv., 4 M in MeOH) at 0 °C. The mixture was warmed to 18 °C and stirred for 30 h. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100 / 1 to 1 / 1). The desired fractions were collected and concentrated under vacuum to give 3-methoxynaphthalen-1-ol (17.7 g, 96.5 mmol, 38.6% yield, 95% purity) as a red oil. 1 H NMR (400 MHz, chloroform-d) δ = 8.17 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.50 (ddd, J = 1.2, 6.8, 8.0 Hz, 1H), 7.38 (ddd, J = 1.2, 6.8, 8.0 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.76 (br s, 1H), 6.62 (d, J = 2.4 Hz, 1H), 3.91 (s, 3H).

[0213] Step B: tert-Butyl-[(3-methoxy-1-naphthyl)oxy]-dimethyl-silane: To a solution of 3-methoxynaphthalen-1-ol (20.0 g, 115 mmol, 1.00 equiv.) and imidazole (23.5 g, 344 mmol, 3.00 equiv.) in THF (400 mL) was added TBSCl (26.0 g, 172 mmol, 21.1 mL, 1.50 equiv.) dropwise at 0 °C. The mixture was warmed to 25 °C and stirred for 16 h. The mixture was diluted with petroleum ether (600 mL) and ethyl acetate (200 mL) and then washed with water (1 × 200 mL) and brine (1 × 200 mL). The separated organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100 / 1 to 10 / 1). tert-Butyl-[(3-methoxy-1-naphthyl)oxy]-dimethyl-silane (28.0 g, 97.1 mmol, 84.6% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 8.01 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.35 (dt, J = 1.2, 7.6 Hz, 1H), 7.24 (dt, J = 1.2, 7.6 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H), 1.02 (s, 9H), 0.23 (s, 6H).

[0214] Step C: tert-Butyl[[3-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]oxy]-dimethyl-silane and tert-Butyl((3-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)oxy)dimethyl-silane: tert-Butyl[(3-methoxy-1-naphthyl)oxy]-dimethyl-silane (26.0 g, 90.1 mmol, 1.00 equiv.), 4,4,5,5 A mixture of -tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (45.8 g, 180 mmol, 2.00 equiv.), (1Z,5Z)-cycloocta-1,5-diene; 2,4-dimethyl-brabicyclo[1.1.0]butane (2.39 g, 3.61 mmol, 0.04 equiv.) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (1.45 g, 5.41 mmol, 0.06 equiv.) was stirred at 100° C. for 16 h under nitrogen atmosphere. The mixture was diluted with water (500 mL) and ethyl acetate (1000 mL). The separated organic layer was washed with brine (1×500 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100 / 1 to 10 / 1). The desired fractions were collected and concentrated under vacuum to give a mixture of tert-butyl[[3-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]oxy]-dimethyl-silane and tert-butyl((3-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)oxy)dimethylsilane (38.0 g, 85.3 mmol, 94.6% yield, 93% purity) as a pale yellow oil. ESI MS m / z 415.5[M+H] + .

[0215] Step D: 8-[tert-Butyl(dimethyl)silyl]oxy-6-methoxy-naphthalen-2-ol: To a solution of a mixture of tert-butyl[[3-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]oxy]-dimethyl-silane and tert-butyl((3-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)oxy)dimethylsilane (36.0 g, 86.9 mmol, 1.00 equiv.) in acetone (400 mL) is added H 2 A solution of oxone (58.7 g, 95.6 mmol, 1.10 equiv) in 2O (400 mL) was added at 0° C. The mixture was stirred at 0° C. for 1 h. The mixture was quenched with 5% aqueous sodium thiosulfate solution (50 mL) and extracted with ethyl acetate (2×300 mL). The extracts were combined, washed with water (1×200 mL), brine (1×200 mL), dried over magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 200 / 1 to 20 / 1). The desired fractions were collected and concentrated under vacuum to give 8-[tert-butyl(dimethyl)silyl]oxy-6-methoxy-naphthalen-2-ol (9.00 g, 28.4 mmol, 32.7% yield, 96% purity) as a colorless oil and 5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-naphthalen-2-ol (9.00 g, 29.0 mmol, 33.4% yield, 98% purity) as a white solid. ESI MS m / z 305.2 [M+H] + .

[0216] Step E: [5-[tert-Butyl(dimethyl)silyl]oxy-7-methoxy-2-naphthyl]trifluoromethanesulfonate: To a solution of 5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-naphthalen-2-ol (11.0 g, 36.1 mmol, 1.00 equiv.) and DIEA (14.0 g, 108 mmol, 18.9 mL, 3.00 equiv.) in DCM (150 mL) was added Tf 2HO (12.2 g, 43.4 mmol, 7.15 mL, 1.20 equiv) was added dropwise at -40 °C. The mixture was stirred for 1 h. The mixture was diluted with dichloromethane (200 mL) and washed with water (1 x 200 mL) and brine (1 x 200 mL). The separated organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100 / 1 to 10 / 1). The desired fractions were collected and concentrated under vacuum to give [5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-2-naphthyl]trifluoromethanesulfonate (13.0 g, 29.8 mmol, 82.4% yield, 100% purity) as a white solid. ESI MS m / z 436.9 [M+H] + .

[0217] Step F: tert-Butyl[(3-methoxy-6-methyl-1-naphthyl)oxy]-dimethyl-silane: [5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-2-naphthyl]trifluoromethanesulfonate (12.5 g, 28.6 mmol, 1.00 equiv.) in dioxane (160 mL) and K 2 CO 3 (11.9 g, 85.9 mmol, 3.00 equiv.) was added to a solution of Pd(PPh 3 ) 4 (3.31 g, 2.86 mmol, 0.10 equiv) and trimethylboroxine (14.4 g, 57.3 mmol, 16.0 mL, 2.00 equiv) were added under nitrogen atmosphere. The reaction was heated to 100 °C for 16 h. The mixture was diluted with ethyl acetate (200 mL) and then washed with water (1 x 200 mL) and brine (1 x 200 mL). The separated organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100 / 1 to 5 / 1). The desired fractions were collected and concentrated under vacuum to give tert-butyl[(3-methoxy-6-methyl-1-naphthyl)oxy]-dimethyl-silane (8.00 g, 24.6 mmol, 85.9% yield, 93% purity) as a colorless oil to a red solid. ESI MS m / z 303.2 [M+H]+ .

[0218] Step G: 3-Methoxy-6-methyl-naphthalen-1-ol: To a solution of tert-butyl-[(3-methoxy-6-methyl-1-naphthyl)oxy]-dimethyl-silane (8.00 g, 26.5 mmol, 1.00 equiv.) in THF (100 mL) was added TBAF (10.4 g, 39.7 mmol, 1.50 equiv.) at 0 °C. The mixture was stirred at 0 °C for 3 h. The mixture was diluted with water (100 mL) and ethyl acetate (200 mL). The separated organic layer was washed with brine (1 x 100 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 50 / 1 to 5 / 1). The desired fractions were collected and concentrated in vacuo to give 3-methoxy-6-methyl-naphthalen-1-ol (4.70 g, 25.0 mmol, 94.4% yield) as a red solid. ESI MS m / z 188.4 [M+H] + .

[0219] Step H: 3-Methoxy-6-methyl-1-naphthyl trifluoromethanesulfonate: To a solution of 3-methoxy-6-methyl-naphthalen-1-ol (4.70 g, 25.0 mmol, 1.00 equiv) and DIEA (9.68 g, 74.9 mmol, 13.1 mL, 3.00 equiv) in DCM (3.00 mL) was added Tf 2 HO (8.45 g, 30.0 mmol, 4.94 mL, 1.20 equiv) was added dropwise at -40 °C. The mixture was stirred for 1 h. The mixture was diluted with dichloromethane (200 mL) and washed with water (1 x 200 mL) and brine (1 x 200 mL). The separated organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100 / 1 to 10 / 1). 3-Methoxy-6-methyl-1-naphthyl trifluoromethanesulfonate (7.70 g, 24.0 mmol, 96.2% yield, 99.9% purity) was obtained as a colorless oil. ESI MS m / z 320.7 [M+H] + .

[0220] The following intermediates disclosed in Table 1 were prepared following the preparation of Intermediate 3, substituting the appropriate phenol for 2-bromo-3-fluorophenol. [Table 1] [ka]

[0221] Step 1: 3-Fluoro-4-methylphenol (1.016 g, 8.055 mmol) was dissolved in Cs 2 (3.9 mL, 64.44 mmol) and cooled to 0° C. 2 (0.4150 mL, 8.055 mmol) was added and the mixture was stirred at room temperature for 2 h. 2 S 2 O 2 was added and the mixture was extracted with DCM. The organic layers were combined, dried and filtered to give 2-bromo-3-fluoro-4-methylphenol (1.389 g, 6.775 mmol, 84.10% yield), which was used directly in the next step.

[0222] Step 2: 2-Bromo-3-fluoro-1-(methoxymethoxy)-4-methylbenzene was prepared following the procedure of Intermediate 8 using 2-bromo-3-fluoro-4-methylphenol instead of 2-bromo-3-fluorophenol. [ka]

[0223] Step 1: 4-Isopropoxyphenol (1.00 g, 6.57 mmol) and TEA (1.83 mL, 13.1 mmol) were placed in DCM (25 mL). Acetyl chloride (7.56 mL, 7.56 mmol) was added dropwise and the reaction was stirred at room temperature for 2 h. Water was added and the mixture was extracted with DCM. The organic layer was dried, filtered and concentrated to give 4-isopropoxyphenyl acetate (1.24 g, 6.38 mmol, 97.2% yield), which was used directly in the next step.

[0224] Step 2: 4-Isopropoxyphenyl acetate (1.24 g, 6.585 mmol) was placed in ACN (20 mL) and N-bromosuccinimide (1.173 g, 6.590 mmol) was added. The mixture was stirred for 18 h. Water was added and the mixture was extracted with ether. The organic layers were combined, dried and concentrated to give 3-bromo-4-isopropoxyphenyl acetate (1.584 g, 5.800 mmol, 88.00% yield), which was used directly in the next step.

[0225] Step 3: 3-Bromo-4-isopropoxyphenyl acetate (500 mg, 1.83 mmol) was placed in MeOH (7 mL). A solution of KOH (111 mg, 1.98 mmol) in water (2 mL) was added to the mixture and stirred at room temperature for 1 h. The reaction mixture was adjusted to pH 3 by the addition of 1N HCl. The mixture was extracted with DCM. The extracts were combined, dried, filtered and concentrated to give crude 3-bromo-4-isopropoxyphenol, which was used directly in the next reaction.

[0226] Step 4: 2-Bromo-1-isopropoxy-4-(methoxymethoxy)benzene was prepared following the procedure of Intermediate 8 using 3-bromo-4-isopropoxyphenol instead of 2-bromo-3-fluorophenol. [ka]

[0227] Step 1: 1-Bromo-3-chloro-2-isopropyl-5-methoxybenzene (952 mg, 3.61 mmol) was placed in DCM (3 mL) and cooled to 0 °C. BBr3 (9030 μL, 9.03 mmol) was added and the reaction was stirred at 0 °C for 2 h. Water was added and the mixture was extracted with DCM. The extracts were combined and concentrated. The resulting residue was purified by silica gel (0-20% EtOAc in hexanes) to give 3-bromo-5-chloro-4-isopropylphenol (575 mg, 2.30 mmol, 63.8% yield).

[0228] Step 2: 1-Bromo-3-chloro-2-isopropyl-5-(methoxymethoxy)benzene was prepared following the procedure of Intermediate 8 using 3-bromo-5-chloro-4-isopropylphenol instead of 2-. [ka]

[0229] To a solution of 4-iodonaphthalen-2-ol (0.80 g, 3.0 mmol) in DCM (20 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.1 mL, 5.9 mmol) and chloro(methoxy)methane (0.29 g, 3.6 mmol) and the reaction was stirred at room temperature for 4 h. After 2 h of stirring, additional chloro(methoxy)methane (0.15 g) was added. The reaction was washed with brine and concentrated in vacuo. The material was purified by chromatography using a gradient of 0-10% EtOAc / hexanes as eluent to give 1-iodo-3-(methoxymethoxy)naphthalene (0.80 g, 2.5 mmol, 86% yield). [ka]

[0230] Step A: 2,4-Dibromonaphthalen-1-amine: Br in AcOH (750 mL) 2To a solution of (246 g, 1.54 mol, 79.3 mL) was added a solution of naphthalene-1-amine (101 g, 705 mmol, 99.0 mL) in AcOH (500 mL) at room temperature and the reaction was stirred at 70° C. for 1 h. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with AcOH (300 mL). The solid was then suspended in 20% aqueous NaOH (1.2 L). The mixture was stirred for 20 min and filtered. The solid was washed with water (1 L) and dried under vacuum to give 2,4-dibromonaphthalene-1-amine (200 g, 664 mmol, 94.2% yield) as a grey solid. ES+APCI MS m / z 301.9[M+H] + . [ka]

[0231] Step B: 4-Bromo-1-diazonio-naphthalene-2-oleate: To a solution of 2,4-dibromonaphthalene-1-amine (60.0 g, 199 mmol) in AcOH (900 mL) and propionic acid (150 mL), NaNO 2 (16.5 g, 239 mmol, 13.0 mL) was added in portions over 30 min at 5-8° C. and the reaction mixture was stirred for 30 min at 5-8° C. The reaction mixture was poured into ice water (4000 mL), the slurry was filtered and the solid was washed with water (2×50 mL) to give 4-bromo-1-diazonio-naphthalene-2-olate (150 g, wet crude), which was used immediately as crude material in the next step. 1 H NMR (400 MHz, CDCl 3 )δ8.12-8.10(d,J=8.4Hz,1H),7.62-7.58(t,J=7.6Hz,1H),7.41-7.37(t,J=7.6Hz,1H),7.31-7.29(d,J=8.0Hz,1H),7.20(s,1H). [ka]

[0232] Step C: 4-Bromonaphthalen-2-ol: To a solution of 4-bromo-1-diazonio-naphthalen-2-olate (100 g, 402 mmol) in EtOH (2.00 L), add NaBH 4 (30.4 g, 803 mmol) was added in portions over 1 h at 13-15 °C and the reaction was stirred at 15-18 °C for 3 h. The reaction was filtered and concentrated to dryness. The residue was dissolved in DCM (1000 mL) and washed with water (500 mL x 2). The organics were washed with Na 2 SO 4 It was dried over and concentrated to dryness. The residue was purified by chromatography eluting with petroleum ether / EtOAc (60 / 1 to 10 / 1) and the material was repurified by reverse phase HPLC to give 4-bromonaphthalen-2-ol (40.0 g, 139 mmol, 17.3% yield, 77.4% purity) as a grey solid. 1 H NMR (400 MHz, CDCl 3 )δ8.07-8.05(d,J=8.0Hz,1H),7.60-7.58(d,J=7.6Hz,1H),7.41-7.36(m,3H),7.07(s,1H). [ka]

[0233] Step D: 3-Benzyloxy-1-bromo-naphthalene: 4-Bromonaphthalen-2-ol (30.0 g, 134 mmol), BnBr (25.3 g, 148 mmol, 17.6 mL), and K in MeCN (500 mL) 2 CO 3 (55.7 g, 403 mmol) was heated at 80° C. for 1 h. The reaction mixture was filtered and concentrated to dryness. The residue was purified by silica gel column eluted with PE / EA (100 / 1 to 60 / 1) to give 3-benzyloxy-1-bromo-naphthalene (40.0 g, 128 mmol, 95% yield). 1 H NMR (400 MHz, CDCl 3)δ8.19-8.17(d,J=8.0Hz,1H),7.75-7.32(d,J=8.8Hz,1H),7.64-7.63(d, J=2.4Hz,1H),7.52-7.37(m,7H),7.23-7.21(d,J=2.0Hz,1H),5.2(s,2H). [ka]

[0234] Step A: 4-Bromo-5-methyl-1-tetrahydropyran-2-yl-indazole: To a mixture of 4-bromo-5-methyl-1H-indazole (3 g, 14.2 mmol) and 3,4-dihydro-2H-pyran (2.39 g, 28.4 mmol, 2.60 mL) in DCM (30 mL) was added TsOH. * H 2 O (270 mg, 1.42 mmol) was added and the mixture was stirred for 2 h at 15° C. After completion, the reaction mixture was concentrated under vacuum and the residue was purified by column chromatography using 5→20&EtOAc / petroleum ether as eluent to give 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole (4 g, 13.6 mmol, 95.3% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.01 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 5.70 (dd, J = 2.8, 9.2 Hz, 1H), 4.05-3.96 (m, 1H), 3.79-3.70 (m, 1H), 2.66-2.44 (m, 4H), 2.25-2.04 (m, 2H), 1.84-1.56 (m, 3H). [ka]

[0235] 4-Bromo-5-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole was prepared by using 4-bromo-5-methoxy-1H-indazole instead of 4-bromo-5-methyl-1H-indazole in step A following intermediate 51. 1H NMR (400 MHz, chloroform-d) δ 8.00 (s, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 9.2 Hz, 1H), 5.70 (dd, J = 2.8, 9.2 Hz, 1H), 4.04-3.98 (m, 1H), 3.96 (s, 3H), 2.55-2.49 (m, 1H), 2.23-2.05 (m, 2H), 1.83-1.69 (m, 3H). [ka]

[0236] Step A: Ethyl 2-methyl-3-oxo-4-phenyl-butanoate. To a dry 250 ml three-neck flask was added ethyl 3-oxo-4-phenyl-butanoate (4.00 g, 19.4 mmol), THF (50.0 mL), sodium hydride (931 mg, 23.3 mmol) and the reaction was stirred at 0° C. for 0.5 h. Then, a solution of methyl iodide (3.03 g, 21.3) was added dropwise. Upon completion of the addition, the reaction mixture was warmed to 20° C. and stirred at 20° C. for 2 h. The reaction mixture was quenched by adding water (10.0 mL) at 20° C. and then diluted with ethyl acetate (20.0 mL) and the layers were separated. The aqueous layer was then extracted with ethyl acetate (20.0 mL×3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 20:1 to 10:1) to give ethyl 2-methyl-3-oxo-4-phenyl-butanoate (3.60 g, 16.3 mmol, 84.3% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 )δ=7.38-7.28(m,3H),7.25-7.19(m,2H),4.22-4.15(m,2H),3.87(d,J=2. 0Hz, 2H), 3.65 (q, J = 7.2Hz, 1H), 1.34 (d, J = 7.2Hz, 3H), 1.30-1.26 (m, 3H).

[0237] Step B: 2-Methylnaphthalene-1,3-diol. A solution of ethyl 2-methyl-3-oxo-4-phenyl-butanoate (3.60 g, 16.3 mmol) in concentrated sulfuric acid (19.9 g, 203 mmol) was stirred at 15° C. for 12 h. The reaction mixture was poured into ice water (30.0 mL) and the resulting solid was collected by filtration and dried under vacuum to give 2-methylnaphthalene-1,3-diol (1.80 g, 10.3 mmol, 63.2% yield) as a red solid. 1 H NMR (400 MHz, CDCl 3 )δ=8.02(d,J=8.0Hz,1H),7.65-7.54(m,1H),7.41(t,J=7.2Hz,1H),7.36-7.31(m,1H),6.80(s,1H),4.29-4.20(s,2H),2.41-2.24(s,3H).

[0238] Step C: 3-Methoxy-2-methyl-naphthalen-1-ol. 2-Methylnaphthalene-1,3-diol (1.70 g, 9.76 mmol) was added to HCl / MeOH (2M, 35.0 mL) and the resulting mixture was stirred at 30° C. for 3 days. The reaction was concentrated in vacuo and the residue was purified by preparative TLC (petroleum ether:ethyl acetate 1:1) to give 3-methoxy-2-methyl-naphthalen-1-ol (800 mg, 4.25 mmol, 43.5% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ=8.02(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),7.44-7.38(m,1H),7.37-7.31(m,1H),6.79(s,1H),5.14(s,1H),3.94(s,3H),2.29(s,3H).

[0239] Step D: (3-Methoxy-2-methyl-1-naphthyl) trifluoromethanesulfonate. To a mixture of 3-methoxy-2-methyl-naphthalen-1-ol (800 mg, 4.25 mmol) and pyridine (504 mg, 6.38 mmol) in DCM (10.0 mL) was added trifluoroacetic anhydride (1.44 g, 5.10 mmol) with N 2Dropwise addition under atmospheric pressure at 0° C. The mixture was warmed to 20° C. and stirred for an additional 5 h. The solvent was removed in vacuo and the residue was purified by preparative TLC (petroleum ether:ethyl acetate 1:1) to give (3-methoxy-2-methyl-1-naphthyl)trifluoromethanesulfonate (1.30 g, 4.06 mmol, 95.5% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ=7.97(d,J=7.6Hz,1H),7.79-7.74(m,1H),7.52-7.43(m,2H),7.14(s,1H),3.99(s,3H),2.42(s,3H).

[0240] Step E: 1-Bromo-3-methoxy-2-methyl-naphthalene: In a sealed tube, add (3-methoxy-2-methyl-1-naphthyl)trifluoromethanesulfonate (466 mg, 1.45 mmol), t-Bu-Brettphos (154 mg, 290 μmol), potassium bromide (259 mg, 2.17 mmol), PEG-200 (175 mg), 2-butanone (157 mg, 2.17 mmol), and Pd in ​​toluene (10.0 mL). 2 (dba) 3 (133 mg, 145 μmol) was added and the mixture was degassed with N2 for 5 min. Then, triisobutylaluminum (431 mg, 2.17 mmol) was added dropwise at 20° C. The mixture was heated to 100° C. for 24 h. The reaction mixture was poured into water (30.0 mL) and the aqueous layer was extracted with ethyl acetate (20.0 mL×3). The combined organic components were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue that was pre-purified by column chromatography (petroleum ether:ethyl acetate 10:1) and then purified by preparative TLC (petroleum ether:ethyl acetate 10:1) to give 1-bromo-3-methoxy-2-methyl-naphthalene (700 mg, 2.79 mmol, 64.1% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3)δ=8.26-8.17(m,1H),7.73-7.69(m,1H),7.47-7.40(m,2H),7.09(s,1H),3.98-3.95(m,3H),2.56(s,3H).

[0241] Step F: 4-Bromo-3-methyl-naphthalen-2-ol: To a solution of 1-bromo-3-methoxy-2-methyl-naphthalene (580 mg, 2.31 mmol) and tetrabutylammonium iodide (2.13 g, 5.78 mmol) in DCM (11.0 mL) cooled to -78 °C, was added BCl 3 (1M, 5.78mL) solution 2 C. for 10 min. The reaction mixture was warmed to 0.degree. C. and stirred at room temperature for 2 h. The solvent was then removed in vacuo and the residue was purified by preparative TLC (petroleum ether:ethyl acetate 5:1) to give 4-bromo-3-methyl-naphthalen-2-ol (500 mg, 2.11 mmol, 91.3% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ=8.26-8.15(m,1H),7.63(dd,J=3.6,6.0Hz,1H),7.45-7.38(m,2H),7.11(s,1H),5.09(s,1H),2.60(s,3H),1.56(s,3H).

[0242] Step G: 3-Benzyloxy-1-bromo-2-methyl-naphthalene. To a mixture of 4-bromo-3-methyl-naphthalen-2-ol (265 mg, 1.12 mmol) and benzyl bromide (201 mg, 1.18 mmol) in acetonitrile (3.00 mL) was added potassium carbonate (310 mg, 2.24 mmol) 2 The mixture was then stirred at 60° C. for 2 h. The solvent was removed under vacuum and the residue was purified by preparative TLC (petroleum ether:ethyl acetate 5:1) to give 3-benzyloxy-1-bromo-2-methylnaphthalene (250 mg, 695 μmol, 31.0% yield, 91.0% purity) as a white solid. ES+APCI MS m / z 327.0, 329.0 [M+H] + . [ka]

[0243] Step A: (4-Bromo-2-naphthyl) 2,2-dimethylpropanoate. To a solution of 4-bromonaphthalen-2-ol (10 g, 44.8 mmol) and TEA (9.07 g, 89.7 mmol) in DCM (200 mL) at 0° C. was added 2,2-dimethylpropanoyl chloride (8.11 g, 67.2 mmol). The reaction mixture was stirred at 0° C. for 10 min. The reaction mixture was quenched by adding water (50 mL) and the layers were separated. The organic layer was washed with brine (30 mL) and diluted with NaCl. 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA=1:0-100:1) to give (4-bromo-2-naphthyl) 2,2-dimethylpropanoate (9 g, 29.3 mmol, 65.4% yield) as a red oil. 1 H NMR (400 MHz, chloroform-d) δ = 8.22 (d, J = 8.0 Hz, 1H), 7.83-7.77 (m, 1H), 7.63-7.49 (m, 4H), 1.41 (s, 9H). [ka]

[0244] Naphthalen-1-yl trifluoromethanesulfonate. In a three-neck flask, alpha-naphthol (4 g, 27.74 mmol) was dissolved in DCM (200 mL). The reaction was cooled to 10 °C in a water bath. N-Ethyl-N-isopropylpropan-2-amine (4.846 ml, 27.74 mmol) and trifluoromethanesulfonic anhydride (4.668 ml, 27.74 mmol) were added dropwise to the solution. The reaction was stirred at 10 °C for 2 h. TLC (25% EtOAc, UV vis) showed the reaction to be complete. The organics were washed with water (2x) and brine (2x). The organics were dried over MgSO4 and concentrated in vacuo. The concentrate was purified using normal phase chromatography on a CombiFlash (0% to 12% EtOAc:Hexanes). All fractions containing pure product were combined and concentrated in vacuo to give naphthalen-1-yl trifluoromethanesulfonate (6.77 g, 24.51 mmol, 88.34% yield). [ka]

[0245] To a solution of (S)-1-Boc-2-hydroxymethylpiperazine (1.0 g, 4.62 mmol) in DCE (92.47 ml, 4.624 mmol) was added formaldehyde (3.474 ml, 46.24 mmol) (37% aqueous solution), followed by sodium triacetoxyborohydride (4.9 g, 23.12 mmol). The mixture was stirred vigorously at room temperature for 2.5 h. The mixture was treated with saturated sodium bicarbonate (30 mL), stirred for 10 min, and then extracted with DCM (3×10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. ES+APCI MS m / z 231.1 [M+H] + . [ka]

[0246] The title compound was prepared similarly to Intermediate 57, using tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate instead of (S)-1-Boc-2-hydroxymethylpiperazine. ES+APCI MS m / z 231.1 [M+H] + . [ka]

[0247] To a round bottom flask was added THF (8.87 ml, 4.44 mmol) followed by sodium hydride, 60% dispersion in mineral oil, (0.213 g, 5.32 mmol). The mixture was cooled to 0° C. and then 3-bromo-5-chloro-4-fluorophenol (1.0 g, 4.44 mmol) was added in portions. Once the bubbling had ceased, the resulting dark mixture was stirred at 0° C. for 30 min. Chloromethyl methyl ether (0.421 ml, 5.54 mmol) was then added and the mixture was allowed to warm to ambient temperature and stirred for 2 h. Saturated aqueous ammonium chloride was added and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was chromatographed (0-15% EtOAc in hexanes) to give the product as a clear oil. [ka]

[0248] Step A: 4-Bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazole: To a solution of 4-bromo-5-(trifluoromethyl)-1H-indazole (500 mg, 1.89 mmol, 1 equiv.) in DCM (10 mL), 3,4-dihydro-2H-pyran (476 mg, 5.66 mmol, 517 μL, 3 equiv.) and TsOH H 2 O (35.9 mg, 188 μmol, 0.1 equiv.) was added. The mixture was stirred at 15° C. for 1 h. The mixture was concentrated. The residue was purified by column chromatography (SiO 2, PE:EA=10:1 to 1:1) to give 4-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazole (480 mg, 1.37 mmol, yield 72.9%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 8.20 (s, 1H), 7.69-7.63 (m, 2H), 5.70 (dd, J=2.8, 8.8 Hz, 1H), 4.05-3.96 (m, 1H), 3.79-3.70 (m, 1H), 2.56-2.50 (m, 1H), 2.27-2.04 (m, 2H), 1.80-1.74 (m, 2H), 1.60-1.54 (m, 1H). [ka]

[0249] 8-Bromo-6-(methoxymethoxy)quinoline: A stirred suspension of 8-bromoquinolin-6-ol (1.00 g, 4.46 mmol) in DCM (20 mL) was cooled to 0° C. and diisopropylethylamine (1.2 mL, 6.7 mmol, 1.5 equiv.) was added, followed by dropwise addition of chloro(methoxy)methane (0.41 mL, 5.4 mmol, 1.2 equiv.) and the reaction mixture was allowed to warm to room temperature overnight. Concentrated aqueous ammonia (0.5 mL, ca. 5 mmol) was then added and the resulting mixture was stirred at room temperature for 1 h. The mixture was evaporated in vacuo and chromatographed on silica gel, Redisep 40 g, using 20% ​​EtOAc / Hexanes as eluent to give a colorless powder (0.52 g, 44%). ES+APCI MS m / z 268.0, [M+H] + . [ka]

[0250] A solution of but-3-enenitrile (80.0 g, 1.19 mol, 96.4 mL, 1.00 equiv.) in tert-butanol (130 mL) and petroleum ether (480 mL) was diluted with Br 2A solution of (191 g, 1.19 mol, 61.5 mL, 1.00 equiv) was added. The mixture was stirred at 10° C. for 4 h. The mixture was used in the next step without any workup.

[0251] To the above mixture (274 mL), N,N'-dibenzylethane-1,2-diamine (160 g, 445 mmol, 157 mL, 2HOAc) and Et 3 A solution of N (178 g, 1.76 mol, 245 mL) was added. After stirring at 110° C. for 2 h, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=3 / 1) to give 2-(1,4-dibenzylpiperazin-2-yl)acetonitrile (75.0 g, 246 mmol, 55.7% yield for two steps) as a yellow solid. LCMS [ESI, M+1]: 306.

[0252] 1 H NMR (400 MHz, chloroform-d) δ = 7.37-7.23 (m, 10H), 3.80 (d, J = 13.2 Hz, 1H), 3.60-3.42 (m, 3H), 3.06-2.96 (m, 1H), 2.95-2.83 (m, 1H), 2.69-2.53 (m, 4H), 2.52-2.35 (m, 3H).

[0253] To a solution of 2-(1,4-dibenzylpiperazin-2-yl)acetonitrile (160 g, 524 mmol, 1.00 equiv) in dichloroethane (1.50 L) was added 1-chloroethyl carbonochloridate (300 g, 2.10 mol, 4.00 equiv) at 15° C. After stirring at 85° C. for 48 h, the mixture was concentrated under vacuum. The residue was then taken up in methanol (1.50 L) and heated to reflux for 1 h. The mixture was concentrated. The solid was treated with methyl tert-butyl ether (1.00 L) to give 2-piperazin-2-ylacetonitrile (Intermediate 62, 90.0 g, 454 mmol, 86.7% yield, 2HCl) as a white solid, which was used in the next step without further purification.

[0254] 1 H NMR (400MHz, DMSO-d6) δ = 10.19 (br s, 2H), 4.01-3.73 (m, 1H), 3.69-3.41 (m, 4H), 3.32 (dt, J = 2.8, 13.2Hz, 1H), 3.27-3.10 (m, 3H). [ka]

[0255] To a solution of tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate (80.0 g, 370 mmol, 1.0 equiv) in ethyl acetate (1400 mL) was added NaHCO 3 (93.2g, 1.11mol, 43.2mL, 3.0eq), H 2 2H2O (700 mL), and benzyl carbonochloridate (82.0 g, 481 mmol, 68.4 mL, 1.30 equiv.) were added. The mixture was stirred at 25° C. for 12 h. After completion, the organic phase was separated and washed with water (500 mL×2) and added with Na 2 SO 4 The mixture was dried over ice and filtered. The solvent was removed under vacuum to give a residue. The residue was purified by column chromatography (SiO 2 The mixture was purified by elution with 20 mL of ethyl acetate / petroleum ether (petroleum ether / ethyl acetate = 40 / 1 to 1 / 1). The product 1-benzyl 4-tert-butyl (2R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (85.0 g, 235 mmol, 64% yield, 96% purity) was obtained as a yellow oil. LCMS [ESI, M-99]: 251.

[0256] To a solution of 1-benzyl 4-tert-butyl (2R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (20.0 g, 57.1 mmol, 1.0 equiv.) in 2-methyltetrahydrofuran (240 mL) was added TEA (17.3 g, 171.23 mmol, 23.8 mL, 3.0 equiv.) and methanesulfonyl chloride (7.74 g, 67.6 mmol, 5.23 mL, 1.18 equiv.). The mixture was stirred at 20° C. for 1 h. The mixture was cooled to 37° C. with 150 mL of H2O at 20° C. 2The reaction mixture was quenched by adding O. The reaction mixture was extracted with ethyl acetate (300 mL x 2). The organic layer was diluted with H 2 Wash with O (100 mL) and add Na 2 SO 4 The mixture was dried over 100 ml and filtered. The solvent was removed under vacuum. 1-benzyl 4-tert-butyl (2R)-2-(methylsulfonyloxymethyl)piperazine-1,4-dicarboxylate (22.0 g, crude) was obtained as a yellow oil. The crude product was used directly in the next step without further purification.

[0257] To a solution of 1-benzyl 4-tert-butyl (2R)-2-(methylsulfonyloxymethyl)piperazine-1,4-dicarboxylate (22.0 g, 51.3 mmol) in DMA (150 mL) was added NaCN (10.4 g, 211 mmol). The mixture was stirred at 60° C. for 12 h. The solvent was removed under vacuum to give a residual oil. The residue was purified by H 2 The mixture was diluted with 200 mL of 2H2O (40.0 mL) and extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were washed with saturated brine (80.0 mL) and diluted with 2H2O (40.0 mL). 2 SO 4 The mixture was dried over hexanes, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 The mixture was purified by elution with 20 mL of ethyl acetate / petroleum ether (petroleum ether / ethyl acetate = 40 / 1 to 5 / 1). The product 1-benzyl 4-tert-butyl (2S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate (18.5 g, 46.4 mmol, 72% yield for two steps) was obtained as a yellow oil. LCMS [ESI, M+1]: 360.

[0258] To a solution of 1-benzyl 4-tert-butyl(2S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate (18.5 g, 43.3 mmol, 1.00 equiv.) in dioxane (40.0 mL) was added HCl·dioxane (4 M, 54.1 mL, 5.0 equiv.). The mixture was stirred at 20 °C for 1 h. The reaction mixture was then treated with NaHCO 3 was added until the pH was above 7 and concentrated under reduced pressure to remove dioxane. 2The mixture was diluted with 200 mL of H2O (50.0 mL) and extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were washed with H 2 Wash with O (20.0 mL) and add Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated under reduced pressure to give a residue. The product benzyl (2S)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate 63, 11.5 g, 91.8% purity, 95% yield) was obtained as a yellow oil. LCMS [ESI, M+1]: 260.

[0259] 1 H NMR (400 MHz, chloroform-d) δ = 7.37-7.31 (m, 5H), 5.14 (s, 2H), 4.49 (br, s, 1H), 3.93 (br, s, 1H), 3.07-2.81 (m, 5H), 2.78-2.54 (m, 2H). [ka]

[0260] Step A: 1-Bromo-8-methyl-naphthalene. To a solution of 1,8-dibromonaphthalene (1 g, 3.50 mmol, 1 equiv) in THF (20 mL) was added MeLi (1.6 M in diethyl ether, 2.62 mL, 1.2 equiv) dropwise at 0° C. After stirring for 30 min at 0° C., iodomethane (3.38 g, 23.8 mmol, 1.48 mL, 6.81 equiv) was added dropwise. The mixture was warmed to 25° C. and stirred for an additional 3 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL) and concentrated to 100° C. with 100% NaCl. 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18 250 * 50mm *The mixture was purified by HPLC using a 10 μm column; mobile phase: [water (0.05 v / v % ammonium hydroxide)-ACN]; B%: 45%–70%, 28 min; B%: 40% min). The title compound, 1-bromo-8-methylnaphthalene (340 mg, 1.49 mmol, 43% yield, 97% purity), was obtained as a yellow solid after lyophilization.

[0261] 1 H NMR (400 MHz, chloroform-d) δ = 7.75 (dd, J = 0.8, 7.2 Hz, 1H), 7.69 (dd, J = 0.8, 8.0 Hz, 1H), 7.66-7.59 (m, 1H), 7.30-7.22 (m, 2H), 7.13 (t, J = 8.0 Hz, 1H), 3.05 (s, 3H). [ka]

[0262] Step A: 1H-naphtho[1,8-de][1,2,3]triazine. To a solution of naphthalene-1,8-diamine (100 g, 632 mmol, 1 equiv.) in AcOH (200 mL) and EtOH (1000 mL), isoamyl nitrite (72.6 g, 619 mmol, 83.4 mL, 0.98 equiv.) was added dropwise over 2 h while controlling the temperature at 18-21 °C under a cold water bath. After addition, the resulting red suspension was stirred at 25 °C for 16 h. The solid was collected by filtration, washed with ethanol (2 × 500 mL), and dried under vacuum. The compound 1H-naphtho[1,8-de][1,2,3]triazine (84 g, 496 mmol, 79% yield) was obtained as a red crystalline solid and used directly in the next step without purification. LCMS [ESI,M+1]: 170.

[0263] Step B: 8-Chloronaphthalen-1-amine. To a solution of 1H-naphtho[1,8-de][1,2,3]triazine (84 g, 496 mmol, 1 equiv.) in HCl (1.5 L) was added Cu (2.10 g, 33.1 mmol, 234 μL, 0.0665 equiv.). The mixture was stirred at 25° C. for 12 h. The resulting mixture was diluted with water (500 mL) and heated at 85° C. for 30 min. The resulting almost clear aqueous solution was filtered, cooled, basified with aqueous ammonia (until litmus paper turned blue) and the solution was extracted with ether acetate (2×1000 mL). The combined extracts were diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 The mixture was purified by elution with petroleum ether / ethyl acetate=200 / 1 to 5 / 1). Compound 8-chloronaphthalene-1-amine (57 g, 259 mmol, yield 52%, purity 81%) was obtained as a red solid. LCMS [ESI, M+1]: 178.

[0264] Step C: 1-Bromo-8-chloronaphthalene. 8-Chloro-naphthalen-1-amine (57 g, 320 mmol, 1 equiv.) in MeCN (1000 mL) and TsOH H 2 To a solution of 219 g, 1.16 mol, 3.6 equiv. 2 NaNO in O (120 mL) 2 A solution of (39.8 g, 577 mmol, 1.8 equiv) and CuBr (138 g, 963 mmol, 29.3 mL, 3 equiv) was added at -5°C, and the reaction mixture was then stirred at 25°C for 12 h. The reaction mixture was diluted with saturated Na 2 SO 3 Solution (100 mL) was added and stirred for 15 min, then extracted with ethyl acetate (1000 mL x 3). The combined organic layers were washed with brine (500 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2, petroleum ether) to give the title compound 1-bromo-8-chloro-naphthalene (56 g, 229 mmol, 72% yield, 99% purity) as a white solid.

[0265] 1 H NMR (400 MHz, chloroform-d) δ = 7.93 (dd, J = 1.2, 7.6 Hz, 1H), 7.82 (dd, J = 1.2, 8.4, 1H), 7.79 (dd, J = 1.2, 8.4, 1H), 7.67 (dd, J = 1.2, 7.6 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H). [ka]

[0266] Step A: 1-Bromo-8-chloro-naphthalene (20.0 g, 82.8 mmol, 1.00 equiv.) in DMF (400 mL), Pin 2 B 2 (52.6g, 207mmol, 2.50eq), KOAc (48.8g, 497mmol, 6.00eq), Pd(dppf)Cl 2 A mixture of (6.06 g, 8.28 mmol, 0.10 equiv.) with N 2 The mixture was stirred at 80° C. for 12 h under reduced pressure. The mixture was diluted with ethyl acetate (60.0 mL) and water (60.0 mL) and the mixture was separated. The aqueous phase was extracted with ethyl acetate (50.0 mL). The combined organic layers were washed with brine (2×50.0 mL) and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , PE / EA=10 / 1) to give 2-(8-chloro-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (210 g, 72.8 mmol, 88% yield) as a yellow solid.

[0267] 1H NMR(400MHz,chloroform-d)δ=7.87(dd,J=1.2,8.0Hz,1H),7.76(dd,J=1.2,8.0Hz,1H),7.68(dd,J=1.0,6 .8Hz,1H),7.59(dd,J=1.2,7.2Hz,1H),7.51(dd,J=6.8,8.0Hz,1H),7.40-7.35(m,1H),1.46(s,12H).

[0268] Step B: To a mixture of 2-(8-chloro-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.00 g, 6.93 mmol, 1.00 equiv) in methanol (20.0 mL), H 2 KHF in O (7 mL) 2 (4.87 g, 62.4 mmol, 2.06 mL, 9.00 equiv) was added. After stirring at 30° C. for 3 h, the mixture was concentrated in vacuo to remove methanol, filtered, and the filter cake was collected to give potassium [(8-chloro-1-naphthyl)-trifluoro-boranyl] (2.6 g, crude) as a yellow solid, which was used in the next step without further purification. [ka]

[0269] Step A: (COCl) 2 A reaction mixture of 2,2,2-trichloroacetamide (100 g, 616 mmol, 1.0 equiv) in 2,2,2-trichloroacetamide (725 g, 5.71 mol, 500 mL, 9.28 equiv) was heated at 70° C. for 24 h. The reaction mixture was concentrated under vacuum. The mixture was treated with 1,2,4-trichlorobenzene (500 mL) and (COCl) 2 (116 g, 914 mmol, 80 mL, 1.48 equiv) was added. The reaction mixture was stirred at 100° C. for 5 h. It was then warmed to 125° C. for 15 h. The mixture was then warmed to 140° C. for 5 h. The reaction mixture was distilled under a water pump (fraction 72° C.-76° C.) to give 2,2,2-trichloroacetyl isocyanate (60 g, 319 mmol, 52% yield) as a colorless oil, which was used in the next step without further purification.

[0270] Step B: 2-Chloro-3-fluoro-pyridine-4-carboxylic acid (180 g, 1.03 mol, 1.0 equiv.), 4A molecular sieves (300 g) and Et 3 A mixture of N (311 g, 3.08 mol, 428 mL, 3.0 equiv) was stirred at 110° C. under nitrogen for 0.5 h, then the mixture was cooled to 25° C. and diphenylphosphoryl azide (423 g, 1.54 mol, 333 mL, 1.5 equiv) was added. The mixture was stirred at 110° C. for 5 h. Upon completion, the mixture was diluted with water (2000 mL) and extracted with ethyl acetate (2×2000 mL). The combined organic layers were washed with brine (1×2000 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). tert-Butyl N-(2-chloro-3-fluoro-4-pyridyl)carbamate (197 g, 799 mmol, 78% yield, 100% purity) was obtained as a white solid. LCMS [ESI, M+1]: 247; LCMS [ESI, M-55]: 191.

[0271] 1 H NMR (400MHz, methanol-d 4 )δ=8.11(t,J=5.6Hz,1H),7.99(d,J=5.6Hz,1H),1.52(s,9H).

[0272] Step C: To a solution of tert-butyl N-(2-chloro-3-fluoro-4-pyridyl)carbamate (199 g, 807 mmol, 1.0 equiv) in MeCN (250 mL) was added HCl / dioxane (4 M, 796 mL, 3.95 equiv). The mixture was stirred at 25° C. for 2 h. Upon completion, the mixture was filtered and the filter cake was washed with saturated NaHCO 3The mixture was diluted with ethyl acetate (2000 mL) and extracted with ethyl acetate (2×2000 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. 2-Chloro-3-fluoro-pyridin-4-amine (107 g, 731 mmol, 91% yield, 99.9% purity) was obtained as a yellow solid, which was used in the next step without further purification. LCMS [ESI, M+1]: 147.

[0273] 1 H NMR (400MHz, methanol-d 4 )δ=7.61(d,J=5.6Hz,1H),6.67(t,J=6.0Hz,1H).

[0274] Step D: To a solution of 2-chloro-3-fluoro-pyrimidin-4-amine (197 g, 730 mmol, 1.0 equiv) and NIS (107 g, 876 mmol, 1.2 equiv) in MeCN (550 mL) was added p-toluenesulfonic acid monohydrate (6.94 g, 36.5 mmol, 0.05 equiv). The mixture was stirred at 70° C. for 16 h. Upon completion, the mixture was diluted with water (300 mL) and ethyl acetate (2000 mL) and the organic layer was washed with saturated Na 2 CO 3 Solution (2 x 1500mL), saturated Na 2 SO 3 (1×2000 mL) solution, and brine (1×1500 mL), and 2 SO 4 It was dried over 100 ml, filtered and concentrated in vacuo to give 2-chloro-3-fluoro-5-iodo-pyridin-4-amine (190 g, 676 mmol, 93% yield, 97.2% purity) as a yellow solid which was used in the next step without further purification. LCMS [ESI, M+1]: 273.

[0275] Step E: To a solution of 2-chloro-3-fluoro-5-iodo-pyridin-4-amine (78.4 g, 288 mmol, 1.0 equiv) in EtOH (1500 mL) was added Pd(PPh 3 ) 2 Cl 2 (20.2 g, 28.8 mmol, 0.1 equiv.) and Et3 N (105 g, 1.04 mol, 144 mL, 3.61 equiv) was added under nitrogen. The suspension was degassed under vacuum and purged with nitrogen several times. The mixture was stirred at 80° C. under CO (15.0 psi) for 15 h. Upon completion, the mixture was filtered, the filtrate was concentrated under vacuum to remove 70% of MeOH, and the residue was filtered. The combined filter cake was concentrated under vacuum. Ethyl 4-amino-6-chloro-5-fluoro-pyridine-3-carboxylate (142 g, crude) was obtained as a yellow solid. LCMS [ESI, M+1]: 219.

[0276] 1 H NMR (400MHz, dmso-d 6 )δ=8.36(s,1H),7.49-7.42(m,2H),4.31(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H).

[0277] Step F: To a solution of ethyl 4-amino-6-chloro-5-fluoro-pyridine-3-carboxylate (20.3 g, 73.2 mmol, 1.0 equiv) in THF (60 mL) was added 2,2,2-trichloroacetyl isocyanate (20.7 g, 110 mmol, 13.0 mL, 1.5 equiv) at 25 °C. The mixture was stirred at 25 °C for 10 min. Upon completion, the mixture was concentrated under vacuum. The crude product was triturated with MTBE (200 mL) at 25 °C for 5 min. Ethyl 6-chloro-5-fluoro-4-[(2,2,2-trichloroacetyl)carbamoylamino]pyridine-3-carboxylate (29.3 g, 67.74 mmol, 92% yield, 94.1% purity) was obtained as a grey solid. LCMS [ESI, M+1]: 408.

[0278] Step G: To a solution of ethyl 6-chloro-5-fluoro-4-[(2,2,2-trichloroacetyl)carbamoylamino]pyridine-3-carboxylate (29.3 g, 63.1 mmol, 1.0 equiv) in MeOH (290 mL), NH 3MeOH (29 mL, 20% purity) was added at 25° C. The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated under vacuum. The crude product was triturated with MTBE (200 mL) at 25° C. for 10 min. 7-Chloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol (18 g, crude) was obtained as a brown solid. LCMS [ESI, M+1]: 216.

[0279] Step H: POCl 3 To a mixture of (165 g, 1.08 mol, 100 mL, 23.2 equiv) and DIEA (30.0 g, 232 mmol, 40.4 mL, 5.0 equiv) was added 7-chloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol (10 g, 46.4 mmol, 1.0 equiv) in portions at 0° C. The mixture was then warmed to 110° C. and stirred for 3 h. Upon completion, the mixture was concentrated under vacuum and the oil was extracted with CHCl. 3 The mixture was dried by azeotropy with 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (11.7 g, crude) was obtained as a black oil, which was used in the next step without further purification. [ka]

[0280] Step A: KNO 3 (26.3 g, 260 mmol, 1.08 equiv.) 2 SO 4 (188 g, 1.88 mol, 102 mL, 98% purity, 7.81 equiv.) and slowly dissolved by careful heating. The resulting solution was heated at 0° C. with H 2 A solution of 4-bromoisoquinoline (50 g, 240 mmol, 1.0 equiv.) in SO4 (375 g, 3.75 mol, 204 mL, 98% purity, 15.6 equiv.) was added dropwise. After removal of the cooling bath, the solution was stirred at 25° C. for 1 h. The reaction mixture was then poured onto crushed ice (1000 g) and made basic (pH approx. 8) with NaOH solution (2N). The mixture was extracted with ethyl acetate (3×2000 mL) and diluted with Na 2 SO 4The mixture was dried over hexane, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (500 ml). 4-Bromo-5-nitro-isoquinoline (50 g, 197 mmol, 82% yield, 100% purity) was obtained as a yellow solid. LCMS [ESI, M+2]: 255.

[0281] Step B: 4-Bromo-5-nitro-isoquinoline (25 g, 98.7 mmol, 1.0 equiv.) and SnCl 2 2H 2 HO (111 g, 493 mmol, 5.0 equiv) was suspended in EtOH (600 mL) and HCl (12 M, 57.5 mL, 6.98 equiv) was added and stirred at 80° C. for 30 min. The reaction mixture was poured onto crushed ice (1000 g) and the pH was adjusted to about 12 with 2N aqueous sodium hydroxide. The mixture was then extracted with ethyl acetate (3×2000 mL). The combined organic layers were washed with brine (1000 mL) and diluted with Na 2 SO 4 Drying over, filtration and concentration under reduced pressure afforded 4-bromoisoquinolin-5-amine (36 g, 150 mmol, 76% yield, 93% purity) as a brown solid which was used in the next step without further purification.

[0282] 1 H NMR (400 MHz, chloroform-d) δ = 8.99 (s, 1H), 8.51 (s, 1H), 7.47-7.32 (m, 2H), 6.93 (dd, J = 1.2, 7.6 Hz, 1H), 5.24 (s, 2H).

[0283] Step C: To a solution of 4-bromoisoquinolin-5-amine (33 g, 147 mmol, 1.0 equiv) in aqueous HCl (2 M, 1000 mL, 13.5 equiv) cooled to 0 °C, add H 2 NaNO in O (400 mL) 2(13.3 g, 192 mmol, 806 μL, 1.3 equiv) was added. The reaction was stirred at 0° C. for 30 min, a solution of CuCl (19.0 g, 192 mmol, 4.60 mL, 1.3 equiv) in concentrated HCl (400 mL) was stirred at 0° C., and the reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was poured onto crushed ice (1000 g) and the pH was adjusted to about 8 with 2N aqueous sodium hydroxide. The mixture was then extracted with ethyl acetate (3×1000 mL). The combined organic layers were washed with brine (500 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 The mixture was purified with ethyl acetate / methanol = 100 / 1 to 10 / 1) to give 4-bromo-5-chloro-isoquinoline (17 g, 69.4 mmol, 47% yield, 99% purity) as a yellow solid.

[0284] 1 H NMR (400 MHz, chloroform-d) δ = 9.11 (s, 1H), 8.79 (s, 1H), 7.91 (dd, J = 1.2, 8.0 Hz, 1H), 7.84 (dd, J = 1.2, 7.6 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H).

[0285] Step D: To a solution of 4-bromo-5-chloro-isoquinoline (5 g, 20.6 mmol, 1.0 equiv) in toluene (100 mL), Pd(PPh 3 ) 4 (2.38 g, 2.06 mmol, 0.1 equiv) and trimethyl(trimethylstannyl)stannane (22.0 g, 67.2 mmol, 13.9 mL, 3.26 equiv) were added at 30° C. The mixture was stirred at 100° C. for 36 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL) and diluted with Na 2 SO 4The mixture was dried over hexane, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (50 mL) and further purified by reverse phase flash [water (0.1% formic acid) / acetonitrile)]. The mixture was concentrated under reduced pressure to give (5-chloro-4-isoquinolyl)-trimethyl-stannane (1.7 g, 5.16 mmol, 25% yield, 99% purity) as a colorless oil. LCMS [ESI, M+1]: 328.

[0286] 1 H NMR (400 MHz, chloroform-d) δ = 9.21 (s, 1H), 8.72 (s, 1H), 7.98-7.87 (m, 1H), 7.82 (dd, J = 1.2, 7.6 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 0.55-0.40 (s, 9H).

[0287] In addition to the above intermediates 1-61, the following exemplary intermediates A-1-A-10 can be used to prepare -YR 2 can be attached to the azaquinazoline core of formula (I). [ka]

[0288] LiAlH in THF (180 mL) 4 (5.55 g, 146 mmol, 2.0 equiv.) was cooled to -20 °C with methyl 1-benzylazetidine-2-carboxylate (15.0 g, 73.1 mmol, 1.0 equiv.) and cooled to -20 °C with N 2 The reaction mixture was stirred at -20°C for 1 h and then quenched with water (5.55 mL), 15% aqueous NaOH (5.55 mL), and water (16.6 mL). The mixture was filtered and the solid was washed with THF (20 mL). The filter cake was slurried in THF (50 mL) at 25°C for 5 min and filtered. The combined filtrate was washed with anhydrous Na 2 SO 4 Drying over rt, filtering and concentrating under reduced pressure gave (1-benzylazetidin-2-yl)methanol (12.1 g, 64.8 mmol, 89% yield) as a yellow oil. LCMS [M+1]: 178.

[0289] To a mixture of (1-benzylazetidin-2-yl)methanol (12.1 g, 68.3 mmol, 1.0 equiv) in THF (80.0 mL) was added DMAP (834 mg, 6.83 mmol, 0.1 equiv), imidazole (13.9 g, 205 mmol, 3.0 equiv), and TBDPSCl (20.6 g, 75.1 mmol, 19.3 mL, 1.1 equiv) at 0° C. The reaction mixture was stirred at 25° C. for 1 h and then concentrated under reduced pressure. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 The material was purified by reverse phase flash chromatography [water (0.1% FA) / acetonitrile] to give (1-benzylazetidin-2-yl)methoxy-tert-butyl-diphenyl-silane (20.0 g, 47.6 mmol, 70% yield) as a yellow oil. LCMS [M+1]: 416. 1 H NMR (400MHz, chloroform-d) δ=7.73-7.65(m,4H),7.48-7.35(m,6H),7.34-7.22(m,5H),3.98(br d,J=12.4Hz,1H),3.84-3.25(m,5H),3.03-2.75(m,1H),2.00(br d,J=1.6Hz,2H),1.07(s,9H).

[0290] A solution of (1-benzylazetidin-2-yl)methoxy-tert-butyl-diphenyl-silane (19.0 g, 45.7 mmol, 1.0 equiv.) in methanol (570 mL) was added to the reaction vessel with N 2 HOAc (1.10 g, 18.3 mmol, 1.05 mL, 0.4 equiv.) and Pd(OH) 2 13.0 g of 100 / C (20 wt%) was added. The suspension was degassed under vacuum and H 2 The mixture was purged with H several times. 2The mixture was stirred at 50° C. under (50 psi) for 48 h. The mixture was filtered and the solid was washed with methanol (100 mL). The filtrate was concentrated to dryness under reduced pressure. The crude product was purified by reverse phase flash chromatography [water (0.1% FA) / acetonitrile] to give azetidin-2-ylmethoxy-tert-butyl-diphenyl-silane (5.7 g, 15.2 mmol, 33% yield) as a yellow oil. LCMS [M+1]: 326. 1 H NMR (400 MHz, chloroform-d) δ 7.72-7.54 (m, 4H), 7.48-7.31 (m, 6H), 4.00-3.86 (m, 1H), 3.79-3.41 (m, 4H), 2.31 (ddd, J = 2.8, 5.2, 10.8 Hz, 1H), 2.17-2.00 (m, 1H), 1.16-0.99 (m, 9H).

[0291] To a mixture of azetidin-2-ylmethoxy-tert-butyl-diphenyl-silane (2.8 g, 7.48 mmol, 1.0 equiv.) and cyclopropylboronic acid (2.57 g, 29.9 mmol, 4.0 equiv.) in 1,2-dichloroethane (30.0 mL) was added Na 2 CO 3 (1.59g, 15.0mmol, 2.0eq), Cu(OAc) 2 (1.36 g, 7.48 mmol, 1.0 equiv.), and 2,2'-bipyridine (1.17 g, 7.48 mmol, 1.0 equiv.) were added at 25°C. The mixture was cooled to 0 2 The mixture was stirred at 70° C. under (15 psi) for 2 h. The mixture was cooled to room temperature, filtered, and washed with ethyl acetate (50 mL). The mixture was diluted with water (40 mL) and then extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (80 mL) and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate, 1:1 to 0:1) followed by reverse phase flash chromatography [water (0.1% FA) / acetonitrile] to give tert-butyl-[(1-cyclopropylazetidin-2-yl)methoxy]-diphenyl-silane (1.48 g, 4.01 mmol, 54% yield) as a yellow oil. LCMS [M+1]: 366.

[0292] To a solution of tert-butyl-[(1-cyclopropylazetidin-2-yl)methoxy]-diphenyl-silane (880 mg, 2.41 mmol, 1.0 equiv.) in THF (5.0 mL) was added TBAF (1.0 M, 2.89 mL, 1.2 equiv.) at 0° C. The mixture was stirred at 0° C. for 12 h. The mixture was then diluted with water (10 mL) and extracted with ethyl acetate (8×20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 It was dried over water, filtered and concentrated under reduced pressure to give crude (1-cyclopropylazetidin-2-yl)methanol (910 mg) as a yellow oil. [ka]

[0293] A solution of 1-cyclopropylpiperidin-4-one (2.0 g, 14.4 mmol, 1.0 equiv) in MeOH (40 mL) was diluted with Raney Nickel (167 mg) and 4M NH 3 MeOH (14.4 mmol, 20 mL, 1.0 equiv.) 2 The suspension was degassed under vacuum and H 2 The mixture was purged with H several times. 2 (15 psi) for 1 h at 15° C. The mixture was filtered and concentrated under reduced pressure to give 1-cyclopropylpiperidin-4-amine (1.7 g, crude) as a green solid.

[0294] A mixture of 1-cyclopropylpiperidin-4-amine (1.3 g, 9.27 mmol, 1.0 equiv.) in tert-butoxycarbonyl tert-butyl carbonate (2.85 g, 13.1 mmol, 3.0 mL, 1.4 equiv.) was stirred at 40° C. for 3 h. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 10:1 to petroleum ether / ethyl acetate, 2:1) to give tert-butyl N-(1-cyclopropyl-4-piperidyl)carbamate (1.7 g, 7.07 mmol, 76% yield) as a white solid. 1 H NMR(400MHz,chloroform-d)δ4.40(br s,1H),3.47(br s,1H),2.95(d,J=12.0Hz,2H),2.35-2.21(m,2H),1.90(d,J=11.6Hz,2H),1.63-1.52(m,1H),1.44(s,9H),1.35(br dd,J=3.2,12.0Hz,1H),0.47-0.41(m,2H),0.40-0.35(m,2H).

[0295] To a solution of tert-butyl N-(1-cyclopropyl-4-piperidyl)carbamate (500 mg, 2.08 mmol, 1.0 equiv) in methanol (2.0 mL) was added HCl (4 M in dioxane, 5.0 mL, 9.6 equiv) at 0° C. The mixture was stirred at 0° C. for 1 h. The mixture was concentrated, diluted with saturated aqueous NaOH (25 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (20 mL) and anhydrous Na 2 SO 4 It was dried over, filtered and concentrated under reduced pressure to give 1-cyclopropylpiperidin-4-amine (120 mg, crude) as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ2.98(d,J=12.0Hz,2H),2.71(br s,1H),2.22(td,J=2.0,11.6Hz,2H),1.79(br d,J=12.0Hz,2H),1.59-1.51(m,1H),1.38-1.25(m,2H),0.48-0.34(m,4H). [ka]

[0296] To a solution of O1-tert-butyl O2-methylpyrrolidine-1,2-dicarboxylate (58.0 g, 253 mmol, 1.0 equiv) in THF (1000 mL) was added LiHMDS (1 M, 379 mL, 1.5 equiv) at -65°C. The mixture was stirred at -65°C for 1 h, and then 1-bromo-3-chloro-propane (199 g, 1.26 mol, 124 mL, 5.0 equiv) was added at -65°C. The solution was allowed to warm to room temperature with stirring for 2 h. The mixture was diluted with saturated NH 4 The mixture was diluted with aqueous Cl (500 mL) and then extracted with ethyl acetate (1200 mL). 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 50:1 to 5:1) to give 1-(tert-butyl) 2-methyl 2-(3-chloropropyl)pyrrolidine-1,2-dicarboxylate (50.0 g, 60% yield) as a yellow oil.

[0297] To a solution of 1-(tert-butyl) 2-methyl 2-(3-chloropropyl)pyrrolidine-1,2-dicarboxylate (11.7 g, 38.3 mmol, 1.0 equiv) in dichloromethane (300 mL) was added TFA (117 g, 1.02 mol, 75.8 mL, 26.7 equiv) at 25° C. The mixture was stirred at 25° C. for 0.5 h. The mixture was then concentrated under vacuum to give methyl 2-(3-chloropropyl)pyrrolidine-2-carboxylate (12 g, crude, TFA salt) as a colorless oil.

[0298] To a solution of methyl 2-(3-chloropropyl)pyrrolidine-2-carboxylate (12.0 g, 37.5 mmol, 1.0 equiv., TFA) in MeOH (250 mL) was added K 2 CO 3(15.6 g, 113 mmol, 3.0 equiv) and KI (623 mg, 3.75 mmol, 0.1 equiv) were added at 25° C. The mixture was stirred at 35° C. for 1.5 h. The mixture was filtered and approximately 80% of the filtrate was removed under reduced pressure. The remaining filtrate was diluted with ethyl acetate (400 mL) and filtered. The filtrate was concentrated under vacuum to give the crude material, which was purified by column chromatography (Al 2 O 3 , dichloromethane / methanol, 10:1) to give methyl tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (5.40 g, 85% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ3.70(br s,3H),3.22-3.08(m,2H),2.71-2.56(m,2H),2.36-2.22(m,2H),1.87-1.73(m,4H),1.72-1.59(m,2H);LCMS[ESI,M+1]:170.

[0299] To a solution of methyl tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (11.8 g, 69.7 mmol, 1.0 equiv) in THF (250 mL) was added LiAlH 4 (7.94 g, 209 mmol, 3.0 equiv) was added at -10°C. The mixture was stirred at this temperature for 30 min and then quenched with water (7 mL) and 15% NaOH solution (8 mL). The mixture was filtered and the filtrate was concentrated in vacuo to give (tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (8.70 g, 88% yield) as a yellow oil. 1 H NMR (400MHz, CD 3 OD) δ3.31(s,2H),3.00-2.91(m,2H),2.67-2.57(m,2H),1.96-1.80(m,4H),1.78-1.68(m,2H),1.62-1.52(m,2H). [ka]

[0300] To a solution of ((2S,4R)-4-fluoropyrrolidin-2-yl)methanol (5.23 g, 33.6 mmol, 1.0 equiv., HCl salt) in MeOH (50 mL), N 2 Acetone (25.5 g, 439 mmol, 32.3 mL, 13 equiv.) and Pd / C (600 mg, 10% w / w) were added under vacuum. The suspension was evacuated under H 2 The mixture was purged with H several times. 2 (45 psi) at 25° C. for 12 h. The mixture was then filtered and the filtrate was concentrated to give the crude material. The crude material was purified by flash chromatography (SiO 2 , petroleum ether / ethyl acetate, 5:1 to DCM / MeOH, 5:1) to give ((2S,4R)-4-fluoro-1-isopropylpyrrolidin-2-yl)methanol (2.7 g, 50% yield) as a colorless oil. Rf=0.30 (10:1, dichloromethane / methanol). 1 H NMR (400 MHz, CDCl 3 )δ5.25-4.99(m,1H),3.81-3.70(m,1H),3.51-3.44(m,1H),3.40-3.24(m,2H),3.18(s, 1H),3.13-2.98(m,1H),2.20-2.03(m,2H),1.18(d,J=6.8Hz,3H),1.05(d,J=6.4Hz,3H). [ka]

[0301] To a solution of ((2S,4R)-4-methoxypyrrolidin-2-yl)methanol (2.5 g, 14.9 mmol, 1 equiv., HCl salt) in MeOH (30 mL), N 2 Acetone (19.1 g, 328 mmol, 24.1 mL, 22 equiv.) and Pd / C (500 mg, 10% w / w) were added under vacuum. The suspension was evacuated under H 2 The mixture was purged with H several times. 2(30.1 mg, 14.9 mmol) was stirred at 25° C. under 45 psi for 12 h. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 5:1 to DCM / MeOH, 5:1) to afford ((2S,4R)-1-isopropyl-4-methoxypyrrolidin-2-yl)methanol (1.1 g, 43% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ3.89-3.79(m,1H),3.56(d,J=4.0Hz,1H),3.35-3.29(m,1H),3.27(s,3H),3.19-3.06(m,2H),2.97(s,1 H),2.64-2.57(m,1H),2.02-1.94(m,1H),1.88-1.77(m,1H),1.09(d,J=6.8Hz,3H),0.96(d,J=6.4Hz,3H). [ka]

[0302] To a solution of (S)-(4,4-difluoropyrrolidin-2-yl)methanol (3.00 g, 17.3 mmol, 1.0 equiv., HCl salt) in methanol (50 mL) was added Pd / C (400 mg, 10% w / w) and acetone (39.5 g, 680 mmol, 50.0 mL, 39 equiv.). The reaction mixture was cooled to 5° C. for 1 hour and then cooled to 5° C. 2 The mixture was stirred under (45 psi) at 25° C. for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in NH 3 (50 mL, NH 3 The mixture was bubbled with methanol at -40°C for 10 minutes and concentrated. The residue was purified by column chromatography (Al 2 O 3 , petroleum ether / ethyl acetate, 3:1 to 0:1) to give (S)-(4,4-difluoro-1-isopropylpyrrolidin-2-yl)methanol (2.50 g, 81% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3)δ3.73-3.66(m,1H),3.38(br d,J=11.2Hz,1H),3.29-3.15(m,2H),3.11-2.95(m,2H),2.65-2.48(m,1H),2.46-2.20(m,2H),1.12(d,J=6.8Hz,3H),0.97(d,J=6.4Hz,3H). LCMS[ESI,M+1]:180. [ka]

[0303] To a solution of N-(2-hydroxyethyl)methanesulfonamide (3.00 g, 21.6 mmol, 1.0 equiv) in dichloromethane (40.0 mL) was added (Boc) 2 O (5.17 g, 23.7 mmol, 5.45 mL, 1.1 equiv), TEA (3.27 g, 32.3 mmol, 4.50 mL, 1.5 equiv), followed by DMAP (527 mg, 4.31 mmol, 0.2 equiv) were added at 0° C. The mixture was stirred at 0° C. for 1 h. The mixture was filtered and concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0 to 4:1) to give tert-butyl (2-hydroxyethyl) (methylsulfonyl)carbamate (1.01 g, 20% yield) as a colorless oil. f =0.25 (dichloromethane / methanol, 1:1). 1 H NMR (400 MHz, CDCl 3 )δ4.27-4.16(m,2H),3.48-3.38(m,2H),3.00(s,3H),1.50(s,9H). [ka]

[0304] To a solution of (1-benzylazetidin-2-yl)methanol (1.50 g, 8.46 mmol, 1.0 equiv.) and acetone (11.8 g, 204 mmol, 15.0 mL, 24 equiv.) in MeOH (15 mL), Pd / C (1.60 g, 10 wt / wt%) was added 2The suspension was evacuated and cooled to room temperature. 2 The mixture was purged with H 2 (45 psi) at 25° C. for 36 h. The mixture was filtered and the filter cake was washed with EtOH (10 mL) and THF (10 ml). The combined filtrate was concentrated to dryness under vacuum. The residue was purified by column chromatography (Al 2 O 3 , dichloromethane / methanol, 1:0 to 10:1) to give (1-isopropylazetidin-2-yl)methanol (800 mg, 73% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ3.67-3.57(m,1H),3.50-3.33(m,3H),2.92(dt,J=7.6,9.2Hz,1H),2.54(td,J=6.4,12.8Hz,1H), 2.25-2.11(m,2H),1.93(dtd,J=3.2,8.4,10.8Hz,1H),0.98(d,J=6.4Hz,3H),0.94(d,J=6.4Hz,3H). [ka]

[0305] To a solution of (1-benzylazetidin-2-yl)methanol (2.00 g, 11.3 mmol, 1.0 equiv) and acetaldehyde (5 M, 9.03 mL, 4.0 equiv) in EtOH (20.0 mL), Pd / C (1.00 g, 10 wt / wt%) was added in N 2 The suspension was evacuated and cooled to room temperature. 2 The mixture was purged with H several times. 2 The mixture was stirred at 40° C. for 48 hours under reduced pressure. The mixture was filtered, and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (Al 2 O 3 , petroleum ether / ethyl acetate, 3:1 to 0:1) to give (1-ethylazetidin-2-yl)methanol (330 mg, 25% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3):δ3.60(dd,J=3.2,11.6Hz,1H),3.46-3.34(m,2H),3.34-3.26(m,1H),2.87-2.77(m,1H),2.7 0-2.58(m,1H),2.46-2.35(m,1H),2.26-2.11(m,1H),1.99-1.86(m,1H),0.97(t,J=7.2Hz,3H). [ka]

[0306] To a solution of (S)-pyrrolidin-2-ylmethanol (1.50 g, 14.8 mmol, 1.44 mL, 1.0 equiv) in methanol (50.0 mL) was added cyclobutanone (3.12 g, 44.5 mmol, 3.32 mL, 3.0 equiv) and Pd / C (150 mg, 10% w / w) under a nitrogen atmosphere. The suspension was evacuated under vacuum and purified with H 2 (15 psi) several times. The mixture was then 2 (15 psi) at 25° C. for 12 h. The mixture was filtered and the filter cake was washed with methanol (40.0 mL). The filtrate was concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography [SiO 2 , petroleum ether / ethyl acetate, from 0:1 to 5:1 petroleum ether / ethyl acetate / ethanol (2% NH 4 OH), 4:3:1] to afford (S)-(1-cyclobutylpyrrolidin-2-yl)methanol (890 mg, 38.7% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ3.52(dd,J=4.4,10.4Hz,1H),3.34(dd,J=3.2,10.4Hz,1H),3.16-3.06(m,1H),3.01-2.95(m,1H),2.67(dt,J =4.4,8.8Hz,1H),2.41-2.33(m,1H),2.11-2.03(m,1H),2.03-1.91(m,4H),1.90-1.81(m,1H),1.76-1.60(m,5H). [ka]

[0307] To a mixture of 1-(tert-butyl) 2-ethyl (S)-4-oxopyrrolidine-1,2-dicarboxylate (25.0 g, 103 mmol, 1.0 equiv) in THF (300 mL) was added LiAlH 4 (7.80 g, 205 mmol, 2.0 equiv) was added at -40°C. The mixture was stirred at this temperature for 30 min, after which water (7.8 mL), 15% aqueous NaOH (7.8 mL), and water (23.4 mL) were slowly added dropwise. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (2S)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (21.0 g, crude) as a yellow oil.

[0308] To a mixture of tert-butyl (2S)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (30.0 g, 138 mmol, 1.0 equiv.) and BnBr (26.0 g, 152 mmol, 18.0 mL, 1.1 equiv.) in MeCN (500 mL) was added Ag 2 O (96.0 g, 414 mmol, 3.0 equiv.) was added. The mixture was stirred at 85° C. for 12 h. The reaction mixture was then filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 30:1 to 1:1) to give tert-butyl (2S)-2-((benzyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate (18.0 g, 42% yield) as a yellow oil.

[0309] To a mixture of tert-butyl (2S)-2-((benzyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate (17.0 g, 55.3 mmol, 1.0 equiv.) in ethyl acetate (160 mL) was added trichloroisocyanuric acid (19.3 g, 83.0 mmol, 1.5 equiv.) and TEMPO (13.0 g, 83.0 mmol, 1.5 equiv.) in ethyl acetate (50 mL) at -5°C. The mixture was stirred at that temperature for 30 min, then warmed to room temperature and stirred for 1 h. The mixture was then washed with saturated NaS 2 O 3 The mixture was diluted with aqueous solution (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (50 mL×1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude residue. The residue was purified by reverse phase flash chromatography [water (0.1% FA) / acetonitrile] to give tert-butyl (S)-2-((benzyloxy)methyl)-4-oxopyrrolidine-1-carboxylate (7.08 g, 37% yield) as a yellow oil. LCMS [ESI, M-99]: 206.

[0310] To a solution of ethyl 2-diethoxyphosphorylacetate (11.0 g, 49.1 mmol, 9.75 mL, 2.0 equiv.) in THF (120 mL) was added NaH (1.18 g, 29.5 mmol, 60% purity, 1.2 equiv.) at 0° C. The mixture was stirred at this temperature for 0.5 h, and then tert-butyl (S)-2-((benzyloxy)methyl)-4-oxopyrrolidine-1-carboxylate (7.50 g, 24.6 mmol, 1.0 equiv.) in THF (50 mL) was added. The resulting mixture was allowed to warm to room temperature and stirred for 30 min. The mixture was diluted with ice-cold water (50 mL) and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate, 20:1 to 1:1) to give tert-butyl (S)-2-((benzyloxy)methyl)-4-(2-ethoxy-2-oxoethylidene)pyrrolidine-1-dicarboxylate (7.50 g, 80% yield) as a yellow oil. LCMS [ESI, M-99]: 276.

[0311] tert-Butyl (S)-2-((benzyloxy)methyl)-4-(2-ethoxy-2-oxoethylidene)pyrrolidine-1-carboxylate (1.50 g, 4.00 mmol, 1.0 equiv.) in THF (2.00 mL) and ethyl alcohol (2.00 mL), PtO 2 (907 mg, 4.00 mmol, 1.0 equiv.), and Na 2 CO 3 A mixture of (423 mg, 4.00 mmol, 1.0 equiv) was purged with hydrogen gas and then H 2 (15 psi) at 25° C. for 3 h. The system was flushed with nitrogen and filtered through a plug of Celite. The filtrate was concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 20:1 to 5:1) to give tert-butyl (2S)-2-((benzyloxy)methyl)-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carbamate (1.00 g, 60% yield) as a colorless oil. LCMS [ESI, M+1]: 378.

[0312] To a solution of tert-butyl (2S)-2-((benzyloxy)methyl)-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate (1.50 g, 3.97 mmol, 1.0 equiv) in THF (20.0 mL) was added LiAlH 4 (452 mg, 11.9 mmol, 3.0 equiv) was added at -40°C and the mixture was stirred at this temperature for 1 h. 2 O (0.45 mL), 15% aqueous NaOH (0.45 mL), and H 2 The reaction mixture was carefully diluted with 2,4-dichloromethane (1.35 mL). The reaction mixture was filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2 , petroleum ether / ethyl acetate, 20:1 to 0:1) to give tert-butyl (2S)-2-((benzyloxy)methyl)-4-(2-hydroxyethyl)pyrrolidine-1-carbamate (1.00 g, 75% yield) as a colorless oil.

[0313] To a solution of tert-butyl (2S)-2-((benzyloxy)methyl)-4-(2-hydroxyethyl)pyrrolidine-1-carboxylate (1.00 g, 2.98 mmol, 1.0 equiv) in THF (10.0 mL) was added NaH (238 mg, 5.96 mmol, 60% purity, 2.0 equiv) and TsCl (1.14 g, 5.96 mmol, 2.0 equiv) at 0° C. The mixture was stirred at room temperature for 12 h and then diluted with H 2 The mixture was concentrated to give a residue. The residue was diluted with H 2 The mixture was diluted with 20 mL of HO (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 50:1 to 0:1) to give tert-butyl (2S)-2-((benzyloxy)methyl)-4-(2-tosyloxy)ethyl)pyrrolidine-1-carbamate (600 mg, 41% yield) as a colorless oil. LCMS [ESI, M-99]: 390.

[0314] A mixture of tert-butyl (2S)-2-((benzyloxy)methyl)-4-(2-(tosyloxy)ethyl)pyrrolidine-1-carboxylate (590 mg, 1.21 mmol, 1.0 equiv.), TFA (1.65 g, 14.5 mmol, 1.07 mL, 12 equiv.) in dichloromethane (5.0 mL) was stirred at 25° C. under nitrogen atmosphere for 0.5 h. The mixture was then concentrated and washed with saturated NaHCO 3 The mixture was diluted with aqueous solution of ethyl acetate (5 mL x 3) and extracted with ethyl acetate. The combined organic layer was washed with anhydrous Na 2 SO 4The mixture was dried over 100 ml of ethyl acetate and filtered. The filtrate was concentrated under reduced pressure to give 2-((5S)-5-((benzyloxy)methyl)pyrrolidin-3-yl)ethyl 4-methylbenzenesulfonate (600 mg, crude) as a colorless oil. LCMS [ESI, M+1]: 390.

[0315] To a solution of 2-((5S)-5-((benzyloxy)methyl)pyrrolidin-3-yl)ethyl 4-methylbenzenesulfonate (600 mg, 1.54 mmol, 1.0 equiv) in MeCN (30.0 mL) was added Na 2 CO 3 (816 mg, 7.70 mmol, 5.0 equiv) was added. The mixture was stirred at 25° C. for 1.0 h and then concentrated. The residue was diluted with saturated NaHCO 3 The mixture was diluted with aqueous solution of ethyl acetate (50 mL x 3) and then extracted with ethyl acetate. The combined organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried over ice and filtered. The filtrate was concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography (Al 2 O 3 , petroleum ether / ethyl acetate, 10:1 to ethyl acetate / ethanol (0.1% NH 4 OH), 3:1] to give (2S)-2-((benzyloxy)methyl)-1-azabicyclo[2.2.1]heptane (250 mg, 93% yield) as a yellow oil.

[0316] Methyl alcohol (4.0 mL) / NH 3 A mixture of (2S)-2-((benzyloxy)methyl)-1-azabicyclo[2.2.1]heptane (100 mg, 460 μmol, 1.0 equiv.) and Pd / C (100 mg, 10 wt %) in (1.0 mL, 20% in MeOH) was purged with hydrogen (3 times) and then stirred at 25 °C for 8 h (15 psi H 2 The mixture was filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (Al 2 O 3 , petroleum ether / ethyl acetate, 10:1 to ethyl acetate / ethanol (0.1% NH 4Purification by ethyl acetate (3:1) (hexanes; 3:4; 1H NMR) or 1:1 (HCl; 4:1; 1H NMR) or 1:1 (pH 7.0 ...1H NMR) or 1:1 (pH 7.0; 1H NMR) or 1:1 (pH 7.0; 1H NMR) or 1:1 [ka]

[0317] To a mixture of compound ethyl 5-oxopyrrolidine-2-carboxylate (1.50 kg, 9.54 mol, 1.00 equiv.) and 3-chloro-2-(chloromethyl)prop-1-ene (1.91 kg, 15.3 mol, 1.77 L, 1.60 equiv.) in THF (7.50 L) under nitrogen, LiHMDS (1 M, 19.1 L, 2.00 equiv.) was added dropwise at −40° C. The mixture was stirred at room temperature for 20 h. TLC (petroleum ether / ethyl acetate, 0:1) indicated that compound 5-oxopyrrolidine-2-carboxylate was consumed (R f =0.05), three new major spots were formed (R f = 0.40, 0.35, 0.27). The reaction mixture was poured into aqueous HCl (1 M, 2.50 L) at 0 °C, and the pH was adjusted to 7 with aqueous HCl (2 M). The resulting mixture was extracted with EtOAc (4.50 L x 3). The combined organic layer was washed with brine (4.50 L) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 10:1 to 1:1) to give ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (898 g, 4.29 mol, 45% yield, 82% purity) as a yellow oil. LCMS [ESI, M+1]: 210.1. 1 H NMR (400 MHz, CDCl 3):δ5.02-5.07(m,2H),4.28(d,J=15.6Hz,1H),4.16-4.22(m,2H),3.71(dd,J=15.6,1.6Hz,1H),3.04(d,J=1 5.6Hz, 1H), 2.73-2.80 (m, 1H), 2.57-2.64 (m, 1H), 2.41-2.49 (m, 2H), 2.03-2.17 (m, 2H), 1.24-1.30 (m, 3H).

[0318] Ozone was bubbled into a mixture of ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (165 g, 788 mmol, 1.00 equiv) in DCM (1650 mL) and MeOH (165 mL) at −70° C. After the solution turned pale blue, excess O 3 The mixture was purged with nitrogen for 30 minutes. 2 S (80.4 g, 1.29 mol, 95.0 mL, 1.6 equiv.) at -70 °C, warmed to room temperature, and stirred for 16 h. TLC (petroleum ether / ethyl acetate, 0:1) showed the 2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (R f =0.55) consumption, and one major spot (R f =0.50). The reaction mixture was concentrated under reduced pressure to give a residue. The combined residues from six identical reactions were purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 10:1 to 1:1) to give 2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (821 g, 3.89 mol, 82% yield, 93% purity) as a yellow oil. LCMS [ESI, M+1]: 212.1. 1 H NMR (400 MHz, CDCl 3 ):δ4.23(q,J=7.2Hz,2H),4.12(d,J=18.8Hz,1H),3.56(d,J=18.4Hz,1H),2.96-3.01( m,2H),2.77-2.86(m,1H),2.43-2.50(m,2H),2.14-2.22(m,1H),1.28(t,J=7.2Hz,1H).

[0319] A solution of ethyl 2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (257 g, 1.22 mol, 1.00 equiv) in EtOH (1300 mL) was treated with NaBH 4 (13.8 g, 365 mmol, 0.30 equiv) was added slowly at 0° C. The mixture was stirred at 0° C. for 10 min. TLC (ethyl acetate) showed that ethyl 2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (R f =0.55) and two major spots (R f = 0.30, 0.20). The reaction was diluted with saturated NH 4 Cl (65.0 mL) at 5° C. and stirred at that temperature for 30 min. The mixture was concentrated under reduced pressure to give a residue. The crude products from three identical reactions were combined. The combined crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 10:1 to 1:1) to give rac-ethyl (2S,7aR)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (450 g, 2.11 mol, 57% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ4.65(s,1H),4.14(q,J=7.2Hz,2H),3.95(dd,J=12.8,6.0Hz,1H),3.10(d,J=12.8Hz,1H),2.75-2.84(m,2H) ,2.49-2.49(m,2H),2.39-2.45(m,1H),2.02-2.10(m,1H),1.84(dd,J=13.6,6.0Hz,1H),1.30(t,J=7.2Hz,1H).

[0320] To a solution of rac-ethyl (2S,7aR)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (100 g, 469 mmol, 1.00 equiv) in DCM (500 mL) under nitrogen was added a solution of DAST (113 g, 703 mmol, 82.9 mL, 1.50 equiv) dropwise at -70°C. The reaction mixture was allowed to warm to 25°C and stirred for 16 h. TLC (petroleum ether / ethyl acetate, 1:1) showed consumption of starting material and one spot (R f =0.30). The reaction mixture was cooled to 10° C., diluted with MeOH (25.0 mL), water (1000 mL), and extracted with DCM (500 mL×3). The combined organic layers were washed with brine (500 mL) and anhydrous Na 2 SO 4 The mixture was dried over hexanes, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0 to 0:1) to give rac-ethyl (2S,7aR)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (55.0 g, 251 mmol, 49% yield) as a yellow oil. LCMS [ESI, M+1]: 216.0. 1 H NMR (400 MHz, CDCl 3 ):δ5.30(dt,J=52.4,4.0Hz,1H),4.17-4.25(m,3H),3.11-3.24(m,1H),2.5 9-2.83(m,3H),2.41-2.47(m,1H),2.09-2.30(m,2H),1.29(t,J=7.2Hz,1H).

[0321] rac-Ethyl (2S,7aR)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (30.0 g, 139 mmol) was first purified by preparative HPLC [Welch Ultimate XB-NH 2 250mm x 50mm x 10μm; Heptane-EtOH (0.1%NH 4The mixture was concentrated under reduced pressure to give a residue (28.0 g, 130 mmol). The residue was purified by preparative SFC (DAICEL CHIRALPAK IC 250 mm × 50 mm × 10 μm; 0.1% NH in IPA). 4 OH;CO 2 %: 40%, 4.7 min; desired product: peak 2, R t =1.959 min) The fractions were concentrated under reduced pressure to give ethyl (2S,7aR)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (12.0 g, 55.4 mmol, 40% yield, 99% purity, ee>99%) as a yellow oil.

[0322] LiAlH in THF (90.0 mL) 4 (4.81 g, 127 mmol, 1.50 equiv) under nitrogen was added dropwise to a solution of ethyl (2S,7aR)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (18.2 g, 85.6 mmol, 1.00 equiv) in THF (55.0 mL) at 0° C. The reaction mixture was heated at 70° C. for 3 h, at which point TLC analysis (petroleum ether / ether, 1:1) indicated the starting material (R f =0.30) and one new spot (R f =0.01). The mixture was cooled to 0 °C and slowly diluted with water (5.00 mL), 15% aqueous NaOH (15.0 mL) and water (15.0 mL). The mixture was stirred at 0 °C for 5 min and filtered. The filter cake was washed with EtOAc (80.0 mL × 4) and the filtrate was washed with anhydrous MgSO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , dichloromethane / methanol, 100:1 to 10:1) to give ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (10.8 g, 67.3 mmol, 99% purity, 80.0% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3):δ5.13-5.28(m,1H),3.26(s,2H),3.13-3.19(m,2H),2.91-3.10(m,2H),2.02-2.12(m,2H),1.76-1.94(m,4H).

[0323] In addition to the above intermediates 1-61 and A-12, the following exemplary intermediates B-1 to B-33 may be used to prepare -YR 2 can be attached to the azaquinazoline core of formula (I). [ka]

[0324] To a mixture of ethyl 1H-pyrrolo[3,2-b]pyridine-2-carboxylate (1.9 g, 9.99 mmol, 1.0 equiv) in DMF (20 mL) was added NaH (599 mg, 15.0 mmol, 60% purity, 1.5 equiv) at 0° C. The mixture was stirred at 15° C. for 30 min before adding SEMCl (2.50 g, 15.0 mmol, 2.65 mL, 1.5 equiv). The mixture was stirred at 15° C. for an additional 30 min and saturated NH 4 The mixture was diluted with aqueous Cl (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (80 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 20:1 to 5:1) to give ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (2 g, 6.05 mmol, 60% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3):δ8.58(dd,J=1.6,4.4Hz,1H),7.90-7.85(m,1H),7.47(d,J=0.8Hz,1H),7.25(dd,J=4.8,8.4Hz,1H),6.01 (s,2H),4.40(q,J=7.2Hz,2H),3.54-3.48(m,2H),1.42(t,J=7.2Hz,3H),0.88-0.81(m,2H),-0.093(s,9H).

[0325] To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (1.9 g, 5.93 mmol, 1.0 equiv) in THF (20 mL) was added LiAlH 4 (450 mg, 11.9 mmol, 2.0 equiv.) was added at −10° C. The mixture was stirred at −10° C. for 30 min, then saturated Na 2 SO 4 Aqueous solution (6 mL) was added at 0° C. The suspension was filtered and the filtrate was concentrated to give (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol (1.5 g, 91% yield) as a colorless oil. LCMS [ESI, M+1]: 279. [ka]

[0326] To a solution of (R)-1-phenylethan-1-amine (10 g, 82.5 mmol, 1 equiv.) in toluene (120 mL) was added ethyl 2-oxoacetate (13.5 g, 66.0 mmol, 0.8 equiv.). The mixture was stirred at 25° C. for 1 h and concentrated under reduced pressure to give ethyl (R,E)-2-((1-phenylethyl)imino)acetate (20 g, crude) as a yellow oil.

[0327] To a solution of ethyl (R,E)-2-((1-phenylethyl)imino)acetate (20 g, 97.4 mmol, 1.0 equiv.) in DMF (200 mL) was added freshly cracked cyclopenta-1,3-diene (13.5 g, 205 mmol, 2.1 equiv.) and TFA (14.4 g, 127 mmol, 9.38 mL, 1.3 equiv.). The mixture was stirred at 25 °C for 12 h and then cooled to room temperature with saturated NaHCO 3 The mixture was diluted with aqueous solution (200 mL). The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 100:1 to 3:1) to give ethyl (1R,3R,4S)-2-((R)-1-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (8.5 g, 32% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ):δ7.39-7.23(m,5H),6.49-6.38(m,1H),6.35-6.16(m,1H),4.34-4.28(m,1H),3.92-3.71(m,2H),3.12- 3.00(m,1H),2.96-2.84(m,1H),2.22(s,1H),2.18-2.10(m,1H),1.47-1.39(m,4H),0.97(t,J=6.8Hz,3H).

[0328] To a solution of ethyl (1R,3R,4S)-2-((R)-1-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (1.80 g, 6.63 mmol, 1 equiv.) in EtOH (50 mL), N 2 Pd / C (300 mg, 10% w / w) was added under vacuum. The suspension was evacuated and H 2 The mixture was purged with H several times. 2(15 psi) at 25° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give ethyl (1S,3R,4R)-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.1 g, crude) as a yellow oil, which was used in the next step without any purification.

[0329] To a solution of ethyl (1S,3R,4R)-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.10 g, 6.50 mmol, 1.0 equiv) in DCM (15 mL) was added (Boc) 2 O (2.84 g, 13.0 mmol, 2 equiv.) and TEA (3.29 g, 32.5 mmol, 5 equiv.) were added. The mixture was stirred at 25° C. for 1 h. Subsequently, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 100:1 to 3:1) to give 2-(tert-butyl) 3-ethyl (1S,3R,4R)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (960 mg, 50% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ4.22(s,1H),4.21-4.09(m,2H),3.85-3.64(m,1H),2.71-2.62(m,1H),1.97-1.88 (m,1H),1.79-1.72(m,1H),1.69-1.58(m,2H),1.49-1.38(m,10H),1.28-1.26(m,4H).

[0330] To a solution of 2-(tert-butyl) 3-ethyl (1S,3R,4R)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (2 g, 7.43 mmol, 1 equiv.) in THF (5 mL) was added LiAlH 4 (845 mg, 22.3 mmol, 3 equiv.) was added at -20°C and the mixture was stirred at this temperature for 1 h. The reaction mixture was then diluted with H 2O (0.85 mL), 15% NaOH (2.55 mL), and H 2 The suspension was filtered and the filtrate was concentrated in vacuo to give ((1S,3R,4R)-2-methyl-2-azabicyclo[2.2.1]heptan-3-yl)methanol (1.1 g, crude) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ4.15-4.08(m,1H),3.59-3.46(m,2H),2.37-2.27(m,1H),1.76-1.70(m,2H),1.63-1.57(m,3H),1.48(s,9H),1.29-1.24(m,2H). [ka]

[0331] To a solution of 1-benzyl 2-methyl(S)-pyrrolidine-1,2-dicarboxylate (5.00 g, 19.0 mmol, 1.0 equiv) in THF (10.0 mL) was added a solution of LiHMDS (1 M, 22.8 mL, 1.2 equiv) dropwise at -78 °C. The mixture was stirred at this temperature for 1 h, after which 4-bromobut-1-ene (5.13 g, 38.0 mmol, 3.86 mL, 2.0 equiv) was added. The mixture was stirred at 25 °C for 12 h. The mixture was diluted with saturated NH 4 It was quenched by the addition of aqueous Cl (25.0 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated brine (2×25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude material. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 10:1 to ethyl acetate / methanol, 5:1) to give 1-benzyl 2-methyl 2-(but-3-en-1-yl)pyrrolidine-1,2-dicarboxylate (3.75 g, 62% yield) as a colorless oil.

[0332] To a solution of 1-benzyl 2-methyl 2-(but-3-en-1-yl)pyrrolidine-1,2-dicarboxylate (3.75 g, 11.8 mmol, 1.0 equiv.) in dichloromethane (50.0 mL) was added m-CPBA (6.37 g, 29.5 mmol, 80% purity, 2.5 equiv.). The mixture was stirred at 25° C. for 5 h. The mixture was then washed with saturated NaS 2 O 3 The reaction was quenched by the addition of aqueous solution (35.0 mL). The aqueous layer was extracted with dichloromethane (3×65 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 10:1 to ethyl acetate / methanol, 3:1) to give 1-benzyl 2-methyl 2-(2-(oxiran-2-yl)ethyl)pyrrolidine-1,2-dicarboxylate (3.15 g, 80% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ):δ7.40-7.29(m,5H),5.17-5.04(m,2H),3.70(d,J=4.0Hz,3H),3.52-3.46(m,2 H),2.97-2.66(m,2H),2.50-2.21(m,2H),2.18-1.78(m,5H),1.71-1.40(m,2H).

[0333] To a solution of 1-benzyl 2-methyl 2-(2-(oxiran-2-yl)ethyl)pyrrolidine-1,2-dicarboxylate (3.10 g, 9.30 mmol, 1.0 equiv) in methanol (1.0 mL) was added Pd / C (0.31 g, 9.30 mmol, 10% w / w) under a nitrogen atmosphere. The suspension was evacuated under vacuum and cooled to 50° C. 2 The mixture was purged with H several times. 2 The mixture was stirred under (15 psi) at 25° C. for 4 hours. After completion, the mixture was filtered. The filtrate was concentrated under reduced pressure to give methyl 3-(hydroxymethyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (1.90 g, crude) as a colorless oil.

[0334] To a solution of methyl 3-(hydroxymethyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (1.85 g, 9.28 mmol, 1.0 equiv.) in dichloromethane (20.0 mL) was added TBSCl (2.10 g, 13.9 mmol, 1.71 mL, 1.5 equiv.) and imidazole (1.90 g, 27.9 mmol, 3.0 equiv.). The mixture was stirred at 25° C. for 1 h, poured into ice water (20.0 mL) and stirred for 5 min. The dichloromethane layer was separated and the aqueous phase was extracted with ethyl acetate (3×35 mL). The combined organic phase was washed with saturated brine (2×20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a crude residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate, 100:1 to 8:1) to give methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-carbamate (750 mg, 26% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ):δ3.89(dd,J=4.4,10.4Hz,1H),3.78(dd,J=6.0,10.4Hz,1H),3.74-3.67 (m,3H),3.36-3.25(m,1H),2.95(td,J=4.4,9.2Hz,1H),2.83(q,J=8.4Hz,1 H),2.51-2.40(m,1H),2.25-2.13(m,1H),1.94-1.86(m,1H),1.84-1.78(m, 3H), 1.75-1.67(m, 1H), 1.65-1.56(m, 1H), 0.90(s, 9H), 0.13-0.01(s, 6H).

[0335] LiAlH in THF (20.0 mL) 4To a mixture of (484 mg, 12.8 mmol, 2.0 equiv.) was added 3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (2.00 g, 6.38 mmol, 1.0 equiv.) at -20°C. The mixture was stirred at this temperature for 1 h. Subsequently, the reaction mixture was quenched with water (0.5 mL), 15% NaOH (0.5 mL), and water (1.5 mL) at 0°C. The resulting suspension was filtered and the filter cake was washed with THF (50 mL). The filter cake was dispersed in THF (30 mL) and stirred at 25°C for 5 min, followed by filtration. The combined filtrate was concentrated under reduced pressure to give the crude material. The residue was diluted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give (3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (1.70 g, 93% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ3.85(dd,J=6.0,10.4Hz,1H),3.72(dd,J=6.0,10.4Hz,1H),3.38-3.21(m,2H),3.18-3.05(m,1H),2.85(ddd,J=2.4,6.0 ,8.8Hz,1H),2.72(dt,J=6.4,9.6Hz,1H),1.97(ddd,J=2.8,7.2,12.4Hz,1H),1.83-1.46(m,7H),0.90(s,9H),0.07(s,6H). LCMS[ELSD,M+1]:286. [ka]

[0336] To a solution of 1-(tert-butyl)-2-methyl 2-methylazetidine-1,2-dicarboxylate (300 mg, 1.31 mmol, 1.0 equiv) in THF (4 mL) was added LiAlH 4 (124 mg, 3.27 mmol, 2.50 equiv) was added at -40°C. The mixture was stirred at this temperature for 1 h, then heated to 70°C and stirred for an additional 1 h. The mixture was cooled to room temperature and saturated Na 2 SO4 The mixture was quenched with aqueous hexanes (0.1 mL). The suspension was filtered and the filter cake was washed with dichloromethane (3 × 5 mL). The mixture was adjusted to pH 3 with 4 M HCl in dioxane and concentrated to give (1,2-dimethylazetidin-2-yl)methanol (200 mg, crude HCl salt) as a yellow oil. 1 H NMR (400MHz, CD 3 OD): δ3.88-3.80(m,2H),3.69-3.64(m,1H),3.62-3.56(m,1H),2.72(s,3H),2.71-2.60(m,1H),2.19-2.10(m,1H),1.57(s,3H). [ka]

[0337] To a solution of 1-(tert-butyl)-2-methyl-(2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate (5.00 g, 20.2 mmol, 1.0 equiv) in THF (10.0 mL) was added LiAlH 4 (2.30 g, 60.7 mmol, 3.0 equiv) was added in portions at 0° C. The mixture was stirred at this temperature for 1 h and then at 65° C. for 30 min. The mixture was cooled to room temperature and H 2 O (2.30 mL), 15% NaOH (2.30 mL) and H 2 The mixture was quenched with O (5.00 mL). The suspension was filtered and the filtrate was concentrated under reduced pressure to give ((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (2.30 g, crude) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ5.22-4.93(m,1H) 3.73(dd,J=11.2,3.2Hz,1H) 3.47(br d,J=11.2Hz,1H) 3.33(br dd,J=18.0,11.2Hz,1H) 2.52-2.06(m,8H). [ka]

[0338] To a solution of (2S,3R)-1-(tert-butoxycarbonyl)-3-fluoropyrrolidine-2-carboxylic acid (400 mg, 1.72 mmol, 1.0 equiv) in DMF (4.0 mL) was added K 2 CO 3 (355 mg, 2.57 mmol, 1.5 equiv) and MeI (1.46 g, 10.3 mmol, 641 μL, 6.0 equiv) were added. The mixture was stirred at 25 °C for 1 h and then saturated NH 4 The mixture was diluted with aqueous Cl (10.0 mL) at 0° C. The aqueous layer was extracted with ethyl acetate (15 mL). The organic layer was washed with brine (3×15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 1-(tert-butyl) 2-methyl(2S,3R)-3-fluoropyrrolidine-1,2-dicarboxylate (420 mg, crude) as a yellow oil. f =0.80 (petroleum ether / ethyl acetate, 1:1). 1 H NMR (400 MHz, CDCl 3 ):δ5.28-5.07(m,1H),4.66-4.40(m,1H),3.77(s,3H),3.75-3.65(m,1H),3.62-3.50(m,1H),2.29-2.00(m,2H),1.49-1.42(m,9H).

[0339] LiAlH in THF (4.0 mL) 4 To a mixture of (193 mg, 5.10 mmol, 3.0 equiv.) in THF (4.0 mL) was added 1-(tert-butyl) 2-methyl(2S,3R)-3-fluoropyrrolidine-1,2-dicarboxylate (420 mg, 1.70 mmol, 1.0 equiv.) at -20°C. The mixture was stirred at this temperature for 30 min and then at 66°C for an additional 1 h. The mixture was cooled to 0°C and quenched with water (0.1 mL), 15% aqueous NaOH (0.1 mL), and water (0.3 mL). The suspension was filtered and the filter cake was dispersed in THF (15 mL) and stirred at 25°C for 5 min before filtering. The combined filtrate was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give ((2S,3R)-3-fluoro-1-methylpyrrolidin-2-yl)methanol (200 mg, crude) as a yellow oil.f =0.50 (dichloromethane / methanol, 5:1). 1 H NMR (400 MHz, CDCl 3 ):δ5.15-5.06(m,1H),3.91-3.75(m,2H),3.10-3.06(m,1H),3.03-2.79(m,2H),2.42(s,3H),1.70(td,J=2.8,6.0Hz,2H). [ka]

[0340] To a solution of tert-butyl 3-aminoazetidine-1-carboxylate (5.00 g, 29.0 mmol, 1.0 equiv) in MeOH (100 mL) was added Pd / C (5.00 g, 10% w / w) and formalin (109 g, 1.34 mol, 100 mL, 37% in water, 46.2 equiv). The mixture was diluted with H 2 (15 psi) at 20° C. for 18 h. The mixture was filtered and the filter cake was washed with MeOH (3×50.0 mL). The filtrate was concentrated in vacuo to give the crude material. The crude product was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 10:1 to 0:1) to give tert-butyl 3-(dimethylamino)azetidine-1-carboxylate (6.00 g, 83% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d 6 ): δ 3.83-3.78 (m, 2H), 3.62-3.59 (m, 2H), 3.00-2.87 (m, 1H), 2.04 (s, 6H), 1.37 (s, 9H). To a solution of tert-butyl 3-(dimethylamino)azetidine-1-carboxylate (2.00 g, 9.99 mmol, 1.0 equiv) in DCM (18.0 mL) was added TFA (6.00 mL) at 0 °C. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and lyophilized to give N,N-dimethylazetidin-3-amine (3.50 g, 96% yield, bis-TFA salt) as a yellow solid. 1 H NMR (400MHz, D 2O): δ4.50-4.41(m,5H),2.84(s,6H). [ka]

[0341] To a solution of (R)-azetidin-2-ylmethanol (1.32 g, 10.7 mmol, 1.0 equiv., HCl salt) and acetaldehyde (5 M in THF, 8.55 mL, 4.0 equiv.) in EtOH (20.0 mL), Pd / C (0.500 g, 10 wt / wt%) was added in N 2 The suspension was evacuated and cooled to room temperature. 2 The mixture was purged with H several times. 2 The mixture was stirred at 50° C. for 36 h under reduced pressure. The mixture was then filtered and the filtrate was concentrated in vacuo to give (R)-(1-ethylazetidin-2-yl)methanol (1.00 g, crude, HCl salt) as a brown oil. The same procedure was used for (S)-(1-ethylazetidin-2-yl)methanol. [ka]

[0342] An oven-dried three-neck flask equipped with a reflux condenser was charged with Mg (584 mg, 24.0 mmol, 1.20 equiv.) and 2 (507 mg, 2.00 mmol, 0.1 equiv) was heated with a heat gun until the iodine evaporated and was evenly distributed in the flask. A solution of homoallyl bromide (2.70 g, 20.0 mmol, 2.03 mL, 1 equiv) in THF (20 mL) was added in portions until gentle reflux began. The solution was then added dropwise over 30 min while maintaining a constant reflux. The dark reaction mixture was then cooled to room temperature and used without filtration.

[0343] To a solution of 4-(((benzyloxy)carbonyl)amino)butanoic acid (5.00 g, 21.1 mmol, 1 equiv) in DCM (150 mL) was added TEA (6.40 g, 63.2 mmol, 8.80 mL, 3.0 equiv), followed by T3P (16.1 g, 25.3 mmol, 15.0 mL, 50% in EtOAc, 1.2 equiv), and N-methoxymethanamine (3.08 g, 31.6 mmol, 1.5 equiv, HCl salt) at 0 °C and the mixture was stirred at 25 °C for 16 h. The mixture was extracted with DCM (3 × 100 mL) and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0 to 1:1) to give benzyl (4-(methoxy(methyl)amino)-4-oxobutyl)carbamate (5.50 g, 19.6 mmol, 93% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ7.33-7.23(m,5H),5.04-4.98(m,3H),3.58(s,3H),3.18(q,J=6.4Hz,2H),3.09(s,3H),2.41(br t,J=6.8Hz,2H),1.82-1.73(m,2H). LCMS[ESI,M+1]:281.2.

[0344] To a solution of benzyl (4-(methoxy(methyl)amino)-4-oxobutyl)carbamate (2.00 g, 7.13 mmol, 1.0 equiv) in THF (10 mL) was added N 2 Grignard reagent (0.500 M in THF, 42.8 mL, 3.0 equiv.) was added at 0° C. The mixture was stirred at 25° C. for 1 h, then the pH was adjusted to 3-4 with 1 M aqueous HCl. The mixture was extracted with ethyl acetate (5×50 mL). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution, brine (50 mL) and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate, 10:1 to 5:1) to give benzyl (4-oxooct-7-en-1-yl)carbamate (1.50 g, 5.45 mmol, 38% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ7.36-7.22(m,5H),5.75-5.65(m,1H),5.12-4.69(m,5H),3.10(q,J=6 .4Hz,2H),2.43-2.32(m,4H),2.22(q,J=6.80Hz,2H),1.75-1.62(m,2H). LCMS[ESI,M+1]:276.1.

[0345] To a solution of triphenylsilane (2.38 g, 9.15 mmol, 1.8 equiv) in DCM (10 mL) was added BF 3 Et 2 2.64 g, 18.6 mmol, 2.30 mL, 3.66 equiv) was added at 20° C. The mixture was stirred for 10 min and then cooled to −78° C., followed by the addition of a solution of benzyl (4-oxooct-7-en-1-yl)carbamate (1.40 g, 5.08 mmol, 1 equiv) in DCM (10 mL). The mixture was stirred at this temperature for 30 min and then warmed to 20° C. with continued stirring for 2 h. The mixture was washed with saturated NaHCO 3 The mixture was diluted with aqueous ethyl acetate (3×50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 30:1 to 3:1) to give benzyl 2-(but-3-en-1-yl)piperidine-1-carboxylate (1.10 g, 4.24 mmol, 83% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3):δ7.41-7.22(m,5H),5.85-5.59(m,1H),5.12-4.82(m,4H),3.79(br s,1H),3.46-3.27(m,2H),2.03-1.95(m,1H),1.89-1.71(m,4H),1.62-1.57(m,1H),1.39-1.28(m,1H),1.25-1.15(m,1H).

[0346] Acetone (25 mL) and H 2 Benzyl 2-(but-3-en-1-yl)pyrrolidine-1-carboxylate (1.00 g, 3.86 mmol, 1 equiv.) in O (25 mL), NaHCO 3 (2.59 g, 30.9 mmol, 8.0 equiv.) was added to a mixture of H 2 A solution of oxone (11.9 g, 19.3 mmol, 5.0 equiv) in 25 mL of H2O was added dropwise at 0 °C. The mixture was stirred at 0 °C for an additional 2 h, then added H 2 The mixture was diluted with 2×O (50 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 10:1 to 1:1) to give benzyl 2-(2-(oxiran-2-yl)ethyl)pyrrolidine-1-carboxylate (800 mg, 2.91 mmol, 75% yield) as a yellow oil. [ka]

[0347] To a mixture of (S)-5-(hydroxymethyl)pyrrolidin-2-one (7.26 g, 63.1 mmol, 1.0 equiv) in toluene (150 mL), 2 Benzaldehyde (7.36 g, 69.4 mmol, 7.01 mL, 1.1 equiv.), TsOH H 2O (163 mg, 946 μmol, 0.015 equiv.) was added. The mixture was stirred at 125° C. for 48 h, then diluted with water (100 mL) and extracted with ethyl acetate (300 mL). The combined organic layers were washed with saturated NaHCO 3 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 20:1 to 1:1) to give (7aS)-3-phenyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one (5.70 g, 33% yield) as a brown oil. LCMS [ESI, M+1]: 204.

[0348] To a solution of (7aS)-3-phenyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one (5.00 g, 24.6 mmol, 1.0 equiv) in THF (50.0 mL) was added LiHMDS (1 M, 49.2 mL, 2.0 equiv) at -65 °C. The mixture was stirred at this temperature for 30 min, after which PhSeBr (6.39 g, 27.1 mmol, 1.1 equiv) in THF (15.0 mL) was added dropwise. The mixture was stirred at -65 °C for 1 h and then washed with saturated NH 4 The mixture was diluted with aqueous Cl (100 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was dissolved in DCM (120 mL) at 0° C., and the solution was diluted with H 2 O 2 (16.7 g, 148 mmol, 14.2 mL, 30% in water, 6.0 equiv.) was added. The mixture was stirred at 25° C. for 3 h, then diluted with DCM (50 mL) and diluted with HCl (150 mL, 1 M), saturated NaHCO 3 Aqueous solution (150mL), saturated Na 2 S 2 O 3 The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate, 20:1 to 1:1) to give (7aS)-3-phenyl-1,7a-dihydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one (3.30 g, 63% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ=7.45(d,J=7.2Hz,2H),7.35-7.24(m,3H),7.19(dd,J=1.6,5.6Hz,1H),6.17 -6.04(m,2H),4.61-4.49(m,1H),4.19(t,J=7.6Hz,1H),3.35(t,J=8.0Hz,1H). LCMS[ESI,M+1]:202.

[0349] To a solution of (7aS)-3-phenyl-1,7a-dihydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one (2.80 g, 13.9 mmol, 1.0 equiv) in DMF (50.0 mL), N 2 Below, K 2 CO 3 (1.92 g, 13.9 mmol, 1.0 equiv) and 70% t-butyl hydroperoxide (5.52 g, 61.2 mmol, 5.87 mL, 4.4 equiv) were added in portions. The mixture was stirred at 25° C. for 30 min, then Bu 4 NF 3H 2 O (13.2 g, 41.7 mmol, 3.0 equiv.) was added. The mixture was stirred at room temperature for 1 h, then saturated NH 4 The mixture was diluted with aqueous Cl (50 mL) and extracted with MTBE (2×100 mL). The organic layer was washed with water (3×100 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 20:1 to 1:1) to give (1aR,1bR,6aR)-4-phenyltetrahydro-4H,6H-oxirene[2',3':3,4]pyrrolo[1,2-c]oxazol-6-one (1.20 g, 38% yield, 94.8% purity) as a brown solid. 1 H NMR (400 MHz, CDCl 3):δ=7.42-7.31(m,5H),6.34(s,1H),4.29-4.17(m,2H),4.06(d,J=2.4Hz,1H),3.81(d,J=2.0Hz,1H),3.56(dd,J=7.6,8.4Hz,1H). LCMS[ESI,M+1]:218.

[0350] To a solution of PhSeSePh (2.09 g, 6.70 mmol, 1.5 equiv) in EtOH (20.0 mL) was added NaBH 4 (506 mg, 13.4 mmol, 3.0 equiv) was added at 0° C., and the mixture was stirred for 15 min, followed by the addition of HOAc (1.21 g, 20.1 mmol, 1.15 mL, 4.5 equiv). The resulting solution was added to (1aR,1bR,6aR)-4-phenyltetrahydro-4H,6H-oxirene[2',3':3,4]pyrrolo[1,2-c]oxazol-6-one (1.20 g, 4.46 mmol, 1.0 equiv) in EtOH (12.0 mL) and stirred at 25° C. for 30 min. The reaction mixture was diluted with EtOAc (150 mL) and oxygen gas was bubbled through for 5 min. The residue was concentrated under vacuum, and the resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 3:1 to 0:1) to give (7S,7aR)-7-hydroxy-3-phenyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one (1.06 g, crude) as a brown solid. LCMS [ESI, M+1]: 220.

[0351] To a solution of (7S,7aR)-7-hydroxy-3-phenyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one (1.39 g, 6.34 mmol, 1.0 equiv) in THF (25.0 mL) was added BH 3 -Me 2 S (10M, 6.34 mL, 10 equiv.) was added. The reaction mixture was stirred at 70° C. for 2 h and then cooled to room temperature. The reaction mixture was quenched with HCl (4M, 12 mL) and stirred at 70° C. for 1 h. The mixture was diluted with saturated Na 2 CO 3 The mixture was diluted with aqueous ethyl acetate (3×100 mL) and extracted with ethyl acetate (3×100 mL). 2SO 4 The mixture was dried over hexane, filtered and concentrated in vacuo to give (2R,3S)-1-benzyl-2-(hydroxymethyl)pyrrolidin-3-ol (1.55 g, 70% yield) as a colorless oil. LCMS [ESI, M+1]: 208.

[0352] To a solution of (2R,3S)-1-benzyl-2-(hydroxymethyl)pyrrolidin-3-ol (500 mg, 1.43 mmol, 1.0 equiv) and tert-butoxycarbonyl tert-butyl carbonate (933 mg, 4.28 mmol, 982 uL, 3.0 equiv) in MeOH (50.0 mL) was added Pd / C (500 mg, 334 umol, 10% w / w). The mixture was diluted with H 2 (50 psi) at 40° C. for 16 h. The system was flushed with nitrogen, the mixture was filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 5:1 to dichloromethane / methanol, 10:1) to afford tert-butyl (2R,3S)-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (380 mg, crude) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ4.56(br s,1H),4.20(br s,1H),3.85-3.62(m,2H),3.44-3.03(m,2H),2.12-1.94(m,1H),1.92-1.79(m,1H),1.46(s,9H).

[0353] To a solution of tert-butyl (2R,3S)-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (380 mg, 1.75 mmol, 1.0 equiv) in DCM (10.0 mL) was added TEA (708 mg, 7.00 mmol, 974 μL, 4.0 equiv) and MsCl (501 mg, 4.37 mmol, 338 uL, 2.5 equiv) at 0° C. The mixture was stirred at 0° C. for 4 h and then concentrated under vacuum. The resulting residue was diluted with ethyl acetate (20 mL) and washed with saturated NaHCO 3 The organic layer was washed with anhydrous Na2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 20:1 to 1:1) to afford tert-butyl (2R,3S)-3-((methylsulfonyl)oxy)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (680 mg, crude) as a colorless oil. 1 H NMR (400MHz, CD 3 OD):δ=5.24(br s,1H),4.46-4.27(m,2H),4.19(br s,1H),3.59-3.45(m,2H),3.19-3.09(m,6H),2.44-2.30(m,1H),2.29-2.18(m,1H),1.49(br s,9H). LCMS[ESI,M-99]:274.

[0354] To a solution of tert-butyl (2R,3S)-3-((methylsulfonyl)oxy)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (680 mg, 1.82 mmol, 1.0 equiv) in toluene (10.0 mL) was added benzylamine (611 mg, 5.70 mmol, 621 μL, 3.13 equiv). The mixture was stirred at 110° C. for 16 h and then cooled to room temperature. The mixture was concentrated under vacuum and the residue was diluted with DCM (20 mL). The organic layer was washed with 1N NaOH and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 20:1 to 3:1) to give tert-butyl (1R,5R)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (320 mg, 58% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3):δ7.25-7.14(m,5H),4.27-4.07(m,1H),3.81(t,J=4.8Hz,1H),3.73-3.5 1(m,4H),3.29-3.11(m,1H),3.10-2.95(m,1H),1.60-1.44(m,2H),1.37(br d,J=16.8Hz,9H). LCMS[ESI,M+1]:289.

[0355] To a solution of tert-butyl (1R,5R)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (320 mg, 1.11 mmol, 1.0 equiv) in EtOH (10.0 mL) was added Pd / C (150 mg, 10 wt / wt%). The mixture was stirred at 60° C. under a hydrogen atmosphere (50 psi) for 36 h. The system was flushed with nitrogen and the mixture was filtered. The filtrate was concentrated in vacuo to give a crude residue. The residue was purified by column chromatography (Al 2 O 3 , petroleum ether / ethyl acetate, 5:1 to 1:1 to ethyl acetate / methanol, 100:1 to 10:1) to give tert-butyl (1R,5R)-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (80.0 mg, 36% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ):δ4.63(br t,J=5.2Hz,1H),4.57-4.34(m,1H),3.95-3.59(m,3H),3.32-3.05(m,2H),1.95-1.71(m,2H),1.48-1.43(m,9H). [ka]

[0356] To a solution of tert-butyl (1R,5R)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (500 mg, 1.73 mmol, 1.0 equiv) in MeCN (8.00 mL) was added HCl in dioxane (4 M, 16.0 mL, 36.9 equiv). The mixture was stirred at 25° C. for 30 min and then concentrated in vacuo to give (1R,5R)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane (1.00 g, crude, bis-HCl salt) as a yellow solid. LCMS [ESI, M-99]: 189.

[0357] To a solution of (1R,5R)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane (900 mg, 4.00 mmol, 1.0 equiv, bis-HCl) in DCM (15.0 mL) was added TEA (1.01 g, 10.0 mmol, 1.39 mL, 2.5 equiv) at 0 °C, followed by TFAA (1.01 g, 4.81 mmol, 668 μL, 1.2 equiv). The mixture was warmed to 25 °C and stirred for 1 h, then diluted with saturated NH 4 Aqueous Cl (15 mL) and water (20 mL) were added. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 10:1 to 3:1) to give (1R,5R)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane (180 mg, 36% for two steps) as a yellow oil. LCMS [ESI, M+1]: 285.

[0358] (1R,5R)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane (180 mg, 633 umol, 1.0 equiv) and (Boc) in MeOH (10.0 mL). 2To a solution of 2H2O (414 mg, 1.90 mmol, 436 μL, 3.0 equiv) was added Pd / C (200 mg, 10 wt / wt%). The mixture was stirred under an atmosphere of hydrogen (50 psi) at 40° C. for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo to give 1-((1R,5R)-6-benzyl-2,6-diazabicyclo[3.2.0]heptan-2-yl)-2,2,2-trifluoroethan-1-one (412 mg, crude) as a colorless oil.

[0359] To a solution of 1-((1R,5R)-6-benzyl-2,6-diazabicyclo[3.2.0]heptan-2-yl)-2,2,2-trifluoroethan-1-one (412 mg, 1.40 mmol, 1.0 equiv) in MeOH (20.0 mL) was added Cs 2 CO 3 (456 mg, 1.40 mmol, 1.0 equiv.) and H 2 O (0.5 mL) was added. The reaction mixture was stirred at 40° C. for 30 min and then concentrated under reduced pressure to remove methanol. The residue was diluted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give tert-butyl (1R,5R)-2-(2,2,2-trifluoroacetyl)-2,6-diazabicyclo[3.2.0]heptane-6-carboxylate (210 mg, crude) as a colorless oil. [ka]

[0360] To a solution of 1-(tert-butyl) 2-methyl (2S,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate (3.0 g, 12.2 mmol, 1.0 equiv.) in dichloromethane (30 mL) was added DAST (5.91 g, 36.7 mmol, 4.85 mL, 3.0 equiv.). The mixture was stirred at 0° C. for 1 h and then diluted with water (20 mL) at 0° C. The aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate, 30:1 to 5:1) to give 1-(tert-butyl) 2-methyl (2R,3S)-3-fluoropyrrolidine-1,2-dicarboxylate (1.60 g, 53% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d): δ 5.25-5.06 (m, 1H), 4.64-4.46 (m, 1H), 3.76 (s, 3H), 3.71-3.62 (m, 1H), 3.60-3.49 (m, 1H), 2.28-1.97 (m, 2H), 1.47-1.41 (m, 9H).

[0361] To a solution of 1-(tert-butyl) 2-methyl(2R,3S)-3-fluoropyrrolidine-1,2-dicarboxylate (1.50 g, 6.07 mmol, 1.0 equiv) in THF (20 mL) was added LiAlH 4 (576 mg, 15.2 mmol, 2.50 equiv) was added at -40°C. The mixture was stirred at this temperature for 1 h, then heated to 70°C and stirred for 1 h. The mixture was cooled to room temperature and saturated Na 2 SO 4 Quenched with aqueous solution (1.5 mL), filtered and concentrated to give ((2R,3S)-3-fluoro-1-methylpyrrolidin-2-yl)methanol (800 mg, crude) as a colorless oil. [ka]

[0362] A mixture of (2R,3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (3.00 g, 13.0 mmol, 1.0 equiv) in DMF (75.0 mL) was diluted with K 2 CO 3(5.38 g, 38.9 mmol, 3.0 equiv) was added in one portion. The mixture was stirred at 0° C. for 5 min before methyl iodide (9.21 g, 64.9 mmol, 4.04 mL, 5.0 equiv) was added. The mixture was stirred at 25° C. for 4 h and then concentrated under reduced pressure. The resulting residue was adjusted to pH=4 using hydrochloric acid (0.5 M) and then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and filtered, and the filtrate was concentrated under reduced pressure to give 1-(tert-butyl) 2-methyl(2R,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate (3.8 g, crude) as a brown oil. 1 H NMR (400 MHz, CDCl 3 ):δ4.44(br s,1H),4.32-4.16(m,1H),3.75(s,3H),3.70-3.56(m,2H),2.48(br d,J=7.6Hz,1H),2.17-2.07(m,1H),1.97-1.85(m,1H),1.50-1.39(m,9H).

[0363] To a solution of 1-(tert-butyl) 2-methyl (2R,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate (1.17 g, 4.77 mmol, 1.0 equiv.) in dichloromethane (50.0 mL) was added DAST (769 mg, 4.77 mmol, 630 μL, 1.0 equiv.) at 0° C. The mixture was stirred at 0° C. for 30 min and subsequently concentrated under reduced pressure. The residue was then dissolved in saturated NaHCO 3 The mixture was diluted with aqueous ethyl acetate (3×10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0 to 7:1) to give 41712-C (204 mg, crude), a black-brown oil; 1 H NMR (400 MHz, CDCl 3)δ5.45-5.27(m,1H),4.62-4.45(m,1H),3.78(s,3H),3.76-3.58(m,2H),2.31-1.96(m,2H),1.49-1.42(m,9H).

[0364] To a solution of 41712-C (320 mg, 1.29 mmol, 1.0 equiv) in THF (10.0 mL), N 2 Below, LiAlH 4 (98.2 mg, 2.59 mmol, 2.0 equiv) was added at -40°C and the mixture was stirred at -40°C for 30 min, then warmed to 50°C and the mixture was stirred at 50°C for 30 min. After completion, the mixture was quenched with water (100 uL) at 0°C, then aqueous NaOH (15%, 100 uL) and water (300 uL) were added. The mixture was stirred at 0°C for 5 min, then the mixture was filtered, washed with THF (20 mL) and the filtrate was concentrated to dryness under reduced pressure at 40°C to give 41711-D (170 mg, crude), a black-brown oil. [ka]

[0365] To a solution of (1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.20 g, 5.28 mmol, 1 equiv.) in THF (20.0 mL) was added LiAlH 4 (601 mg, 15.8 mmol, 3 equiv.) was added at -20°C. The mixture was stirred at this temperature for 2 h and then heated at 55°C for 2 h. The mixture was diluted with H 2 The reaction mixture was quenched with 2H2O (0.60 mL), 15% aqueous NaOH (0.6 mL), and water (1.8 mL) at 0 °C. The suspension was filtered and concentrated under reduced pressure to give ((1S,2S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methanol (420 mg, 3.14 mmol, 59% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3):δ3.66-3.56(m,1H),3.55-3.44(m,1H),3.36-3.25(m,1H),2.75-2.60(m,2H),2.54 -2.44(m,1H),2.37(s,3H),1.55-1.34(m,2H),0.82-0.69(m,1H),0.30-0.20(m,1H). [ka]

[0366] Using the method shown in Intermediate B-13, ((1R,2S,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methanol was prepared: yellow oil; 1 H NMR (400 MHz, CDCl 3 )δ3.81-3.74(m,1H),3.70-3.63(m,1H),3.11(d,J=8.8Hz,1H),2.62-2.55(m,1H),2.52(dd,J=4.0,8 .8Hz,1H),2.29(s,3H),1.51-1.42(m,1H),1.37-1.27(m,1H),0.82-0.79(m,1H),0.39-0.34(m,1H). [ka]

[0367] To a solution of ((1S,3R,4R)-2-azabicyclo[2.2.1]heptan-3-yl)methanol (0.4 g, 2.44 mmol, 1 equiv., HCl salt) in MeCN (2 mL), 2 CO 3 (1.01 g, 7.33 mmol, 3 eq.) and 1-fluoro-2-iodoethane (850 mg, 4.89 mmol, 2 eq.) were added. The mixture was stirred at 50° C. for 12 h, then filtered and concentrated in vacuo. The residue was purified by preparative TLC (PE / EA, 0:1) to give ((1S,3R,4R)-2-(2-fluoroethyl)-2-azabicyclo[2.2.1]heptan-3-yl)methanol (0.2 g, 1.15 mmol, 47% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3 ):δ4.66-4.35(m,2H),3.53-3.29(m,3H),3.04-2.50(m,4H),2.17(br d,J=4.0Hz,1H),2.14(t,J=5.6Hz,1H),1.93-1.83(m,1H),1.80-1.74(m,1H),1.64-1.55(m,1H),1.43-1.32(m,1H),1.31-1.26(m,1H). [ka]

[0368] Using the method shown for intermediate B-16, ((1S,3R,4R)-2-(2,2-difluoroethyl)-2-azabicyclo[2.2.1]heptan-3-yl)methanol was prepared: pale yellow oil; 1 H NMR (400 MHz, CDCl 3 )δ6.01-5.59(m,1H),3.52-3.27(m,3H),3.10-2.74(m,2H),2.23-2.18(m,1H),2.15(br t,J=5.20Hz,2H),1.88-1.75(m,2H),1.69-1.57(m,1H),1.46-1.35(m,1H),1.33-1.27(m,1H). [ka]

[0369] To a solution of cis-racemic 1-((benzyloxy)carbonyl)-4-fluoroporozidine-3-carboxylic acid (3.70 g, 13.8 mmol, 1 equiv.) in THF (40 mL) was added BH 3 THF (1M, 41.5 mL, 3 equiv.) was added at 0 °C. The mixture was stirred at 25 °C for 16 h, then quenched with MeOH (20 mL) and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , PE:EA, 2:1 to 1:1) to give cis-racemic benzyl 3-fluoro-4-(hydroxymethyl)pyrrolidine-1-carboxylate (2.6 g, 10.3 mmol, 74% yield) as a colorless oil. 1H NMR (400 MHz, CDCl 3 ):δ7.40-7.28(m,5H),5.31-5.09(m,3H),3.95-3.69(m,4H),3.68-3.50(m,1H),3.27(td,J=2.8,10.8Hz,1H),2.57-2.37(m,1H). LCMS[ESI,M-1]:252.0.

[0370] Cis-racemic benzyl 3-fluoro-4-(hydroxymethyl)pyrrolidine-1-carboxylate (2.6 g, 10.3 mmol) was purified by SFC chromatography [column: DAICEL CHIRALPAK AD (250 mm * 50mm, 10μm)] Mobile phase-A:CO 2 B: 0.1% NH in [MeOH 4 OH], B%: 35%, 4 min to give benzyl (3R,4S)-3-fluoro-4-(hydroxymethyl)pyrrolidine-1-carboxylate (1.00 g, 3.95 mmol, 77% yield, 99.8% ee) as a pale yellow oil and benzyl (3S,4R)-3-fluoro-4-(hydroxymethyl)pyrrolidine-1-carboxylate (1.00 g, 3.95 mmol, 77% yield, 99.1% ee) as a pale yellow oil. The absolute stereochemical configurations of these two compounds are given arbitrarily.

[0371] To a solution of (3R,4S)-3-fluoro-4-(hydroxymethyl)pyrrolidine-1-carboxylate (1 g, 3.95 mmol, 1 equiv.) in MeOH (6 mL) was added Pd / C (70 mg, 10% w / w) and formalin (2.56 g, 31.59 mmol, 2.35 mL, 37% in water, 8 equiv.). The mixture was diluted with H 2 (15 psi) at 25° C. for 16 h. The system was purged with nitrogen, and the mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (Al 2 O 3, EA:PE, 1:1 to EA:EtOH, 6:1) to give ((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)methanol (110 mg, 826 umol, 21% yield). Yellow oil; 1 H NMR (400 MHz, CDCl 3 )δ5.36-5.04(m,1H),3.94-3.57(m,2H),2.92-2.82(m,1H),2.67-2.49(m,3H),2.47-2.26(m,4H).

[0372] Using the same reductive amination procedure, ((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)methanol was obtained: yellow oil; 1 H NMR (400 MHz, CDCl 3 ):δ5.36-5.04(m,1H),3.94-3.57(m,2H),3.11-2.71(m,2H),2.67-2.49(m,2H),2.47-2.20(m,4H). [ka]

[0373] To a mixture of (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine (3 g, 8.84 mmol, 1.0 equiv) and cyclopropylboronic acid (3.17 g, 36.9 mmol, 4.18 equiv) in DCE (40 mL) was added Na 2 CO 3 (1.95g, 18.4mmol, 2.08eq), Cu(OAc) 2 (1.67 g, 9.19 mmol, 1.04 equiv.), and 2-(2-pyridyl)pyridine (1.44 g, 9.22 mmol, 1.04 equiv.). The mixture was diluted with O 2 The mixture was stirred at 70° C. under (15 psi) for 2 h, then filtered. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (80 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate, 10:1 to 4:1) to give (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-cyclopropylpyrrolidine (1.5 g, 44% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ):δ7.75-7.70(m,4H),7.47-7.38(m,6H),3.95(dd,J=4.0,9.6Hz,1H),3.47(dd,J=8.8,10.0Hz,1H),3.10-3.02(m ,1H),2.88-2.80(m,1H),2.57-2.49(m,1H),2.12-2.03(m,1H),1.84-1.64(m,4H),1.11(s,9H),0.39-0.25(m,4H).

[0374] To a solution of (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-cyclopropylpyrrolidine (1.5 g, 3.95 mmol, 1.0 equiv.) in DMF (15 mL) was added CsF (1.75 g, 11.5 mmol, 2.9 equiv.). The mixture was stirred at 50° C. for 20 h. The reaction mixture was cooled to room temperature and purified by H 2 The mixture was diluted with 20 mL of 2H2O and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (80 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 10:1 to 1:1) to give (S)-(1-cyclopropylpyrrolidin-2-yl)methanol (380 mg, 68% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ3.74(dd,J=3.6,10.4Hz,1H),3.42(dd,J=2.4,10.8Hz,1H),3.13-3.04(m,1H),2.82-2.75(m,1H),2.60- 2.52(m,1H),2.48-2.30(m,1H),1.98-1.88(m,1H),1.80-1.60(m,4H),0.53-0.39(m,3H),0.38-0.30(m,1H). [ka]

[0375] To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-fluoropyrrolidine-1,2-dicarboxylate (5.0 g, 20.2 mmol, 1.0 equiv) and HMPA (4.71 g, 26.3 mmol, 4.62 mL, 1.30 equiv) in THF (20 mL) was added LiHMDS (1.0 M, 26.3 mL, 1.3 equiv) at -70 °C. The mixture was stirred at this temperature for 1 h before 1-bromo-3-chloro-propane (15.9 g, 101 mmol, 9.95 mL, 5.0 equiv) was added. The mixture was allowed to warm to room temperature over 1 h and was diluted with saturated NH 4 Quench with aqueous Cl (50 mL) and then H 2 The mixture was diluted with 2×O (30 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 20:1 to 5:1) to give 1-(tert-butyl) 2-methyl (4R)-2-(3-chloropropyl)-4-fluoropyrrolidine-1,2-dicarboxylate (2.7 g, 37% yield) as a yellow oil. LCMS [ESI, M-99]: 224.

[0376] CH 3 To a solution of 1-(tert-butyl) 2-methyl (4R)-2-(3-chloropropyl)-4-fluoropyrrolidine-1,2-dicarboxylate (2.70 g, 8.34 mmol, 1.0 equiv) in CN (6 mL) was added HCl in dioxane (4 M, 20 mL). The mixture was stirred at 20° C. for 2 h and then concentrated under reduced pressure to give methyl (4R)-2-(3-chloropropyl)-4-fluoropyrrolidine-2-carboxylate (2.2 g, crude, HCl salt) as a yellow oil.

[0377] CH 3To a solution of methyl (4R)-2-(3-chloropropyl)-4-fluoropyrrolidine-2-carboxylate (2.0 g, 7.69 mmol, 1.0 equiv., HCl salt) in CN (20 mL) was added NaHCO 3 (3.23 g, 38.4 mmol, 5.0 equiv) and KI (128 mg, 769 μmol, 0.10 equiv) were added. The mixture was stirred at 50° C. for 12 h, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 10 / 1 to 1 / 1) to give methyl (2R)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (1.10 g, 76% for two steps) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ5.37-5.08(m,1H),3.74(s,3H),3.60-3.45(m,1H),3.29-3.17(m,1H),2 .95-2.74(m,2H),2.73-2.63(m,1H),2.20-2.09(m,1H),2.03-1.72(m,5H). LCMS[ESI,M+1]:188.

[0378] To a solution of methyl (2R)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (1.10 g, 5.88 mmol, 1.0 equiv) in THF (15 mL) was added LiAlH 4 (669 mg, 17.6 mmol, 3.0 equiv.) was added at -40°C. The mixture was stirred at this temperature for 1 h, then saturated Na 2 SO 4 (1.7 mL) at 0° C. The mixture was diluted with THF (15 mL), filtered, and concentrated under reduced pressure to give ((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (950 mg, 90% purity, 91% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3):δ5.36-5.08(m,1H),3.51-3.29(m,3H),3.25-3.10(m,1H),3.04-2.93(m,1H),2.90-2 .73(m,1H),2.71-2.59(m,1H),2.28-2.12(m,1H),1.95-1.73(m,4H),1.65-1.53(m,1H).

[0379] To a mixture of ((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (600 mg, 3.77 mmol, 1.0 equiv) and TBDPSCl (2.07 g, 7.54 mmol, 1.94 mL, 2 equiv) in DMF (10 mL) was added imidazole (1.03 g, 15.1 mmol, 4.0 equiv). The mixture was stirred at 20° C. for 2 h. The mixture was poured into water (20 mL) and the aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine (2×20 mL) and anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 * 40mm * 15 μm; mobile phase: A: [water (0.1% TFA)]; B% (ACN): 30%-60%, 10 min), and then purified using SFC column: DAICEL CHIRALPAK IC (250 mm * Mobile phase: B: [0.1% NH in MeOH 4 OH]; B%: 30% to 30%, 2.4 min; 60 min to give (2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine (660 mg, 1.58 mmol, 42% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d 6):δ7.64-7.59(m,4H),7.49-7.37(m,6H),5.40-5.20(m,1H),3.46(d,J=9.2Hz,1H),3.31-3.27( m,1H),3.23-3.15(m,1H),2.85-2.82(m,1H),2.81-2.65(m,1H),2.54-2.51(m,1H),2.28-2.23(m 1H), 1.97-1.92(m, 1H), 1.87-1.52(m, 4H), 1.00(s, 9H).

[0380] To a solution of (2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine (580 mg, 1.46 mmol, 1.0 equiv.) in DMF (3 mL) was added CsF (665 mg, 4.38 mmol, 161 μL, 3.0 equiv.). The mixture was stirred at 50° C. for 20 h, then cooled to room temperature and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 2:1 to ethyl acetate / methanol, 5:1) to give ((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (210 mg, 90% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ):δ5.32-5.14(m,1H),3.55-3.49(m,1H),3.45-3.31(m,2H),3.06-2.84(m,2H ),2.81-2.63(m,2H),2.27-2.16(m,1H),1.98-1.76(m,4H),1.67-1.57(m,1H). [ka]

[0381] To a solution of (S)-pyrrolidin-2-ylmethanol (5 g, 49.4 mmol, 4.81 mL, 1 equiv) in MeCN (50 mL), 2 CO 3(7.52 g, 54.38 mmol, 1.1 equiv.) was added. The mixture was cooled to 0° C. and 1-fluoro-2-iodo-ethane (8.94 g, 51.41 mmol, 1.04 equiv.) was added dropwise and the resulting mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , DCM:MeOH, 20:1) to give (S)-(1-(2-fluoroethyl)pyrrolidin-2-yl)methanol (4 g, 27.2 mmol, 55% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ4.65-4.53(m,1H),4.52-4.41(m,1H),3.61(dd,J=3.6,10.8Hz,1H),3.41(dd,J=2.8,10.8Hz,1 H),3.33-3.18(m,1H),3.14-2.97(m,1H),2.76-2.58(m,2H),2.44-2.32(m,1H),1.95-1.69(m,4H). [ka]

[0382] The procedure used to prepare intermediate B-22 was used to prepare (S)-(1-(2,2-difluoroethyl)pyrrolidin-2-yl)methanol. Yellow oil; 1 H NMR (400 MHz, CDCl 3 ):δ6.17-5.83(m,1H),3.38-3.31(m,1H),3.29-3.12(m,2H),3.08-3.00(m,1H),2. 77-2.52(m,2H),2.32(td,J=7.2,9.2Hz,1H),1.83-1.56(m,3H),1.49-1.37(m,1H). [ka]

[0383] CH 3To a solution of methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (1.00 g, 3.19 mmol, 1.0 equiv) in CN (10.0 mL) was added HCl in dioxane (4.0 M, 10.0 mL, 12.5 equiv). The mixture was stirred at 0° C. for 0.5 h. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with methanol (30.0 mL) and washed with solid Na 2 CO 3 The pH was adjusted to 8 using hexanes. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with dichloromethane (30.0 mL) and filtered. The filtrate was concentrated under reduced pressure to give methyl 3-(hydroxymethyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (700 mg, crude) as a yellow oil. R f =0.20[Petroleum ether / ethyl acetate / ethanol (2%NH 4 OH), 4:3:1]. 1 H NMR (400 MHz, CDCl 3 ):δ3.90-3.84(m,1H),3.75(dd,J=5.2,11.2Hz,1H),3.71(s,3H),3.37(tdd,J=5.2,8.0,10.8Hz,1H),3.11-2.95(m,1 H),2.79-2.60(m,2H),2.54-2.45(m,1H),2.20(ddd,J=8.0,10.4,13.2Hz,1H),1.88-1.73(m,4H),1.67-1.49(m,2H).

[0384] To a solution of methyl 3-(hydroxymethyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (700 mg, 3.51 mmol, 1.0 equiv) in dichloromethane (7.0 mL) was added DAST (1.70 g, 10.5 mmol, 1.39 mL, 3.0 equiv) at 0° C. The mixture was stirred at 0° C. for 0.5 h. The reaction mixture was then diluted with saturated Na 2 CO 3The mixture was diluted with aqueous solution (5.0 mL) and water (5.0 mL). The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give methyl 3-(fluoromethyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (700 mg, 99% yield) as a yellow oil. R f =0.50 (petroleum ether / ethyl acetate, 1:1). 1 H NMR (400 MHz, CDCl 3 ): δ4.82-4.61(m,1H),3.71(s,3H),3.28-3.05(m,4H),2.18-2.00(m,4H),1.92-1.75(m,4H).

[0385] LiAlH in THF (10.0 mL) 4 (264 mg, 6.96 mmol, 2.0 equiv.) was added with methyl 3-(fluoromethyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (700 mg, 3.48 mmol, 1.0 equiv.) at -20°C, and the mixture was stirred at this temperature for 1 h. The reaction mixture was then quenched with water (0.3 mL), 15% NaOH (0.3 mL), and water (0.9 mL). The suspension was filtered and the THF was collected. The filter cake was dispersed in THF (30.0 mL), stirred at 25°C for 5 min, and filtered. The combined filtrate was concentrated under reduced pressure to give a residue. The residue was diluted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give (3-(fluoromethyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (400 mg, 66% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ4.76-4.66(m,1H),4.63-4.54(m,1H),3.80-3.69(m,1H),3.40-3.26(m,2H),3.22-3.17(m,1H),3.15-3.09(m,1H),2.07-1.85(m,8H). [ka]

[0386] To a solution of (3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (1.30 g, 4.55 mmol, 1.0 equiv) in dichloromethane (10.0 mL) was added TEA (921 mg, 9.11 mmol, 1.27 mL, 2.0 equiv) and benzoyl chloride (960 mg, 6.83 mmol, 793 μL, 1.5 equiv) at 0° C. The mixture was stirred at 25° C. for 0.5 h. Subsequently, the reaction mixture was diluted with water (40.0 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The crude product was purified by reverse-phase flash chromatography to give methyl (3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)benzoate (1.10 g, 62% yield) as a yellow oil. f =0.50 (petroleum ether / ethyl acetate, 3:1). 1 H NMR (400 MHz, CDCl 3 ):δ8.10-8.04(m,2H),7.54-7.52(m,1H),7.46-7.40(m,2H),4.42-4.26(m,2H),3.94(d,J=4.8Hz,2H),3.57-3.42(m,1H),3.22(br s,1H),3.09-2.93(m,1H),2.15(ddd,J=2.4,6.8,12.4Hz,1H),2.02-1.79(m,6H),1 .66(ddd,J=7.2,11.2,12.4Hz,1H),0.90(s,9H),0.08(s,6H);LCMS[ESI,M+1]:390.

[0387] CH 3 To a solution of methyl (3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)benzoate (1.10 g, 2.82 mmol, 1.0 equiv) in CN (10.0 mL) was added HCl in dioxane (4 M, 10.0 mL, 14.2 equiv) at 0° C. The mixture was stirred at 0° C. for 0.5 h. The reaction mixture was then diluted with water (20 mL) and solid NaHCO3 The pH was adjusted to 8 using hexanes. The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give methyl (3-(hydroxymethyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)benzoate (800 mg, 95% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ8.10-8.01(m,2H),7.61-7.53(m,1H),7.49-7.41(m,2H),3.92-3.75(m,2H),3.46-3.33(m,1H ),3.13-3.04(m,1H),2.83-2.55(m,3H),2.19-2.11(m,1H),1.93-1.72(m,5H),1.70-1.53(m,2H). LCMS[ESI,M+1]:276. [ka]

[0388] A mixture of 1-((tert-butyldimethylsilyl)oxy)propan-2-one (25.0 g, 133 mmol, 1.0 equiv), phenylmethanamine (14.2 g, 133 mmol, 14.5 mL, 1.0 equiv), and 4Å MS (25.0 g) in dichloromethane (100 mL) was stirred at 45° C. for 12 h. To this suspension was added a mixture of 2-methoxyacetyl chloride (18.3 g, 168 mmol, 15.4 mL, 1.3 equiv) and TEA (30.6 g, 302 mmol, 42.1 mL, 2.3 equiv) in dichloromethane (20.0 mL) dropwise at −78° C. The mixture was allowed to warm to room temperature, stirred for 12 h, and then filtered. The filtrate was diluted with saturated NH 4 The mixture was diluted with aqueous Cl (100 mL) and concentrated under reduced pressure to remove volatiles. The remaining aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL x 1) and anhydrous Na 2 SO 4The mixture was dried over 100 ml of ethyl acetate and filtered. The filtrate was concentrated under reduced pressure to give a crude residue. The crude product was purified by reverse-phase flash chromatography to give 1-benzyl-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-methoxy-4-methylazetidin-2-one (7.00 g, 13.4% yield) as a brown oil. 1 H NMR (400 MHz, CDCl 3 ):δ7.35-7.28(m,5H),4.46-4.33(m,2H),4.11(s,1H),3.68-3.59(m,2H),3.51( s,3H),1.25-1.22(m,1H),1.24(s,2H),0.89-0.87(m,9H),0.00(d,J=8.0Hz,6H).

[0389] AlCl in THF (20.0 mL) 3 (916 mg, 6.87 mmol, 1.2 equiv.) was added to a mixture of LiAlH 4 (434 mg, 11.4 mmol, 2.0 equiv) was added at −10° C., and the mixture was warmed to 25° C. and stirred for 3 h. To this mixture was added dropwise a solution of 1-benzyl-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-methoxy-4-methylazetidin-2-one (2.00 g, 5.72 mmol, 1.0 equiv) in THF (10 mL) at −10° C., and the mixture was stirred at 25° C. for 30 min. The mixture was subsequently diluted with water (434 μL), 15% aqueous NaOH (434 μL), and water (1.30 mL) at 0° C. The suspension was filtered, washed with THF (20.0 mL), and the filtrate was concentrated under reduced pressure to give a crude residue. The crude product was purified by reverse-phase flash chromatography to give 1-benzyl-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methoxy-2-methylazetidine (700 mg, 35.7% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3):δ7.34-7.27(m,4H),7.25-7.20(m,1H),3.84-3.69(m,4H),3.62(br d,J=12.8Hz,1H),3.41-3.31(m,1H),3.30(s,3H),3.06(br s, 1H), 1.30 (s, 3H), 0.91 (s, 9H), 0.07 (d, J=2.8Hz, 6H).

[0390] To a solution of 1-benzyl-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methoxy-2-methylazetidine (700 mg, 2.09 mmol, 1.0 equiv) in MeOH (20.0 mL), N 2 Formalin (2.18 g, 2.00 mL, 37% in water) and Pd / C (300 mg, 10% w / w) were added under vacuum. The suspension was evacuated under H 2 The mixture was purged with H several times. 2 The mixture was stirred at 25° C. for 12 h under (15 psi). The mixture was then adjusted to pH 4 with HCl in dioxane (4M) and back-charged with hydrogen (45 psi). The mixture was left stirring at 25° C. for 16 h. The mixture was flushed with nitrogen, filtered and the filtrate was concentrated. The residue was purified by column chromatography [SiO 2 , petroleum ether / ethyl acetate, 1:0 to 0:1 to ethyl acetate / ethyl alcohol (1% NH 4 OH), 3:1] to afford (3-methoxy-1,2-dimethylazetidin-2-yl)methanol (454 mg, crude) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ4.18(d,J=12.8Hz,1H),3.91(dd,J=4.4,6.8Hz,1H),3.62-3.57(m,2H),3.56(d,J=6.8Hz,1H),3.32(s,3H),2.53(s,3H),1.41(s,3H). [ka]

[0391] To a mixture of tert-butyl 2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (412 mg, 2.08 mmol, 1.0 equiv) and benzaldehyde (661 mg, 6.23 mmol, 630 μL, 3.0 equiv) in MeOH (10.0 mL) was added AcOH (249 mg, 4.16 mmol, 238 μL, 2.0 equiv). The mixture was stirred at 25 °C for 10 min and then cooled to 0 °C. To this solution was added NaBH 3 CN (392 mg, 6.23 mmol, 3.0 equiv) was added and the mixture was stirred at 0° C. for 1 h and then concentrated under reduced pressure. The residue was taken up in ethyl acetate (20 mL) and saturated NaHCO 3 The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC [Phenomenex luna C18 150×40 mm×15 μm; A: water (0.225% FA), B: ACN, B%: 2-32%, 11 min]. The enantiomers were separated by chiral SFC [daicel chiralpak AD-H (250 mm×30 mm×5 μm); A: 0.1% NH in MeOH, 100% CO, 100% CI, 100% CI, 100% CI]. 4 OH, B:CO 2 , B%: 20%]] to give tert-butyl (1S,5S)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (239 mg, 25% yield) as a white solid. Analytical SFC conditions: [Chiralpak AD-3 50 × 4.6 mm ID, 3 μm, A:CO 2 , B: MeOH (0.05% DEA), B: 5% to 40%, 3 mL / min, column temperature: 35°C, back pressure: 100 bar, t R = 0.724 min, isomer = 0.607 min]. LCMS[ESI,M+1]:289.

[0392] To a solution of tert-butyl (1S,5S)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (239 mg, 829 μmol, 1.0 equiv.) in MeCN (5.00 mL) was added HCl (4 M in dioxane, 10.0 mL, 48.3 equiv.). The mixture was stirred at 25° C. for 0.5 h and then concentrated under reduced pressure to give (1S,5S)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane (186 mg, bis-HCl salt).

[0393] To a solution of (1S,5S)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane (186 mg, 828 μmol, 1.0 equiv, bis-HCl) in DCM (5.00 mL) was added TEA (335 mg, 3.31 mmol, 461 μL, 4.0 equiv) and TFAA (209 mg, 993 μmol, 138 μL, 1.2 equiv) at 0 °C. The reaction was stirred at this temperature for 1 h and then diluted with water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 20:1 to 3:1) to give 1-((1S,5S)-6-benzyl-2,6-diazabicyclo[3.2.0]heptan-2-yl)-2,2,2-trifluoroethan-1-one (80.0 mg, 34% for two steps) as a yellow oil. LCMS [ESI, M+1]: 285.

[0394] 1-((1S,5S)-6-benzyl-2,6-diazabicyclo[3.2.0]heptan-2-yl)-2,2,2-trifluoroethan-1-one (80.0 mg, 281 μmol, 1.0 equiv.) and Boc in MeOH (10.0 mL). 2 To a solution of 2,4-dichlorophenyl ether (184 mg, 844 μmol, 194 μL, 3.0 equiv.) under nitrogen was added Pd / C (40.0 mg, 10 wt %). The mixture was diluted with H 2 (50 psi) at 50° C. for 16 h. The system was flushed with nitrogen and the suspension was filtered through a plug of Celite and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2 , petroleum ether / ethyl acetate, 20:1 to 3:1) to give tert-butyl (1S,5S)-2-(2,2,2-trifluoroacetyl)-2,6-diazabicyclo[3.2.0]heptane-6-carboxylate (60.0 mg, 71% yield) as a yellow oil. LCMS [ESI, M-55]: 239.

[0395] To a solution of tert-butyl (1S,5S)-2-(2,2,2-trifluoroacetyl)-2,6-diazabicyclo[3.2.0]heptane-6-carboxylate (60.0 mg, 204 μmol, 1.0 equiv.) in MeOH (5.00 mL) was added Cs 2 CO 3 (66.4 mg, 204 μmol, 1.0 equiv.) and H 2 O (0.200 mL) was added at room temperature. The reaction mixture was stirred at 40° C. for 30 min and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (1S,5S)-2,6-diazabicyclo[3.2.0]heptane-6-carboxylate (41.0 mg, crude) as a colorless oil. [ka]

[0396] To a solution of tert-butyl 1,6-diazaspiro[3.3]heptane-6-carboxylate (500 mg, 2.06 mmol, 1.0 equiv, 0.5 oxalic acid) in DCM (10 mL) was added TEA (520 mg, 5.14 mmol, 715 μL, 2.5 equiv) at 0 °C, followed by TFAA (518 mg, 2.47 mmol, 343 μL, 1.2 equiv). The reaction was warmed to 20 °C and stirred for 1 h. Additional portions of TEA (312 mg, 3.08 mmol, 429 μL, 1.5 equiv) and TFAA (647 mg, 3.08 mmol, 429 μL, 1.5 equiv) were added and the reaction was stirred at 25 °C for an additional 1 h. The mixture was diluted with water (10 mL) and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4The mixture was dried over 1000 ml, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate, 5:1 to 1:1) to give tert-butyl 1-(2,2,2-trifluoroacetyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate (390 mg, 64%) as a yellow solid. f = 0.98 (10:1, dichloromethane / methanol); 1 H NMR (400 MHz, CDCl 3 ): δ4.69-4.67(d,J=10.0Hz,2H),4.31-4.24(m,2H),3.98-3.95(d,J=9.6Hz,2H),2.63-2.59(t,J=7.6Hz,2H),1.44(s,9H).

[0397] tert-Butyl 1-(2,2,2-trifluoroacetyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate (390 mg, 1.33 mmol, 1.0 equiv) in ACN (3.0 mL) was added with HCl (4 M in dioxane, 4.97 mL, 15 equiv) at 0° C. The mixture was stirred at this temperature for 1 h and concentrated under reduced pressure to give 2,2,2-trifluoro-1-(1,6-diazaspiro[3.3]heptane-1-yl)ethan-1-one (400 mg, crude, HCl salt) as a yellow solid. [ka]

[0398] To a solution of 1-((1R,5R)-6-benzyl-2,6-diazabicyclo[3.2.0]heptan-2-yl)-2,2,2-trifluoroethan-1-one (1.50 g, 5.28 mmol, 1.0 equiv) in MeOH (100 mL) was added Pd / C (1.00 g, 10 wt%). The mixture was stirred under hydrogen (50 psi) at 40° C. for 16 h. The system was purged with nitrogen and the mixture was filtered through a plug of Celite. The filtrate was concentrated under reduced pressure to give 1-((1R,5R)-2,6-diazabicyclo[3.2.0]heptan-2-yl)-2,2,2-trifluoroethan-1-one (1.00 g, crude) as a colorless oil. [ka]

[0399] To a mixture of compound 1-(tert-butyl) 2-methyl (2S,3S) 3-hydroxypyrrolidine-1,2-dicarboxylate (100 g, 407.7 mmol, 1.00 equiv.) in DMF (1.3 L), DMAP (4.98 g, 40.7 mmol, 0.100 equiv.), TBDPSCl (126 mL, 489.3 mmol, 1.2 equiv.), and imidazole (138.8 g, 2.04 mol, 5.0 equiv.) were added at 0 °C. The mixture was stirred at 20 °C for 2 h, then poured into water (2500 mL) and extracted with EtOAc (1000 mL × 3). The combined organic layer was washed with brine (1500 mL × 3) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 50:1 to 10:1) to give 1-(tert-butyl) 2-methyl(2S,3S)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (90 g, 186.1 mmol, 45.6% yield) as a yellow oil. LCMS [ESI, M+1]: 384.2; 1 H NMR (400 MHz, CDCl 3 ):δ7.66-7.64(m,4H),7.41-7.39(m,6H),4.39-4.38(m,1H),4.33-4.18(m, 1H), 3.64-3.58(m, 5H), 1.84-1.80(m, 2H), 1.65-1.41(m, 9H), 1.03(s, 9H).

[0400] A mixture of compound 1-(tert-butyl) 2-methyl(2S,3S)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (90.0 g, 186.1 mmol, 1.00 equiv.) in EtOH (200 mL) was added to a solution of NaOH (14.9 g, 372.2 mmol, 2.00 equiv.) in water (20 mL). The mixture was stirred at room temperature for 1 h, then poured into water (500 mL) and adjusted to pH 6 with 0.1 M HCl. The mixture was partially concentrated to remove EtOH, then extracted with EtOAc (150 mL x 3). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was evaporated, dried at 40° C., filtered and concentrated to dryness to give (2S,3S)-1-(tert-butoxycarbonyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-2-carboxylic acid (88 g) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ):δ7.73-7.43(m,4H),7.40-7.37(m,6H),4.75-4.47(m,1H),4.25-4.12(m, 1H), 3.68-3.43(m, 2H), 1.84-1.82(m, 2H), 1.52-1.40(m, 8H), 1.23(s, 9H).

[0401] To a mixture of (2S,3S)-1-(tert-butoxycarbonyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-2-carboxylic acid (82.0 g, 174.6 mmol, 1.00 equiv.) and N-methoxymethanamine (16.5 g, 168.6 mmol, 1.20 equiv., HCl salt) in ACN (600 mL) was added Et 3 N (59 mL, 421.6 mmol, 3.00 equiv.) and T 3 P (125 mL, 211 mmol, 50.0% in EtOAc, 1.50 equiv.) was added. The reaction mixture was stirred at 20° C. for 10 h, then concentrated, poured into water (3 L) and extracted with EtOAc (1000 mL×3). The combined organic layers were washed with water (2000 mL×3) and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate, 10:1 to 1:1) to give tert-butyl (2S,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (63.0 g, 122.9 mmol, 87.4% yield) as a yellow oil. LCMS [ESI, M-100]: 413.2; 1 H NMR (400 MHz, CDCl 3 ):δ7.69-7.66(m,4H),7.44-7.39(m,6H),4.85-4.82(m,1H),4.36-4.33(m,1H),3.72-3 .69(m,2H),3.63-3.53(m,3H),3.38-3.06(m,3H),1.89-1.83(m,2H),1.74-1.50(d,9H) 1.03(s,9H).

[0402] To a solution of compound tert-butyl (2S,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (60 g, 117.0 mmol) in THF (200 mL) was added MeMgBr (3.00 M, 78.02 mL, 2.00 equiv.) at −70° C. under nitrogen atmosphere. The mixture was allowed to warm to room temperature and stirred for 10 h. The reaction mixture was diluted with NH 4 The mixture was diluted with Cl (1.50 L) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate, 20:1 to 3:1) to give tert-butyl (2S,3S)-2-acetyl-3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carboxylate (54 g, 115.5 mmol, 98.7% yield) as a yellow oil.

[0403] To a mixture of tert-butyl (2S,3S)-2-acetyl-3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carboxylate (46 g, 98.36 mmol, 1.00 equiv) in MeOH (500 mL) was added NH 4 OAc (303 g, 3.93 mol, 40 equiv.) and NaBH 3 CN (7.42 g, 118.0 mmol, 1.2 equiv) was added. The mixture was stirred at 85° C. for 1 h and then concentrated. To the residue, water (1.00 L) was added and the mixture was extracted with EtOAc (500 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness to give tert-butyl (2R,3S)-2-(1-aminoethyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carboxylate (51 g) as a pale yellow oil. LCMS [ESI, M+1]: 469.2.

[0404] tert-Butyl (2R,3S)-2-(1-aminoethyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carboxylate (57 g, 121.61 mmol, 1.00 equiv) in DCM (500 mL) and Et 3 To a mixture of N (51 mL, 364.8 mmol, 3.00 equiv.) was added CbzCl (18 mL, 123 mmol, 1.0 equiv.). The mixture was stirred at 20° C. for 1 h, then diluted with water (1000 mL) and extracted with EtOAc (500 mL×3). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate, 10:1 to 3:1) to give tert-butyl (2R,3S)-2-(1-(((benzyloxy)carbonyl)amino)ethyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carboxylate (25 g, 41.47 mmol, 34% yield) as a yellow oil. LCMS [ESI, M+1]: 603.4.

[0405] To a mixture of tert-butyl (2R,3S)-2-(1-(((benzyloxy)carbonyl)amino)ethyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carboxylate (25.00 g, 41.5 mmol, 1.00 equiv.) in DMF (200 mL) was added TBAF (1.00 M in THF, 50 mL, 1.2 equiv.). The mixture was stirred at 20° C. for 2 h, then diluted with water (500 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (300 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate, 10:1 to 2:1) to give tert-butyl (2R,3S)-2-(1-(((benzyloxy)carbonyl)amino)ethyl)-3-hydroxypyrrolidine-1-carboxylate (7.00 g, 19.2 mmol, 46.3% yield) as a yellow oil. LCMS [ESI, M+1]: 364.2.

[0406] To a mixture of tert-butyl (2R,3S)-2-(1-(((benzyloxy)carbonyl)amino)ethyl)-3-hydroxypyrrolidine-1-carboxylate (7.00 g, 19.2 mmol, 1.00 equiv) and TEA (5.4 mL, 38 mmol, 2.0 equiv) in DCM (100 mL) was added MsCl (3.0 mL, 38 mmol, 2.0 equiv). The mixture was stirred at room temperature for 60 h and then diluted with water (150 mL). The mixture was extracted with DCM (50 mL x 3). The combined organic layers were washed with water (50 mL x 3), dried over sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate, 10:1 to 1:1) followed by reverse phase chromatography [Phenomenex luna C18 250×50 mm×10 μm; A: water (0.225% FA), B: ACN; B%: 30% to 60%, 15 min] to give tert-butyl (2R,3S)-2-(1-(((benzyloxy)carbonyl)amino)ethyl)-3-((methylsulfonyl)oxy)pyrrolidine-carboxylate (8.2 g) as a yellow oil. LCMS [ESI, M+1]: 343.0.

[0407] To a mixture of NaH (1.30 g, 32.5 mmol, 60.0% purity, 2.0 equiv.) in DMF (70.0 mL) was added dropwise a solution of tert-butyl (2R,3S)-2-(1-(((benzyloxy)carbonyl)amino)ethyl)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (7.20 g, 16.3 mmol, 1.00 equiv.) in DMF (20 mL) at room temperature. The mixture was stirred at room temperature for 1 h, followed by addition of saturated NaHCO 3 The mixture was diluted with aqueous solution (200 mL) and extracted with EtOAc (200 mL×3). The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by preparative HPLC [Phenomenex luna C18 (250×70 mm, 10 μm)]; A: [water (0.1% TFA)], B: ACN; B%: 40% to 70%, 20 min], followed by chiral SFC [DAICEL CHIRALPAK IG (250 mm×30 mm, 10 μm); A: MeOH (0.1% NH4 OH), B:CO 2 ; B%: 40%, 4.5 min] to give 6-benzyl 2-(tert-butyl) (1R,5R,7R)-7-methyl-2,6-diazabicyclo[3.2.0]heptane-2,6-dicarboxylate (B-30, first elution) (1.5 g) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.37-7.27 (m, 5H), 5.10 (m, 2H), 4.80-4.77 (m, 1H), 4.48-4.43 (m, 2H), 4.15-3.96 (m, 1H), 3.46-3.41 (m, 1H), 3.19-3.16 (m, 1H), 2.14-2.05 (m, 1H), 1.76-1.72 (m, 1H) 1.47-1.45 (m, 9H), 1.26-1.19 (m, 3H). The second eluting peak, 6-benzyl 2-(tert-butyl)(1R,5R,7S)-7-methyl-2,6-diazabicyclo[3.2.0]heptane-2,6-dicarboxylate (B-31), was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ7.38-7.27(m,5H),5.17-5.13(m,2H),4.87-4.86(m,1H),4.03-3.79(m, 3H), 3.47(s, 1H), 2.41-2.36(m, 1H), 1.84-1.81(m, 1H), 1.78-1.26(m, 12H). [ka]

[0408] A mixture of 6-benzyl 2-(tert-butyl)(1R,5R,7R)-7-methyl-2,6-diazabicyclo[3.2.0]heptane-2,6-dicarboxylate (B-30) (600 mg, 1.73 mmol, 1.00 equiv.) and Pd / C (200 mg, 10.0 wt%) in MeOH (10.0 mL) was subjected to H 2The mixture was stirred under (15.0 psi) for 1 h at 15° C. The vessel was flushed with nitrogen, the reaction mixture was filtered, and the filtrate was concentrated to give tert-butyl (1R,5R,7R)-7-methyl-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (B-32) (278.9 mg, 1.24 mmol, 71.6% yield, 94% purity) as a white solid. 1 H NMR (400 MHz, CDCl 3 ):δ4.37(s,1H),3.86-3.78(m,1H),3.59-3.49(m,2H),3.19-3.16(m,1H),1.68-1.64(m,2H),1.39-1.36(m,9H),1.23-1.21(m,3H).

[0409] Intermediate B-33 Same procedure as for B-32: tert-butyl (1R,5R,7S)-7-methyl-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (B-33) as a white solid; LCMS [ESI, M+1]: 213.3; 1 H NMR (400 MHz, CDCl 3 ):δ4.30-4.16(m,2H),3.87-3.68(m,1H),3.40-3.38(m,1H),3.36-3.22(m,1H),1.55-1.52(m,2H),1.47-1.36(d,9H),0.84-0.79(m,3H)

[0410] In addition to the aforementioned intermediates above, the following exemplary intermediates C-1 to C-25 can be used to prepare -LR 4 can be attached to the azaquinazoline core of formula (I). [ka]

[0411] Trimethyl(trimethylstannyl)stannane (12.6 g, 38.4 mmol, 7.97 mL, 3.7 equiv.), tert-butyl N-(6-bromo-5-chloro-2-pyridyl)carbamate (3.2 g, 10.4 mmol, 1.0 equiv.), Pd(PPh3 ) 4 (1.20 g, 1.04 mmol, 0.1 equiv.) was added to a mixture of N 2 The mixture was purged with 500 ml of ethyl acetate and then the mixture was stirred at 100° C. for 12 h. The reaction mixture was filtered and concentrated. The residue was purified by reverse phase flash chromatography [water (0.1% formic acid) / acetonitrile]. The mixture was concentrated under reduced pressure to give tert-butyl N-(5-chloro-6-trimethylstannyl-2-pyridyl)carbamate (2.5 g, 6.39 mmol, 61% yield) as a brown solid. LCMS [ESI, M+1]: 393. [ka]

[0412] To a mixture of 1-bromo-3-chloro-2,4-difluorobenzene (250 g, 1.10 mol, 1.00 equiv.) and furan (150 g, 2.20 mol, 160 mL, 2.00 equiv.) in toluene (2.50 L), n-BuLi (2.50 M, 528 mL, 1.2 equiv.) was added dropwise at -15°C over 0.5 h. The mixture was allowed to warm to room temperature and continued to stir for 12 h. The mixture was then quenched with water (2 L) and filtered. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (2 L x 2). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried over ice and filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase flash [C18, 0.1% FA in water, 0-80% MeCN] to give 5-chloro-6-fluoro-1,4-dihydro-1,4-epoxynaphthalene (81.0 g, 37% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ7.11-7.06(m,2H),7.06-7.01(m,1H),6.73(dd,J=7.6,9.6Hz,1H),5.88(s,1H),5.74(s,1H).

[0413] A mixture of 5-chloro-6-fluoro-1,4-dihydro-1,4-epoxynaphthalene (162 g, 824 mmol, 1.00 equiv) in concentrated hydrochloric acid (1.02 kg, 10.1 mol, 1.00 L, 12.2 equiv) and ethyl alcohol (1.20 L) was heated at 80° C. with stirring for 6 h. The reaction mixture was then concentrated under vacuum. The residue was diluted with saturated NaHCO 3 The pH was adjusted to about 7 with aqueous solution of sodium hydroxide, and then extracted with ethyl acetate (2 L x 2). The combined organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of petroleum ether (100 mL), filtered, and the filtrate was concentrated under vacuum. The residue was triturated with petroleum ether (100 mL), then filtered, and the filter cake was dried under vacuum to give 8-chloro-7-fluoronaphthalen-1-ol (124 g, 76% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ):δ7.92(s,1H),7.75(dd,J=5.2,8.8Hz,1H),7.44-7.36(m,2H),7.33-7.26(m,1H),7.12-7.06(m,1H).

[0414] A mixture of 8-chloro-7-fluoronaphthalen-1-ol (124 g, 631 mmol, 1.00 equiv), DIEA (489 g, 3.78 mol, 659 mL, 6.00 equiv), 4Å MS (120 g) in dichloromethane (1.5 L) was stirred at 20° C. for 10 min. To this suspension cooled to −40° C., trifluoromethylsulfonyl trifluoromethanesulfonate (231 g, 820 mmol, 135 mL, 1.30 equiv) was added dropwise. After 20 min, the reaction mixture was diluted with water (1 L) and the organic layer was collected. The aqueous layer was then extracted with ethyl acetate (1 L×2). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate, 1:0 to 20:1) to give 8-chloro-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (196 g, 92% yield). Yellow solid; 1 H NMR (400 MHz, CDCl 3)δ7.86(d,J=8.0Hz,1H),7.83-7.76(m,1H),7.57(d,J=8.0Hz,1H),7.53-7.44(m,1H),7.43-7.35(m,1H). [ka]

[0415] A mixture of 1-bromo-2,3,4-trifluorobenzene (10.0 g, 47.4 mmol, 5.62 mL, 1.0 equiv.) and furan (6.45 g, 94.8 mmol, 6.89 mL, 2.0 equiv.) in toluene (130 mL) was treated with N 2 Under the conditions below, n-BuLi (2.50 M, 22.7 mL, 1.2 equiv.) was added in one portion at -15°C. The mixture was stirred at -15°C for 30 min, then warmed to room temperature and stirred for 12 h. The reaction mixture was then diluted with water (100 mL) and filtered. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of water, filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash [C18, 0.1% FA in water, 0-65% MeCN]. The fractions were concentrated under vacuum and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated in vacuo to give 5,6-difluoro-1,4-dihydro-1,4-ethoxynaphthalene (1.6 g, 19% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ7.11-7.06(m,2H),6.93(dd,J=3.2,7.6Hz,1H),6.77-6.74(m,1H),5.98(s,1H),5.72(s,1H).

[0416] To a solution of 5,6-difluoro-1,4-dihydro-1,4-epoxynaphthalene (4.30 g, 23.9 mmol, 1.0 equiv) in EtOH (90.0 mL) was added concentrated HCl (40.6 g, 334 mmol, 39.8 mL, 14.0 equiv) at 25 °C. The mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by reverse phase flash chromatography [C18, 0.1% FA in water, 0-80% MeCN]. The fractions were purified by NaCl extraction with ethyl acetate (2 × 100 mL). 2 CO 3 The pH was adjusted to 8 with 100. The combined organic layers were washed with anhydrous Na 2 SO 4 It was dried over ice, filtered and concentrated in vacuo to give 7,8-difluoronaphthalen-1-ol (3.8 g, 88% yield) as a black solid. 1 H NMR (400 MHz, CDCl 3 ): δ7.51-7.49(m,1H), 7.31-7.29(m,2H), 7.20-7.17(m,1H), 6.95-6.93(m,1H), 6.59-6.53(m,1H).

[0417] A mixture of 7,8-difluoronaphthalen-1-ol (3.30 g, 18.3 mmol, 1.0 equiv), DIEA (11.8 g, 91.5 mmol, 16.0 mL, 5.0 equiv), and 4 Å MS (3.00 g, 18.3 mmol, 1.0 equiv) in dichloromethane (10.0 mL) was stirred at 20° C. for 10 min. The mixture was cooled to −40° C. followed by addition of Tf 2 2O (6.72 g, 23.8 mmol, 3.93 mL, 1.3 equiv) was added and stirring was continued at this temperature for 30 min. The reaction mixture was cooled to 5°C and then cooled to 5°C. 2 The mixture was diluted with 2×O (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (40 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate, 1:0 to 50:1) to give 7,8-difluoronaphthalen-1-yl trifluoromethanesulfonate (5.58 g, 98% yield) as a red oil. 1 H NMR (400 MHz, CDCl 3 ): δ7.89-7.87(m,1H), 7.73-7.67(m,1H), 7.52-7.46(m,3H).

[0418] To a mixture of 7,8-difluoronaphthalen-1-yl trifluoromethanesulfonate (1.50 g, 4.80 mmol, 1.0 equiv.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.05 g, 12.0 mmol, 2.5 equiv.) in dioxane (15.0 mL), N 2 Below, Pd(dppf)Cl 2 (352 mg, 480 μmol, 0.1 equiv) and KOAc (1.41 g, 14.4 mmol, 3.0 equiv) were added. The mixture was stirred at 25° C. for 5 min, then heated to 100° C. and stirred for 16 h. The reaction mixture was then diluted with H 2 The mixture was diluted with 2×O (40 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (80 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0 to 100:1) to give 2-(7,8-difluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.28 g, 92% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ):δ7.86-7.84(m,1H),7.73-7.71(m,1H),7.61-7.58(m,1H),7.49-7.45(m,1H),7.37-7.32(m,1H),1.46(s,12H). [ka]

[0419] 8-Chloro-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (27.0 g, 82.1 mmol, 1.00 equiv.) in DMF (300 mL), (PinB) 2 (41.7 g, 164 mmol, 2.00 equiv.), KOAc (40.3 g, 411 mmol, 5.00 equiv.), and Pd(dppf)Cl 2 A mixture of (6.01 g, 8.22 mmol, 0.10 equiv) was purged with nitrogen, then the mixture was stirred at 80° C. for 12 h. The mixture was cooled to room temperature and diluted with ethyl acetate (500 mL) and water (400 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (400 mL×2). The combined organic layers were washed with brine (800 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0 to 50:1) to give 2-(8-chloro-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (19 g, 74% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ): δ7.86(dd,J=1.2,8.4Hz,1H),7.76(dd,J=5.6,9.2Hz,1H),7.71(d,J=6.8Hz,1H),7.49(dd,J=7.2,8.0Hz,1H),7.33(t,J=8.8Hz,1H),1.46(s,12H). [ka]

[0420] (8-Chloro-7-fluoro-1-naphthyl)trifluoromethanesulfonate (80.0 mg, 243 μmol, 1.0 equiv.), trimethyl(trimethylstannyl)stannane (360 mg, 1.10 mmol, 228 μL, 4.5 equiv.), Pd(PPh 3 ) 4A mixture of LiCl (28.1 mg, 24.3 μmol, 0.1 equiv.), LiCl (61.9 mg, 1.46 mmol, 6.0 equiv.) and N 2 The mixture was then purged under reduced pressure and stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water (5 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of water and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0 to 10:1) to give (8-chloro-7-fluoro-1-naphthyl)-trimethyl-stannane (50.0 mg, 96.1 μmol, 39% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 7.88 (d, J = 6.8 Hz, 1H), 7.83 (dd, J = 1.2, 8.0 Hz, 1H), 7.78 (dd, J = 6.0, 9.2 Hz, 1H), 7.45 (dd, J = 6.8, 8.0 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 0.44 (s, 9H). [ka]

[0421] 7,8-Dichloronaphthalen-1-yl trifluoromethanesulfonate (200 mg, 579 μmol, 1.0 equiv.), trimethyl(trimethylstannyl)stannane (522 mg, 1.59 mmol, 330 μL, 2.7 equiv.), Pd(PPh 3 ) 4 A mixture of LiCl (67.0 mg, 57.9 μmol, 0.1 equiv.), LiCl (98.3 mg, 2.32 mmol, 4.0 equiv.) and N 2 The mixture was purged under reduced pressure and then stirred at 100° C. for 16 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0) followed by purification by reverse phase flash to give (7,8-dichloronaphthalen-1-yl)trimethylstannane (80.0 mg, 36% yield) as a colorless oil.1 H NMR (400 MHz, CDCl 3 ): δ7.89(dd,J=1.2,6.8Hz,1H),7.82(d,J=8.0Hz,1H),7.72(d,J=8.8Hz,1H),7.53(d,J=8.8Hz,1H),7.48(dd,J=7.2,8.0Hz,1H),0.44(s,9H). [ka]

[0422] To a mixture of 1-bromo-2,4-difluoro-3-methylbenzene (20.0 g, 96.6 mmol, 1.0 equiv.) and furan (13.1 g, 193 mmol, 14.0 mL, 2.0 equiv.) in toluene (300 mL) was added n-BuLi (2.5 M, 46.4 mL, 1.2 equiv.) dropwise at −20° C. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was then washed with saturated NH 4 It was diluted with aqueous Cl (200 mL) and then extracted with ethyl acetate (150 mL x 3). The combined organic layers were concentrated under reduced pressure to give a crude residue. The residue was purified by reverse-phase flash chromatography [C18, 0.1% FA in water, 0-65% MeCN] to give 7-fluoro-5-methyl-11-oxatricycloundeca-1,3,5(7),6(8)-tetraene (5.0 g, 27.8 mmol, 28.8% yield) as a yellow oil. LCMS [ESI, M+1]: 177.

[0423] To a solution of 7-fluoro-5-methyl-11-oxatricycloundeca-1,3,5(7),6(8)-tetraene (5.0 g, 28.4 mmol, 1.0 equiv.) in ethanol (80.0 mL) was added concentrated hydrochloric acid (30.7 mL, 13.0 equiv.). The mixture was stirred at 80 °C for 3 h and cooled to room temperature. The mixture was concentrated under reduced pressure to give a crude residue. The residue was purified by reverse-phase flash chromatography [C18, 0.1% FA in water, 0-65% MeCN] to give 7-fluoro-8-methyl-naphthalen-1-ol (5.0 g, 28.4 mmol, 100% yield) as a brown oil. 1H NMR (400 MHz, chloroform): δ 7.60 (dd, J = 5.6, 8.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.25-7.18 (m, 2H), 6.75 (d, J = 7.6 Hz, 1H), 5.26 (s, 1H), 2.84 (d, J = 2.8 Hz, 3H).

[0424] A mixture of 7-fluoro-8-methyl-naphthalen-1-ol (5.0 g, 28.4 mmol, 1.0 equiv.), DIEA (11.0 g, 85.1 mmol, 14.8 mL, 3.0 equiv.), and molecular sieves 4 Å (500 mg) in dichloromethane (100 mL) was stirred under nitrogen at −40° C. for 20 min, followed by the addition of Tf 2 O (8.81 g, 31.2 mmol, 5.15 mL, 1.1 equiv) was added. The mixture was stirred at -40 °C for 40 min and then concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1:0 to 100:1) to obtain (7-fluoro-8-methyl-1-naphthyl)trifluoromethanesulfonate (7.4 g, 24.0 mmol, yield 84.6%) as a white solid. 1 H NMR (400 MHz, chloroform-d): δ = 7.84 (dd, J = 1.2, 8.4 Hz, 1H), 7.74 (dd, J = 5.6, 8.8 Hz, 1H), 7.54 (dJ = 7.6 Hz, 1H), 7.45-7.40 (m, 1H), 7.34 (t, J = 9.2 Hz, 1H), 2.78 (d, J = 2.8 Hz, 3H). [ka]

[0425] (7-Fluoro-8-methyl-1-naphthyl)trifluoromethanesulfonate (2.0 g, 6.49 mmol, 1.0 equiv.) in dioxane (30.0 mL), Pin 2 B 2 (3.30 g, 13.0 mmol, 2.0 equiv.), KOAc (1.91 g, 19.5 mmol, 3.0 equiv.), and Pd(dppf)Cl 2(949 mg, 1.30 mmol, 0.2 equiv) was heated at 90° C. for 10 h. The mixture was then concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography (SiO 2 The crude product was purified by a crude oil (petroleum ether / ethyl acetate=1:0 to 30:1) to give 2-(7-fluoro-8-methyl-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.4 g, 4.89 mmol, 75.4% yield) as a yellow oil. 1 H NMR(400MHz,chloroform-d)δ=7.85(dd,J=1.2,8.0Hz,1H),7.74-7.66(m,2H),7.41 (dd,J=6.8,8.0Hz,1H),7.27-7.20(m,1H),2.66(d,J=2.4Hz,3H),1.45(s,12H).

[0426] Methanol (21.0 mL) and H 2 A solution of 2-(7-fluoro-8-methyl-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.4 g, 4.89 mmol, 1.0 equiv) in 2H2O (7.0 mL) was diluted with KHF 2 (3.82 g, 48.9 mmol, 10.0 equiv) was added at 10° C. The mixture was stirred at this temperature for 30 min and then concentrated under reduced pressure to give a white solid. The solid was slurried in acetone (100 mL) for 30 min and filtered. The filtrate was concentrated under reduced pressure at 40° C. to give potassium (8-chloro-7-fluoronaphthalen-1-yl)trifluoroborate (1.7 g, 2.62 mmol, 53.5% yield) as a yellow oil. [ka]

[0427] To a mixture of 2-bromo-1-fluoro-3-methyl-benzene (30 g, 158 mmol, 1.0 equiv) in THF (300 mL) was added LDA (2 M in THF, 119 mL, 1.5 equiv) dropwise at −70° C. under nitrogen. The mixture was stirred at −70° C. for 0.5 h, after which DMF (34.8 g, 476 mmol, 36.6 mL, 3.0 equiv) was added dropwise. The reaction mixture was stirred at −70° C. for an additional 2 h, then saturated NH 4 The mixture was poured into aqueous Cl (400 mL). The mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 The material was then triturated with petroleum ether (50 mL) and the solid was collected and dried in vacuo to give 3-bromo-2-fluoro-4-methyl-benzaldehyde (9.2 g, 42.4 mmol, 27% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d): δ = 10.31 (s, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 2.51 (s, 3H).

[0428] 3-Bromo-2-fluoro-4-methyl-benzaldehyde (9.2 g, 42.4 mmol, 1.0 equiv.) and NH in DMSO (150 mL). 2 NH 2 H 2 A solution of 2H2O (42.4 g, 848 mmol, 41.2 mL, 20 equiv) was stirred at 60° C. for 2 h and then at 130° C. for 16 h. The solution was then cooled to 20° C., poured into brine (600 mL), and filtered. The white solid was collected, washed with water (100 mL), and dried under reduced pressure to give 7-bromo-6-methyl-1H-indazole (6.2 g, 29.4 mmol, 69% yield) as a pale yellow solid. 1 H NMR (400 MHz, chloroform-d): δ 10.69 (br s, 1H), 8.15 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 2.55 (s, 3H).

[0429] CH 3 CN (250 mL), Cs 2 CO 3 (15.9 g, 48.7 mmol, 1.3 equiv.), and CH 3 A mixture of 7-bromo-6-methyl-1H-indazole (7.9 g, 37.4 mmol, 1.0 equiv) in I (15.9 g, 112 mmol, 6.99 mL, 3.0 equiv) was heated at 80° C. for 1.5 h. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated to give a crude residue. The residue was diluted with water (200 mL) and extracted with ethyl acetate (60 mL×3). The combined organic layers were washed with 200 mL of brine and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 10:1 to 2:1) to give 7-bromo-1,6-dimethyl-indazole (4.9 g, 21.8 mmol, 58% yield) as a yellow solid.

[0430] To a mixture of 7-bromo-1,6-dimethyl-indazole (2.00 g, 8.89 mmol, 1.0 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (6.77 g, 26.7 mmol, 3.0 equiv), and KOAc (2.62 g, 26.7 mmol, 3.0 equiv) in DMF (40 mL) was added N 2 Below, Pd(dppf)Cl 2 (325 mg, 444 umol, 0.05 equiv.) was added. The mixture was diluted with N 2 The mixture was heated at 80° C. for 15 h under reduced pressure. The mixture was then cooled to room temperature and diluted with ethyl acetate (50 mL) and water (200 mL). The aqueous phase was extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine (3×40 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate, 30:1) to give 1,6-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (1.46 g, 4.98 mmol, 56% yield, 92.9% purity) as a white solid. LCMS [ESI, M+1]: 273. 1 H NMR (400 MHz, chloroform-d) δ = 7.89 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.15 (s, 3H), 2.60 (s, 3H), 1.46 (s, 12H). [ka]

[0431] 1,8-Dibromonaphthalene (7 g, 24.5 mmol, 1.0 equiv), ethynyl(triisopropyl)silane (4.91 g, 26.9 mmol, 6.04 mL, 1.1 equiv), CuI (466 mg, 2.45 mmol, 0.1 equiv), PPh in TEA (100 mL). 3 (642 mg, 2.45 mmol, 0.1 equiv.), and Pd(PPh 3 ) 2 Cl 2 (859 mg, 1.22 mmol, 0.05 equiv.) was added to a mixture of N 2 The mixture was stirred at 80° C. for 3 h under reduced pressure. The mixture was warmed to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether) to give ((8-bromonaphthalen-1-yl)ethynyl)triisopropylsilane (7 g, 18.1 mmol, 74% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d): δ = 7.87 (dd, J = 1.2, 7.2 Hz, 1H), 7.82-7.73 (m, 3H), 7.41-7.34 (m, 1H), 7.24 (t, J = 7.6 Hz, 1H), 1.19-1.16 (m, 21H).

[0432] ((8-bromonaphthalen-1-yl)ethynyl)triisopropylsilane (6.5 g, 16.8 mmol, 1.0 equiv.), trimethyl(trimethylstannyl)stannane (27.5 g, 83.9 mmol, 17.4 mL, 5.0 equiv.), and Pd(PPh 3 ) 4 (1.94 g, 1.68 mmol, 0.1 equiv.) was added to a mixture of N 2 The mixture was stirred at 110° C. for 48 h under reduced pressure. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether) followed by reverse-phase flash chromatography [water (FA, 0.1%) / acetonitrile] to give triisopropyl((8-(trimethylstannyl)naphthalen-1-yl)ethynyl)silane (0.65 g, 1.37 mmol, 8.1% yield, 99% purity) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.90 (dd, J = 1.2, 7.2 Hz, 1H), 7.86-7.79 (m, 3H), 7.47-7.39 (m, 2H), 1.25-1.18 (m, 21H), 0.54-0.44 (m, 9H). [ka]

[0433] To a solution of ((8-bromonaphthalen-1-yl)ethynyl)triisopropylsilane (1.50 g, 3.87 mmol, 1.00 equiv) in THF (15.0 mL) under argon atmosphere was added dtbbpy (125 mg, 465 μmol, 0.12 equiv), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (257 mg, 387 μmol, 0.10 equiv) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.24 g, 9.68 mmol, 1.40 mL, 2.50 equiv). The mixture was stirred at 60° C. for 10 h and concentrated under reduced pressure to give a mixture of two boronated isomers (15.0 g, crude).

[0434] H 2 To a solution of the crude mixture of boronated isomers (15.0 g, 29.2 mmol, 1.00 equiv) in HO (20.0 mL) and THF (60.0 mL) was added H 2 O 2 (29.8 g, 263 mmol, 25.3 mL, 9.00 equiv.) and acetic acid (121 g, 2.02 mol, 115 mL, 69.0 equiv.) were added and the mixture was stirred at 10 °C for 1 h before being added with saturated NaHSO 3 The mixture was diluted with aqueous solution (300 mL). The mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (200 mL) and anhydrous Na 2 SO 4 The mixture was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0 to 20:1), and then purified by preparative HPLC [column: Phenomenex luna C18 (250 * 70 mm, 10 μm); mobile phase: water (0.225% FA)-ACN; ACN: 70%-99%, 40 min], followed by SFC separation [column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); Mobile phase: (0.1% NH in IPA 4 OH)] to give 4-bromo-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (3.00 g, 7.44 mmol, 13% yield) as a pale yellow solid.1 H NMR (400 MHz, CDCl 3 ):δ7.73-7.72(m,1H),7.64-7.51(m,1H),7.49(d,J=2.8Hz,1H),7.35-7.32(m,1H),7.12(d,J=2.8Hz,1H),1.20-1.16(m,21H).

[0435] To a solution of 4-bromo-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (2.90 g, 7.19 mmol, 1.00 equiv) and DIEA (2.79 g, 21.6 mmol, 3.76 mL, 3.00 equiv) in DCM (3.00 mL) was added MOMCl (1.10 g, 13.7 mmol, 1.04 mL, 1.90 equiv) dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h and then diluted with H 2 The mixture was diluted with 20 mL of DCM (40 mL). The mixture was extracted with DCM (90 mL). The organic layer was washed with brine (20 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0 to 50:1) to give ((8-bromo-6-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (2.00 g, 4.47 mmol, 62% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ7.75(dd,J=1.2,7.2Hz,1H),7.72-7.65(m,1H),7.60(d,J=2.4Hz,1H),7.39-7.30(m,2H),5.27(s,2H),3.52(s,3H),1.21-1.15(m,21H).

[0436] To a mixture of ((8-bromo-6-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (400 mg, 893 umol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (454 mg, 1.79 mmol, 2.00 equiv), and KOAc (263 mg, 2.68 mmol, 3.00 equiv) in toluene (8.00 mL) was added Pd(dppf)Cl under nitrogen atmosphere. 2 (196 mg, 268 umol, 0.30 equiv.) was added. The mixture was stirred at 80° C. for 12 hours and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate, 5:1, Rf=0.5) to give triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (390 mg, 787 μmol, 88% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ7.69(dd,J=3.2,7.6Hz,2H),7.47(d,J=2.8Hz,1H),7.40-7.31(m,2H),5.29(s,2H),3.51(s,3H),1.44(s,12H),1.20-1.12(m,21H). [ka]

[0437] To a solution of 4-bromo-5-chloronaphthalen-2-ol (0.90 g, 3.49 mmol, 1.0 equiv) and DIEA (1.36 g, 10.5 mmol, 1.83 mL, 3.0 equiv) in DCM (20.0 mL) was added MOMCl (422 mg, 5.24 mmol, 398 μL, 1.5 equiv) dropwise at 0° C. The mixture was stirred at 0° C. for 0.5 h and then diluted with H 2 The organic layer was washed with brine (20.0 mL) and diluted with 20.0 mL of anhydrous NaCl. 2 SO 4The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0 to 20:1) to give 1-bromo-8-chloro-3-(methoxymethoxy)naphthalene (2.00 g, 5.97 mmol, 85% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ):δ7.73-7.62(m,2H),7.50(dd,J=1.2,7.6Hz,1H),7.38(d,J=2.50Hz,1H),7.33-7.26(m,1H),5.27(s,2H),3.52(s,3H).

[0438] A solution of 1-bromo-8-chloro-3-(methoxymethoxy)naphthalene (1.60 g, 5.31 mmol, 1.0 equiv) in toluene (30.0 mL) was treated with trimethyl(trimethylstannyl)stannane (7.82 g, 23.9 mmol, 4.95 mL, 4.5 equiv), Pd(PPh 3 ) 4 (613 mg, 530 μmol, 0.1 equiv.), and LiCl (1.35 g, 31.8 mmol, 6.0 equiv.) were added. The mixture was cooled to 37° C. for 1 hour with 5% CO.sub.2. 2 The mixture was stirred at 110° C. for 12 h under reduced pressure. The mixture was then filtered and concentrated to give a crude residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:10 to 20:1) to give (8-chloro-3-(methoxymethoxy)naphthalen-1-yl)trimethylstannane (1.50 g, 3.89 mmol, 73% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ):δ7.71-7.66(m,1H),7.57(d,J=2.4Hz,1H),7.49-7.43(m,1H),7.39-7.37(m,1H),7.35-7.30(m,1H),5.31(s,2H),3.54(s,3H),0.42(s,9H). [ka]

[0439] To a mixture of 1-bromonaphthalen-2-ol (1.5 g, 6.72 mmol, 1.0 equiv) in DCM (15 mL) was added DIEA (2.61 g, 20.2 mmol, 3.51 mL, 3.0 equiv) at -40 °C, followed by MOMCl (704 mg, 8.74 mmol, 664 μL, 1.3 equiv) in DCM (0.5 mL). The solution was stirred at 0 °C for 30 min and then diluted with water (5.0 mL). The aqueous phase was extracted with ethyl acetate (3 × 10 mL) and the combined organic phase was washed with brine (15 mL) and anhydrous NaCl. 2 SO 4 The resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0 to 10:1) to give 1-bromo-2-(methoxymethoxy)naphthalene (1.55 g, 86% yield) as a yellow solid.

[0440] To a mixture of 1-bromo-2-(methoxymethoxy)naphthalene (1.55 g, 5.80 mmol, 1.0 equiv), KOAc (1.71 g, 17.4 mmol, 3.0 equiv), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.95 g, 11.6 mmol, 2.0 equiv) in dioxane (16 mL) was added Pd(dppf)Cl under nitrogen. 2 (424 mg, 580 μmol, 0.1 equiv.) was added. The mixture was stirred at 110° C. for 1.5 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL). The aqueous phase was extracted with ethyl acetate (3×15 mL) and the combined organic phase was washed with brine (15 mL) and anhydrous Na 2 SO 4 The resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0 to 20:1) to give 2-(2-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.7 g, 93% yield) as a white solid. 1 H NMR (400 MHz, CDCl3 ):δ=7.94(d,J=8.4Hz,1H),7.82(d,J=8.8Hz,1H),7.8-7.74(m,1H),7.47-7 .41(m,1H),7.37-7.3(m,2H),5.26(s,2H),3.54(s,3H),1.52-1.46(m,12H). [ka]

[0441] A sealed tube was charged with a mixture of CuI (387 mg, 2.03 mmol, 0.1 equiv), 1,10-phenanthroline (732 mg, 4.06 mmol, 0.2 equiv), and t-BuONa (11.7 g, 122 mmol, 6.0 equiv). The system was evacuated and backfilled with nitrogen three times, after which a solution of 1-(2-iodophenyl)ethan-1-one (5 g, 20.3 mmol, 1.0 equiv) and acetone (3.54 g, 61.0 mmol, 4.48 mL, 3.0 equiv) in toluene (50 mL) was added at -20 °C. The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was diluted with water (50 mL) and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL) and the combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate (2×20 mL), filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase flash chromatography [water (0.1% FA) / acetonitrile]. The desired fractions were collected and concentrated under reduced pressure to remove MeCN, then extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (petroleum ether / ethyl acetate, 20:1 to 5:1) to give 3-methylnaphthalen-1-ol (1.12 g, 33%) as a brown solid; f = 0.60 (5:1, petroleum ether / ethyl acetate); 1 H NMR (400 MHz, CDCl 3):δ8.15-8.09(m,1H),7.73(d,J=7.6Hz,1H),7.50-7.39(m,2H),7.26-7.21 (m,1H),6.70-6.66(m,1H),5.38(s,1H),2.46(s,3H);LCMS[ESI,M-1]:157.

[0442] To a solution of 3-methylnaphthalen-1-ol (0.1 g, 632 μmol, 1.0 equiv) in DCM (2.0 mL) was added TEA (160 mg, 1.58 mmol, 220 μL, 2.5 equiv) and Tf 2 O (232 mg, 822 μmol, 135 μL, 1.3 equiv) was added at −40° C. The mixture was stirred at this temperature for 15 min and then diluted with water (2.0 mL). The aqueous phase was extracted with ethyl acetate (3×2.0 mL) and the combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate, 100:1 to 20:1) to give 3-methylnaphthalen-1-yl trifluoromethanesulfonate (120 mg, 64%) as a yellow oil; f = 0.70 (10:1, petroleum ether / ethyl acetate); LCMS [ESI, M-1]: 289.

[0443] 3-Methylnaphthalen-1-yl trifluoromethanesulfonate (120 mg, 413 μmol, 1.0 equiv.), Pd(dppf)Cl in dioxane (2.5 mL) 2 A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaneboron-2-yl)-1,3,2-dioxaneboron (30.2 mg, 41.3 μmol, 0.1 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaneboron-2-yl)-1,3,2-dioxaneboron (315 mg, 1.24 mmol, 3.0 equiv) and KOAc (122 mg, 1.24 mmol, 3.0 equiv) was purged with nitrogen and then heated at 80° C. for 6 h. The mixture was cooled to room temperature and diluted with water (4.0 mL). The aqueous layer was extracted with ethyl acetate (2×5.0 mL). The combined organic layers were washed with anhydrous Na 2 SO 4The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate, 1:0 to 50:1) to give 4,4,5,5-tetramethyl-2-(3-methylnaphthalen-1-yl)-1,3,2-dioxaborolane (100 mg, 81%) as a yellow solid; f = 0.43 (3:1, petroleum ether / ethyl acetate); 1 H NMR (400 MHz, CDCl 3 ):δ8.74-8.69(m,1H),7.94-7.91(m,1H),7.78-7.74(m,1H),7.72-7.69(m,1H),7.49-7.41(m,2H),2.52(s,3H),1.44(s,12H). [ka]

[0444] 1,4-Dioxane (18.0 mL) and H 2 To a solution of 1-bromo-3-chloro-2-iodobenzene (2.50 g, 7.88 mmol, 1.00 equiv) in O (6.0 mL), 3 PO 4 (6.02g, 28.4mmol, 3.60eq), Pd(dppf)Cl 2 (288 mg, 394 μmol, 0.05 equiv.), and cyclopropylboronic acid (880 mg, 10.2 mmol, 1.30 equiv.) were added. The mixture was stirred at 100° C. for 18 h, then cooled to room temperature and diluted with water (30 mL). The mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0) followed by reverse-phase flash chromatography [water (0.1% FA) / acetonitrile] to give 1-bromo-3-chloro-2-cyclopropylbenzene (1.18 g, 40% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3): δ7.46(dd,J=1.2,8.0Hz,1H),7.30(dd,J=1.2,8.0Hz,1H),6.99(t,J=8.0Hz,1H),1.88-1.73(m,1H),1.23-1.14(m,2H),0.80-0.74(m,2H).

[0445] To a solution of 1-bromo-3-chloro-2-cyclopropylbenzene (0.980 g, 4.23 mmol, 1.00 equiv) in 1,4-dioxane (30.0 mL), KOAc (1.25 g, 12.7 mmol, 3.00 equiv), Pin 2 B 2 (2.15 g, 8.47 mmol, 2.00 equiv.), and Pd(dppf)Cl 2 (310 mg, 423 μmol, 0.100 equiv.) was added. The mixture was stirred at 110° C. for 6 h. The mixture was cooled to room temperature and diluted with water (30 mL). The mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1 / 0), reverse phase flash chromatography [water (0.1% FA) / acetonitrile], and finally preparative HPLC (Phenomenex luna C18 150×40 mm×15 μm; A: water (0.225% FA), B: ACN; B%: 68%-98%, 11 min) to give 2-(3-chloro-2-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (320 mg, 27% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ):δ7.45(dd,J=1.2,7.2Hz,1H),7.37(dd,J=1.2,8.0Hz,1H),7.17-7.06(m,1H), 2.07(tt,J=5.6,8.4Hz,1H),1.39(s,12H),1.08-0.97(m,2H),0.62-0.53(m,2H). [ka]

[0446] TFA (50 mL) and H 2 SO 4 To a solution of 1-chloro-2,5-dimethyl-4-nitrobenzene (6.50 g, 35.0 mmol, 1.0 equiv) in (12.0 g, 122 mmol, 6.50 mL, 3.5 equiv) at 40° C., NBS (6.86 g, 38.5 mmol, 1.1 equiv) was added in portions. The mixture was stirred at 40° C. for 8 h and cooled to room temperature. The mixture was diluted with water (300 mL) at 0° C. and then filtered. The filter cake was washed with water (50 mL) and dried under reduced pressure to give a solid. The crude product was purified by reverse-phase flash chromatography [water (0.1% TFA) / acetonitrile] to give 3-bromo-2-chloro-1,4-dimethyl-5-nitrobenzene (6.25 g, 19.8 mmol, 57% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ):δ=7.65(s,1H),2.60(s,3H),2.49(s,3H).

[0447] A flask containing 3-bromo-4-chloro-2,5-dimethylaniline (500 mg, 2.13 mmol, 1.0 equiv.) was charged with HBF 4 (3.86 g, 17.6 mmol, 2.74 mL, 40 wt % in water, 8.2 equiv.) was added, followed by saturated NaNO 2 Aqueous solution (221 mg, 3.20 mmol, 1.5 equiv) was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 h and then at room temperature for 30 min. The mixture was cooled to 0° C. and additional saturated NaNO 2 Aqueous solution (147 mg, 2.13 mmol, 1.0 equiv) was added. The mixture was stirred at 0° C. for 0.5 h and then filtered. The filter cake was treated with i-Pr 2 O (30 mL) to give 3-bromo-4-chloro-2,5-dimethylbenzenediazonium tetrafluoroborate (700 mg, crude) as a white solid.

[0448] CHCl 3To a stirred mixture of KOAc (412 mg, 4.20 mmol, 2.0 equiv) and 18-Crown-6 (27.8 mg, 105 μmol, 0.05 equiv) in (15 mL) under nitrogen was added 3-bromo-4-chloro-2,5-dimethylbenzenediazonium tetrafluoroborate (700 mg, 2.10 mmol, 1.0 equiv) in one portion at 25 °C. The mixture was stirred at room temperature for 30 min before being filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate, 1:0 to 3:1) to give 4-bromo-5-chloro-6-methyl-1H-indazole (270 mg, 52% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ):δ8.02(s,1H),7.35(d,J=0.8Hz,1H),2.57(d,J=0.8Hz,3H). LCMS[ESI,M+1]:247.

[0449] A solution of 4-bromo-5-chloro-6-methyl-1H-indazole (1.00 g, 4.07 mmol, 1.0 equiv) in DCM (40 mL) was added to TsOH H 2 HO (77.5 mg, 407 μmol, 0.1 equiv) was added followed by DHP (685 mg, 8.15 mmol, 2.0 equiv). The reaction mixture was stirred at 25° C. for 15 h and then concentrated under vacuum. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate, 1:0 to 4:1) to give 4-bromo-5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.30 g, 93% yield) as a yellow solid. LCMS [ESI, M+1]: 329.

[0450] Trimethyl(trimethylstannyl)stannane (656 mg, 2.00 mmol, 2.7 equiv), 4-bromo-5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (240 mg, 728 μmol, 1.0 equiv), Pd(PPh 3 ) 4A mixture of (84.1 mg, 72.8 μmol, 0.1 equiv.), and LiCl (123 mg, 2.91 mmol, 4.0 equiv.) was purged with nitrogen and then stirred at 100° C. for 16 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (SiO 2 , petroleum ether) followed by reverse phase flash chromatography [water (0.1% FA) / acetonitrile] afforded 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(trimethylstannyl)-1H-indazole (190 mg, 444 μmol, 61% yield) as a colorless oil. LCMS [ESI, M+1]: 415. 1 H NMR (400 MHz, CDCl 3 ):δ8.00(s,1H),7.43(s,1H),5.67(dd,J=2.8,9.2Hz,1H),4.07-3.95(m,1H),3.81-3.68(m,1 H),2.63-2.53(m,1H),2.50(s,3H),2.22-2.01(m,2H),1.80-1.64(m,3H),0.59-0.41(m,9H). [ka]

[0451] To a solution of 4-bromonaphthalen-1-amine (20 g, 90.0 mmol, 1 equiv) in MeOH (160 mL) was added acetic anhydride (10.1 mL, 108 mmol, 1.2 equiv). The reaction mixture was stirred at 60° C. for 1 h and then concentrated under vacuum. The mixture was triturated with MTBE (80 mL). The solid was collected, washed with MTBE (20 mL) and dried under vacuum to give N-(4-bromonaphthalen-1-yl)acetamide (23.5 g, 99% yield) as a yellow solid. LCMS [ESI, M+1]: 266.

[0452] To a solution of N-(4-bromonaphthalen-1-yl)acetamide (24.4 g, 92.4 mmol, 1 equiv) in HOAc (200 mL) was added fuming nitric acid (4.19 mL, 102 mmol, 1.1 equiv) dropwise at 45° C. The mixture was stirred at 75° C. for 30 min and then cooled to room temperature. The suspension was filtered and the solid was washed with cold MeOH (50 mL), MTBE (150 mL) and dried under vacuum to give N-(4-bromo-2-nitronaphthalen-1-yl)acetamide (21 g, 74% yield) as a yellow solid. LCMS [ESI, M-41] 267, 269.

[0453] A mixture of N-(4-bromo-2-nitronaphthalen-1-yl)acetamide (18 g, 58.2 mmol, 1 equiv) in aqueous HCl (2 M, 108 mL, 3.71 equiv), EtOH (100 mL), and THF (200 mL) was heated to 80° C. for 50 h. The reaction mixture was then concentrated under vacuum and filtered. The solid was washed with ethyl acetate (50 mL) and dried under vacuum to give 4-bromo-2-nitronaphthalen-1-amine (12 g, 76% yield) as a red solid. LCMS [ESI, M+1]: 267, 269.

[0454] HOAc (100 mL) and concentrated H 2 SO 4 To a solution of 4-bromo-2-nitronaphthalen-1-amine (10 g, 37.4 mmol, 1 equiv.) in NaNO 2 (4.65 g, 67.4 mmol, 1.8 equiv) was added at 5° C. The reaction mixture was stirred at 5-20° C. for 2 h. EtOH (100 mL) was added to the mixture, followed by H 3 PO 2 CuSO in aqueous solution (30.00 g, 148 mmol, 100 mL water, 3.95 equiv.) 4 (7.17 g, 44.9 mmol, 1.2 equiv.) was added. The mixture was stirred at 65° C. for 1 h and then cooled to room temperature. The mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (80 mL) and anhydrous Na 2 SO 4The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate, 1:0 to 20:1) to give 1-bromo-3-nitronaphthalene (8.6 g, 91% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ8.80(d,J=2.0Hz,1H),8.59(d,J=2.0Hz,1H),8.35(d,J=8.8Hz,1H),8.07(d,J=8.0Hz,1H),7.84(dt,J=0.8,7.6Hz,1H),7.77-7.68(m,1H).

[0455] To a solution of 1-bromo-3-nitronaphthalene (2.00 g, 7.93 mmol, 1.0 equiv) in EtOH (20 mL) was added H 2 O (10 mL) and HCl (12 M, 661 μL, 1.0 equiv) were added at 25° C. The reaction mixture was heated at 80° C. before Fe (2.22 g, 39.7 mmol, 5.0 equiv) was added in one portion. The mixture was stirred at 80° C. for 1 h, then cooled to room temperature, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 10:1 to 3:1) to give 4-bromonaphthalen-2-amine (1.58 g, 88% yield) as a brown solid. 1 H NMR (400 MHz, CDCl 3 ):δ8.06(d,J=8.4Hz,1H),7.58(d,J=8.4Hz,1H),7.44-7.38(m,1H),7.36-7.29(m,2H),6.96(d,J=2.0Hz,1H),3.85(br s,2H). LCMS[ESI,M+1]:222, 224.

[0456] A solution of 4-bromonaphthalen-2-amine (1.10 g, 4.95 mmol, 1.0 equiv) in pyridine hydrogen fluoride (11.0 mL, 122 mmol, 25 equiv) was added to NaNO 2(444 mg, 6.44 mmol, 1.3 equiv) was added in one portion at 0° C. The reaction mixture was stirred at 25° C. for 10 min, and then the mixture was heated at 80° C. for 2 h. The mixture was then cooled to 0° C. and saturated NaHCO 3 (50 mL) to adjust the pH to 8. The mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether) to give 1-bromo-3-fluoronaphthalene (620 mg, 55% yield) as a white solid.

[0457] Pin in dioxane (10 mL) 2 B 2 (429 mg, 1.69 mmol, 2.0 equiv.), 1-bromo-3-fluoronaphthalene (190 mg, 844 μmol, 1.0 equiv.), Pd(dppf)Cl 2 A mixture of (61.8 mg, 84.4 μmol, 0.1 equiv.), and KOAc (248 mg, 2.53 mmol, 3.0 equiv.) was added to N 2 The mixture was purged with hexanes and then stirred at 110° C. for 1.5 hours. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate, 1:0 to 10:1) to give 2-(3-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (60.0 mg, 184 μmol, 22% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ):δ8.78-8.70(m,1H),7.84(dd,J=2.8,8.8Hz,1H),7.80-7.75(m,1H),7.56-7.46(m,3H),1.43(s,12H). [ka]

[0458] EtOH (100 mL) and H 2To a solution of 1-chloro-5-fluoro-2-methyl-4-nitrobenzene (20 g, 105 mmol, 1 equiv.) in 2O (100 mL) was added HCl (12 M, 8.79 mL, 1 equiv.). The mixture was heated to 80° C. and Fe (20.6 g, 369 mmol, 3.5 equiv.) was added slowly over 30 min. The mixture was stirred at this temperature for an additional 1 h. The mixture was cooled to room temperature, diluted with ethyl acetate (300 mL) and washed with saturated NaHCO 3 The pH was adjusted to 8-9 with aqueous solution. The mixture was filtered and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×300 mL). The combined organic layers were...

Claims

1. A compound, comprising: 【Chemistry 1-1】 【change】 【Chemistry 1-2】 【Chemistry 1-3】 【Chemistry 1-4】 【Chemistry 1-5】 and pharma- ceutically acceptable salts thereof.

2. 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharma- ceutically acceptable excipient.

3. A pharmaceutical composition for use in a method for inhibiting KRas G12C activity in a cell, the pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharma- ceutical acceptable salt thereof, the method comprising contacting the cell in which inhibition of KRas G12C activity is desired with the pharmaceutical composition.

4. 11. A pharmaceutical composition for use in a method for treating cancer, said pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharma- ceutical acceptable salt thereof, said pharmaceutical composition optionally comprising a pharma- ceutical acceptable carrier, excipient, or diluent, said method comprising administering said pharmaceutical composition to a patient having cancer.

5. 5. The pharmaceutical composition of claim 4, wherein said therapeutically effective amount of said compound is about 0.01 to 100 mg / kg per day.

6. 5. The pharmaceutical composition of claim 4, wherein said therapeutically effective amount of said compound is about 0.1 to 50 mg / kg per day.

7. The cancer is cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrotic hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' 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, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder 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, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid, and giant cell tumor; Nervous system: skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecology: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa follicular 5. The pharmaceutical composition of claim 4, wherein the therapeutic agent is selected from the group consisting of: theca cell carcinoma, Sertoli-Leydig cell carcinoma, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematological: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

8. The pharmaceutical composition of claim 4, wherein the cancer is a cancer associated with KRas G12C.

9. The pharmaceutical composition of claim 8, wherein the cancer is non-small cell lung cancer.

10. 11. A pharmaceutical composition for use in a method for treating cancer in a patient in need of such treatment, the pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharma- ceutical acceptable salt thereof, the method comprising: (a) determining that the cancer is associated with a KRas G12C mutation; and (b) administering the pharmaceutical composition to the patient.

11. The pharmaceutical composition of claim 10, wherein the method comprises: (a) determining that the cancer is a KRas G12C-associated cancer; and (b) administering the pharmaceutical composition to the patient.

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