EGFR inhibitors

Abstract

The present disclosure provides compounds of structural formula (A) or (I): [Formula 1] The present invention provides a compound represented by TIFF2025512957000752.tif58163, or a pharma- ceutically acceptable salt thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from U.S. Provisional Application No. 63 / 327,631, filed April 5, 2022. The entire contents of the aforementioned application are incorporated herein by reference. [Background technology]

[0002] EGFR (epidermal growth factor receptor) is a member of the erbB receptor family, which includes transmembrane protein tyrosine kinase receptors. Upon binding to its ligand (e.g., epidermal growth factor (EGF)), EGFR can form homodimers on the cell membrane or heterodimers with other receptors in the family (e.g., erbB2, erbB3, and erbB4). The formation of these dimers triggers phosphorylation of key tyrosine residues in EGFR, thereby activating multiple downstream signaling pathways within the cell. These intracellular signaling pathways play important roles in cell proliferation, survival, and anti-apoptosis. Disruptions to the EGFR signaling pathway (including increased expression of the ligand and receptor, and amplification and alterations (e.g., mutations, deletions, etc.) of the EGFR gene) promote cellular malignant transformation and play an important role in tumor cell proliferation, invasion, metastasis, and angiogenesis. For example, alterations such as mutations and deletions in the EGFR gene are observed in non-small cell lung cancer (NSCLC) tumors. The two most frequently observed EGFR alterations in NSCLC tumors are a short in-frame deletion (del19) in exon 19 and a single missense mutation L858R in exon 21 (Cancer Discovery 2016 6(6)601). These two mutations, called sensitizing mutations, cause ligand-independent EGFR activation and are referred to as primary or activating mutations in EGFR-mutant NSCLC (EGFR M+).Clinical experience has demonstrated that the objective response rate (ORR) in patients with EGFR M+ NSCLC treated with first-line (1L) EGFR tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, afatinib, and osimertinib is approximately 60–85% (Lancet Oncol. 2010 Vol. 11,121; Lancet Oncol. 2016 Vol. 17,577; N.Engl. J.Med. 2017 Nov 18 Doi:10.1056 / NEJMoa1713137; Lancet Oncol. 2011 Vol. 12,735). Thus, EGFR-mutant NSCLC tumors are dependent on oncogenic EGFR activity for survival and growth, establishing del19 and L858R mutant EGFR as tumorigenic drivers of the disease and thus identifying potential drug targets and biomarkers for the treatment of NSCLC.

[0003] Osimertinib is a third-generation covalent EGFR TKI currently approved as the first-line (1L) standard of care (SOC) for the treatment of NSCLC harboring del19 and L858R mutations. Its progression-free survival (PFS) was 18.9 months (JC Soria et al., NEJM, 2018 Jan;378(2):113-125), demonstrating transformative patient outcomes compared with first-generation TKIs. However, resistance has been observed in nearly all NSCLC patients after a median of 10–12 months of treatment (Lancet Oncol. 2010 Feb;11(2):121-8; Lancet Oncol. 2016 May;17(5):577-89; Lancet Oncol. 2011 Aug;12(8):735-42). Additional third-generation TKIs are currently being used in the frontline setting (e.g., lazertinib) and rely on the same covalent EGFR binding mechanism. The most prominent on-target resistance mechanism is a secondary mutation in EGFR, C797X (where "X" can be "S" or "G" or "N" or "Y" or "T" or "D"), which occurs in 7% to 22% of patients who progress on frontline third-generation EGFR inhibitors (Blakely, 2012; Kobayashi, 2005). This secondary C797S mutation reduces the affinity of the drug to its target, resulting in drug resistance and tumor recurrence or disease progression. The resulting "double-mutant" tumors, carrying the sensitizing mutation del19 or L858R and the resistance mutation C797X (e.g., C797S), are no longer sensitive to second- or third-generation TKIs. There are no approved drugs for treating double-mutant patients. First-generation TKIs (gefitinib and erlotinib) have activity against C797X (e.g., C797S), but are poorly tolerated due to activity associated with wild-type EGFR inhibition and do not control brain disease due to their poor ability to cross the blood-brain barrier (BBB).

[0004] There is an unmet need for selective therapeutic agents that treat double mutant tumors, are brain penetrant, treat brain disease, and have reduced toxicities (diarrhea, skin rash) associated with wild-type EGFR inhibition. Summary of the Invention

[0005] Applicants have discovered novel compounds that are effective inhibitors of specific mutant forms of EGFR (see Synthesis Examples 1-454 and 458-500). In particular, compounds of the present disclosure have been demonstrated to effectively inhibit specific mutant forms of EGFR. The compounds of the present disclosure (also referred to herein as "disclosed compounds"), or pharmaceutically acceptable salts thereof, effectively inhibit EGFRs with one or more alterations, including an L858R or exon 19 deletion mutation and a C797X (e.g., C797S) mutation (hereinafter "EGFRs with LRCS mutations" or "double-mutated EGFRs") (see Biological Example 1) and can be used to treat various cancers, such as lung cancer (see Biological Example 2). Importantly, the disclosed compounds are selective EGFR inhibitors, i.e., they have no or reduced activity against wild-type EGFR and the kinome. Advantages associated with such selectivity may include facilitating effective dosing and reducing EGFR-mediated on-target toxicity. Some of the disclosed compounds exhibit good brain and blood-brain barrier penetration (e.g., PGP efflux ratios of less than 5). Therefore, the disclosed compounds, or pharmaceutically acceptable salts thereof, are expected to be effective in treating metastatic cancer (including brain metastases, including leptomeningeal disease, and other systemic metastases). Some of the disclosed compounds also have the advantage of high microsomal stability. Additionally, the disclosed compounds may have favorable toxicity profiles relative to other non-kinase targets.

[0006] In one embodiment, the present disclosure provides a compound having the following structural formula (A) or (I): [ka] or a pharmaceutically acceptable salt thereof (wherein the definition of each variable is provided below).

[0007] In another aspect, the present disclosure provides a pharmaceutical composition ("pharmaceutical composition of the present disclosure") comprising a pharmaceutically acceptable carrier or diluent and one or more of the compounds disclosed herein or pharmaceutically acceptable salts thereof.

[0008] The present disclosure provides a method for treating a subject with cancer, comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula (A) or (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In one embodiment, the cancer is non-small cell lung cancer. In another embodiment, the subject's cancer has metastasized to the brain. In another embodiment, the subject has brain metastasis from non-small cell lung cancer.

[0009] In one embodiment, the cancer to be treated has an epidermal growth factor receptor (EGFR) L858R mutation or an exon 19 deletion mutation. In another embodiment, the cancer to be treated may further have an epidermal growth factor receptor (EGFR) L858R mutation or an exon 19 deletion mutation and a C797X (e.g., C797S) mutation. In another embodiment, the cancer to be treated in any of the foregoing embodiments is lung cancer, such as non-small cell lung cancer. In a specific embodiment, the cancer is non-small cell lung cancer with brain metastasis or leptomeningeal disease.

[0010] The methods of treatment disclosed herein further include administering to a subject an effective amount of an EGFR inhibitor (e.g., afatinib and / or osimertinib) and a MET inhibitor, in combination with an effective amount of a compound of the present disclosure.

[0011] The present disclosure also provides a method for inhibiting epidermal growth factor receptor (EGFR) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula (A) or (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0012] The present disclosure also provides use of an effective amount of a compound of the present disclosure (e.g., a compound of Formula (A) or (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, to prepare a medicament for the treatment of cancer.

[0013] In another aspect, provided herein is a compound of Formula (A) or (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure, for use in the treatment of cancer. DETAILED DESCRIPTION OF THE INVENTION

[0014] definition The term "halo," as used herein, means halogen and includes chloro, fluoro, bromo, and iodo.

[0015] The term "alkyl," used alone or as part of a larger moiety, e.g., "alkoxy," refers to a saturated aliphatic, straight-chain or branched, monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 6 carbon atoms, i.e., (C1-C6) alkyl. As used herein, a "(C1-C6) alkyl" group refers to a radical having 1 to 6 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, isopropyl, and the like.

[0016] "Haloalkyl" or "C 1-4 The term "haloalkyl" refers to an alkyl group in which at least one of the hydrogen atoms is replaced by a halo atom. 1-4 The haloalkyl group is a monohalo-C 1-4 Alkyl, dihalo-C 1-4 Alkyl, or polyhalo-C 1-4 Alkyl (perhalo-C 1-4 (including alkyl). 1-4 The alkyl may have one iodo, bromo, chloro, or fluoro within the alkyl group. 1-4 Alkyl and polyhalo-C 1-4The alkyl group may have two or more of the same halo atoms or a combination of different halo groups within the alkyl group. Typically, polyhalo-C 1-4 The alkyl group may contain up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. 1-4 Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. 1-4 Alkyl groups are C groups in which all hydrogen atoms have been replaced by halo atoms. 1-4 Refers to an alkyl group.

[0017] The term "alkoxy" refers to an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0018] The term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic saturated hydrocarbon ring system. Cycloalkyls can include fused and / or bridged rings and / or spirocyclic rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyls also include spirocyclic rings (e.g., spirocyclic bicycles in which two rings share one ring atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. Unless otherwise specified, cycloalkyls have 3 to 12 carbon atoms. For example, C 3- C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, a "cycloalkyl" has from 3 to 6 carbon atoms.

[0019] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 4- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone ("4- to 12-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 4- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 (typically 1 to 2) ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("4- to 8-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence allows. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a bicyclic system ("bicyclic heterocyclyl") or a tricyclic system ("tricyclic heterocyclyl")). Polycyclic ring systems include fused, bridged, or spiro ring systems. When a heterocyclyl group is a polycyclic ring system, the ring system contains at least one non-aromatic ring. Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems may contain heteroatoms in one or more rings of the polycyclic ring system, including polycyclic ring systems having a non-aromatic ring fused to a phenyl or heteroaryl ring. Exemplary polycyclic heterocyclic groups include 2H-benzo[b][1,4]oxazin-3(4H)-onyl, isoindolin-1-onyl, isoquinolin-1(2H)-onyl, 3-oxabicyclo[3.1.0]hexanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, tetrahydropyrazolo[1,5-a]pyridinyl, and the like. Substituents may be present on one or more rings in the polycyclic ring system.

[0020] "Heteroaryl" refers to a radical of a 4- to 12-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5- or 6-membered heteroaryl having ring carbon atoms and 1 to 4 ring heteroatoms (typically 1 to 2). Representative heteroaryl groups include ring systems in which each ring contains a heteroatom and is aromatic, such as imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenylpyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.

[0021] Bridged bicyclic systems have two non-aromatic rings (heterocyclyl or cycloalkyl) containing 5 to 12 ring atoms, which share three or more ring atoms, and the two bridgehead ring atoms are separated by a bridge containing at least one atom. "Bridged heterocyclyl" includes bicyclic or polycyclic hydrocarbon or aza-bridged hydrocarbon groups, such as bicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.2.1]octanyl, 6-oxa-2-azabicyclo[3.2.1]octanyl, 6-oxa-3-azabicyclo[3.2.1]octanyl, and 8-oxa-3-azabicyclo[3.2.1]octanyl.

[0022] Fused bicyclic ring systems have two rings containing 6 to 12 ring atoms, which share two adjacent ring atoms. When the fused bicyclic ring system is a heterocyclyl, at least one of the rings is non-aromatic. Examples of fused bicyclic ring systems include hexahydro-1H-furo[3,4-b]pyrrolyl and hexahydro-1H-furo[3,4-c]pyrrolyl.

[0023] Spiro bicyclic systems have two non-aromatic rings (heterocyclyl or cycloalkyl) containing 7 to 12 ring atoms, which share one ring atom. Examples of spiro bicyclic systems include 1-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, and 1,4-dioxa-9-azaspiro[5.5]undecan-9-yl.

[0024] Compounds of the Disclosure Disclosed herein are embodiments of compounds having the general structure of Formula (A) or (I). These compounds are selective inhibitors of L858R, Ex19del, L858RC797S, and Ex19DelC797S EGFR. Unlike other EGFR inhibitors, such as osimertinib, which bind irreversibly to EGFR, the compounds of the present disclosure are non-covalent inhibitors.

[0025] In a first embodiment, the present disclosure provides a compound of the following structural formula (A): [ka] or a pharmaceutically acceptable salt thereof, wherein X is CR x or N, R x is H or F, L 1 is the bond, NH, -NHC(O)- * , -NHC(O)O- * , O, or -OC(O)- * (where - * is R 1 represents the point where L 2 is a bond or O, R 1 is H, or Halo, Deuterium, OR a , N.R. a R b, C1-C4 alkyl optionally substituted with 1 to 4 groups independently selected from C3-C6 cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein heterocyclyl and heteroaryl are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium, and C1-C4 alkyl; or C3-C8 cycloalkyl, phenyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl (R 1 The cycloalkyl, phenyl, heterocyclyl, and heteroaryl represented by R 11 and optionally substituted with 1 to 4 groups independently selected from Each R 11 Halo, deuterium, OR a , C(O)R a , C(O)NR a R b , N.R. a C(O)OR a , N.R. a R b , S(O)2R a , C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, 4-12 membered heterocyclyl, and 5-12 membered heteroaryl (R 11 The alkyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl represented by the formula (I) are each selected from deuterium, halo, C1-C4 alkyl, OR a , and NR a R b and optionally substituted with 1 to 4 groups selected from: 11 are united to form =O, R 2 teeth, H, C1-C4 alkyl, C3-C8 cycloalkyl, C2-C4 alkenyl, or C2-C4 alkynyl (each of which is substituted with halo, deuterium, OR a , N.R. a R band 4- to 12-membered heterocyclyl optionally substituted with 1-4 groups independently selected from halo, deuterium, and C1-C4 alkyl), or 4-12 membered heterocyclyl or 5-12 membered heteroaryl (R 2 Heterocyclyl and heteroaryl represented by the formula (I) are each selected from deuterium, C1-C4 alkyl, C(O)R a and 4- to 12-membered heterocyclyl optionally substituted with 1-4 groups selected from halo, deuterium, and C1-C4 alkyl; R 3 is bonded to any nitrogen atom in the pyrazole ring and is selected from H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocyclyl (R 3 The alkyl, cycloalkyl, and heterocyclyl represented by each of the following are optionally substituted with halo, deuterium, OR a , N.R. a R b and C-C cycloalkyl), Each R 4 Halo, deuterium, and OR a are independently selected from R 5 H, deuterium, halo, and halo, deuterium, OR a , N.R. a R b , C1-C4 alkyl optionally substituted with 1 to 4 groups independently selected from C3-C6 cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein heterocyclyl and heteroaryl are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium, and C1-C4 alkyl; Each R a are independently selected from H, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocyclyl; Each R b are independently selected from H, deuterium, and C1-C4 alkyl; n is 0, 1, 2, 3, 4 or 5.

[0026] In a second embodiment, the compound according to structural formula (A) is selected from the group consisting of (B) and (C): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first embodiment.

[0027] In a third embodiment, the present disclosure provides compounds according to structural formula (A), (B), or (C), or a pharmaceutically acceptable salt thereof, wherein L 1 and L 2 If each of is a bond, then R 1 is H and R 2 is not H, and the remaining variables are as defined in the first embodiment.

[0028] In a fourth embodiment, the present disclosure provides compounds according to structural formula (A), (B), or (C), or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C4 alkyl, C3-C8 cycloalkyl, C2-C4 alkenyl, or C2-C4 alkynyl (each of which is substituted with halo, deuterium, OR a , N.R. a R b and 4- to 12-membered heterocyclyl optionally substituted with 1-4 groups independently selected from halo, deuterium, and C1-C4 alkyl), or 4- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl (R 2 Heterocyclyl and heteroaryl represented by the formula (I) are each selected from deuterium, C1-C4 alkyl, C(O)R a and 4-12 membered heterocyclyl optionally substituted with 1-4 groups selected from halo, deuterium, and C1-C4 alkyl), and the remainder of the variables are as defined in the first or third embodiment.

[0029] In a fifth embodiment, the present disclosure provides a compound according to structural formula (A), (B), or (C), or a pharmaceutically acceptable salt thereof, wherein R 5 is H, F, or methyl, and the remaining variables are as defined in the first, third, or fourth embodiment.

[0030] In a sixth embodiment, the present disclosure provides a compound of the following structural formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein X is CR x or N, R x is H or F, L 1 is the bond, NH, -NHC(O)- * , -NHC(O)O- * , O, or -OC(O)- * (where - * is R 1 represents the point where L 2 is a bond or O, R 1 is H, or Halo, Deuterium, OR a , N.R. a R b , C1-C4 alkyl optionally substituted with 1 to 4 groups independently selected from C3-C6 cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein heterocyclyl and heteroaryl are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium, and C1-C4 alkyl; or C3-C8 cycloalkyl, phenyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl (R 1 The cycloalkyl, phenyl, heterocyclyl, and heteroaryl represented by R 11and optionally substituted with 1 to 4 groups independently selected from Each R 11 Halo, deuterium, OR a , C(O)R a , C(O)NR a R b , N.R. a C(O)OR a , N.R. a R b , S(O)2R a , C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, 4-12 membered heterocyclyl, and 5-12 membered heteroaryl (R 11 The alkyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl represented by the formula (I) are each selected from deuterium, halo, C1-C4 alkyl, OR a , and NR a R b and optionally substituted with 1 to 4 groups selected from: 11 are united to form =O, R 2 teeth, C1-C4 alkyl, C3-C8 cycloalkyl, C2-C4 alkenyl, or C2-C4 alkynyl (each of which may be substituted with halo, deuterium, OR a , N.R. a R b and 4- to 12-membered heterocyclyl optionally substituted with 1-4 groups independently selected from halo, deuterium, and C1-C4 alkyl), or 4-12 membered heterocyclyl or 5-12 membered heteroaryl (R 2 Heterocyclyl and heteroaryl represented by the formula (I) are each selected from deuterium, C1-C4 alkyl, C(O)R a and 4- to 12-membered heterocyclyl optionally substituted with 1-4 groups selected from halo, deuterium, and C1-C4 alkyl; R 3is H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclyl (R 3 The alkyl, cycloalkyl, and heterocyclyl represented by each of the following are optionally substituted with halo, deuterium, OR a , N.R. a R b and C-C cycloalkyl), Each R 4 Halo, deuterium, and OR a are independently selected from Each R a are independently selected from H, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocyclyl; Each R b are independently selected from H, deuterium, and C1-C4 alkyl; n is 0, 1, 2, 3, 4, or 5. Alternatively, the variables in Structural Formula (I) are as defined in the first, third, or fourth embodiment.

[0031] In a seventh embodiment, the compound according to structural formula (I) is represented by structural formula (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), or (II-12): [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first, third, fourth, or sixth embodiment.

[0032] In an eighth embodiment, the compound of Formula (I) has structural formula (II-1a), (II-3a), (II-3b), (II-4a), (II-5a), (II-7a), (II-7b), (II-8a), (II-9a), (II-9b), (II-11a), (II-11b), or (II-12a): [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first, third, fourth, or sixth embodiment.

[0033] In a ninth embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R x is H, and the remaining variables are as defined in the first, third, fourth, fifth, or sixth embodiment.

[0034] In a tenth embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R1 is H, or halo, OR a , N.R. a R b , C 3- C1-C3 alkyl optionally substituted with 1 to 2 groups independently selected from C5 cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein heterocyclyl and heteroaryl are each optionally substituted with 1 to 2 groups independently selected from halo and -CH3, or C 3- C cycloalkyl, phenyl, 4- to 9-membered heterocyclyl, or 5- to 10-membered heteroaryl (R 1 The cycloalkyl, phenyl, heterocyclyl, and heteroaryl in the group represented by 11 and optionally substituted with 1 to 3 groups independently selected from a are independently H or -CH3, and each R b is —CH 3 , and the remainder of the variables are as defined in the first, third, fourth, fifth, sixth, or ninth embodiment.

[0035] In an eleventh embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 1 is H or R 1is selected from -CH3, -CH2CH3, -CH2CH3CH3, and -CH(CH3)2, each of which is optionally substituted with 1 to 3 groups selected from F, -OH, -OCH3, -N(CH3)2, cyclopropyl, morpholinyl, oxadiazolyl, oxetanyl, oxazolyl, pyridinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, and triazolyl, and pyridinyl, thiadiazolyl, thiazolyl, and triazolyl are each optionally substituted with F, -CH3, or -CH2CH3; or R 1 are azabicyclo[3.1.0]hexanyl, azetidinyl, 1H-benzo[d]imidazolyl, bicyclo[1.1.1]pentanyl, cubanyl, cyclobutyl, cyclopropyl, dihydroisoquinolinyl, dihydropyrrolyl, dihydro-2H-benzo[b][1,4]oxazinyl, dioxepanyl, hexahydro-1H-pyrrolidinyl, imidazolidinyl, indazolyl, isoindolinyl, isothiazolyl, morpholinyl, octahydropyrrolyl, oxa[1,2-a]pyrazinyl, oxabicyclo[3.1.0]hexanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, oxabicyclo[3.3]heptanyl, 7-oxa-4-azaspiro[2.5]octanyl, oxetanyl, phenyl, piperidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolopyridinyl, tetrahydrofuranyl, tetrahydropyranyl, and thiazolyl (each of which is R 11 and optionally substituted with 1 to 3 groups independently selected from:

[0036] In a twelfth embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 1 is H, -CH3, -CH2(R 11 ), -CH(R 11 )2, -CH2CH3, -CH(R 11 )-CH3, -CH(CH3)2, -C(CH3)2-R 11 , -CH2CH2CH2-R 11 , -CH(CH3)CH2-R 11 , [ka] [ka] [ka] and the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, or eleventh embodiment.

[0037] In a thirteenth embodiment, the present disclosure provides a compound according to structural formula (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein each R 11 Ha, Hello, ORa , C(O)R a , C(O)NR a R b , N.R. a C(O)OR a , N.R. a R b , C1-C4 alkyl, C3-C6 cycloalkyl, 4-12 membered heterocyclyl, and 5-12 membered heteroaryl (R 11 The alkyl, cycloalkyl, heterocyclyl, and heteroaryl represented by the formula (I) are each optionally substituted with deuterium, halo, OR a , and NR a R b and optionally substituted with 1 to 3 groups selected from the group consisting of: 11 are united to form =O, and each R a is independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocyclyl; and each R b are independently selected from H and C1-C4 alkyl, and the remainder of the variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, or twelfth embodiment.

[0038] In a fourteenth embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein each R 11 Ha, Hello, OR a , C(O)R a , C(O)NR a R b , N.R. a C(O)OR a , N.R. a R b , C1- C3 alkyl, morpholinyl, oxazolyl, oxadiazolyl, oxetanyl, pyridinyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl, and thiazolyl (R 11 Alkyl, morpholinyl, oxazolyl, oxadiazolyl, oxetanyl, pyridinyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl, and thiazolyl each represented by the formula: a , and NR a R b and optionally substituted with 1 to 3 groups selected from the group consisting of: 11 are united to form =O, and each R a is H, -CH3, -CH2CH3, -C(CH3)3, [ka] are independently selected from b is independently H or —CH3, and the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0039] In a fifteenth embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein each R 11is Cl, F, -OH, -OCH3, -C(O)CH2CH3, -N(CH3)2, -NHC(O)OC(CH3)3, -CH3, -CD3, -CHF2, -CF3, -CH2 OH, -CH2OCH3, -CH2-N(CH3)2, -CH2CH3, -CH2CF3, -CH2CH2-N(CH3)2, -CH(CH3)2, -C(CH3)2-OH, [ka] or two R attached to the same carbon atom 11 together form =0, and the remainder of the variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.

[0040] In a sixteenth embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein L 2 is O, and the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment.

[0041] In a seventeenth embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C4 alkyl, C3-C8 cycloalkyl, C2-C4 alkenyl, or C2-C4 alkynyl (each of which is optionally substituted with halo, OR a , N.R. a R b and 4- to 12-membered heterocyclyl), or 4- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl (R 2 Heterocyclyl and heteroaryl represented by the formula (I) are each C1-C4 alkyl, C(O)R a and 4- to 12-membered heterocyclyl optionally substituted with 1-3 groups selected from halo and C1-C4 alkyl, and each R a are independently selected from H and C1-C4 alkyl, and each R b are independently selected from H and C1-C4 alkyl, and the remainder of the variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment.

[0042] In an eighteenth embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C3 alkyl, C3-C5 cycloalkyl, or C 3- C4 alkynyl (each of which is halo, OR a , N.R. a R b and 4- to 6-membered heterocyclyl), or 5- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl (R 2 Heterocyclyl and heteroaryl in the group represented by the formula (I) are each C1-C2 alkyl, C(O)R a and 6-membered heterocyclyl optionally substituted with C1-C2 alkyl), and each R a are independently selected from H and —CH3, and each R b is —CH3, and the remainder of the variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment.

[0043] In a nineteenth embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 2 is -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, or [ka] (each of which is optionally substituted with F, —OCH3, —N(CH3)2, morpholinyl, or oxetanyl), or R 2 is diazaspiro[3.3]heptanyl, pyrazolyl, pyrimidinyl, or tetrahydrofuranyl (each of which is optionally substituted with C-C alkyl, C(O)C-C alkyl, or piperidinyl, which is optionally substituted with —CH), and the remainder of the variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment.

[0044] In a twentieth embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 2are -CH3, -CHF2, -CH2CH3, -CH2CH2-OCH3, -CH2CH2-N(CH3)2, -CH(CH3)2, cyclopropyl, [ka] or R 2 teeth, [ka] (These are -CH3, C(O)CH3, or [ka] and optionally substituted with ), and the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth embodiment.

[0045] In a twenty-first embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 3 is H, C1-C4 alkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclyl (R 3 The alkyl, cycloalkyl, and heterocyclyl represented by each of the following are optionally substituted with halo, deuterium, OR a , N.R. a R b , and C 3- and optionally substituted with 1 to 3 groups independently selected from C cycloalkyl, a is independently H or C1-C4 alkyl, and each R bis independently H or C1-C4 alkyl, and the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0046] In a twenty-second embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 3 is H, cyclopropyl, oxetanyl, tetrahydropyranyl, or C1-C3 alkyl optionally substituted with 1 to 3 groups independently selected from halo, deuterium, OH, N(CH3)2, and cyclopropyl, and the remainder of the variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment.

[0047] In a twenty-third embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 3is H, -CH3, -CHF2, -CD3, -CH2CH3, -CH2CHF2, -CH2CF3, -CH2CH2-OH, -CH2CH2-N(CH3)2, -CH2CH3CH3, -CH(CH3)2, [ka] and the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment.

[0048] In a twenty-fourth embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein each R 4 is halo OR a and each R a are independently selected from H and C1-C4 alkyl; n is 0, 1, 2, or 3; and the remainder of the variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment.

[0049] In a twenty-fifth embodiment, the present disclosure provides a compound represented by structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10) , (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein n is 0 and the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth embodiment.

[0050] In a twenty-sixth embodiment, the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), or (II-12a), or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2; and each R 4 are independently selected from F and OH, and the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, or twenty-fifth embodiment.

[0051] In a 27th embodiment, the compound of Formula (I) has structural formula (II-3c) or (II-3b): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first, third, fourth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment.

[0052] In a twenty-eighth embodiment, the compound of formula (I) has structural formula (II-7a) or (II-7b): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first, third, fourth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment.

[0053] In a twenty-ninth embodiment, the present disclosure provides a compound according to structural formula (II-3c), (II-3b), (II-7a), or (II-7b), or a pharmaceutically acceptable salt thereof, wherein R 1 is C1-C4 alkyl optionally substituted with 5-10 membered heteroaryl (5-10 membered heteroaryl optionally substituted with C1-C2 alkyl), or C3-C8 cycloalkyl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl (R 1 The cycloalkyl, heterocyclyl, and heteroaryl represented by each are R 11 and optionally substituted with 1 to 3 groups independently selected from 11 Ha, Halo, NR a R b , C-C cycloalkyl, and C-C alkyl optionally substituted with 1 to 3 halo; a are independently selected from H and C1-C4 alkyl; R 2 and R 3 are each independently C1-C4 alkyl, and R 4is halo, n is 0, 1, or 2, and the remainder of the variables are as defined in the first, third, fourth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment.

[0054] In a thirtieth embodiment, the present disclosure provides a compound according to structural formula (II-3c), (II-3b), (II-7a), or (II-7b), or a pharmaceutically acceptable salt thereof, wherein R 1 is C1-C2 alkyl optionally substituted with a 5-membered heteroaryl (5-membered heteroaryl optionally substituted with C1-C2 alkyl), or C3-C5 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl (R 1 The cycloalkyl, heterocyclyl, and heteroaryl represented by each are R 11 and optionally substituted with 1 to 2 groups independently selected from 11 are independently selected from halo, N(CH3)2, C3-C5 cycloalkyl, and C1-C2 alkyl optionally substituted with 1 to 3 halo; R 2 and R 3 are each independently C1-C2 alkyl, and R 4 is halo, n is 0, 1, or 2, and the remainder of the variables are as defined in the first, third, fourth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, or twenty-ninth embodiment.

[0055] In a thirty-first embodiment, the present disclosure provides a compound according to structural formula (II-3c), (II-3b), (II-7a), or (II-7b), or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH2CH3 substituted with oxadiazolyl optionally substituted with -CH3, or R 1are azabicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cyclopropyl, 3-oxabicyclo[3.1.0]hexanyl, piperidinyl, pyrazolyl, and pyridinyl (each of which is R 11 and each R is optionally substituted with 1 to 2 groups independently selected from 11 are F, -N(CH3)2, -CH3, -CF3, [ka] and the remaining variables are as defined in the first, third, fourth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-ninth, or thirtieth embodiment.

[0056] In a thirty-second embodiment, the present disclosure provides a compound according to structural formula (II-3c), (II-3b), (II-7a), or (II-7b), or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] Each R 11 are F, -N(CH3)2, -CH3, -CF3, [ka] and the remaining variables are as defined in the first, third, fourth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-ninth, thirtieth, or thirty-first embodiment.

[0057] In a thirty-third embodiment, the present disclosure provides a compound according to structural formula (II-3c), (II-3b), (II-7a), or (II-7b), or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C4 alkyl, and R 3is C1-C4 alkyl, and each R 4 is independently halo, n is 0, 1, or 2, and the remainder of the variables are as defined in the first, third, fourth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-ninth, thirty-first, or thirty-second embodiment.

[0058] In a thirty-fourth embodiment, the present disclosure provides a compound according to structural formula (II-3c), (II-3b), (II-7a), or (II-7b), or a pharmaceutically acceptable salt thereof, wherein R 2 is -CH3 or -CH2CH3, and R 3 is -CH3 and R 4 is F, n is 0 or 1, and the remaining variables are as defined in the first, third, fourth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-ninth, thirty-first, thirty-second, or thirty-third embodiment.

[0059] In a thirty-fifth embodiment, the compound of formula (I) has the following structural formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first, third, fourth, sixth, ninth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, thirty-third, and thirty-fourth embodiments.

[0060] In a thirty-sixth embodiment, the compound of formula (I) has the following structural formula (III-1) or (III-2): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first, third, fourth, sixth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, thirty-third, and thirty-fourth embodiments.

[0061] In a thirty-seventh embodiment, the present disclosure provides a compound according to structural formula (III), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein L 2 is a bond, and the remaining variables are as defined in the first, third, fourth, sixth, ninth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, thirty-third, and thirty-fourth embodiments.

[0062] In a 38th embodiment, the compound of the present disclosure is any one of the compounds disclosed in the Examples (including neutral forms, pharmaceutically acceptable salts, and intermediates) and Table 1, or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

[0063] In one embodiment, the compounds of Examples 455-457 and 458A in Table 3, and pharmaceutically acceptable salts thereof, are excluded from the present disclosure.

[0064] In some embodiments, the present disclosure provides compounds represented by Structural Formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-3c), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12), (II-12a), (III), (III-1), or (III-2), or any one of the compounds disclosed in the Examples (including intermediates) and Table 1, or a pharmaceutically acceptable salt thereof.

[0065] The term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic reaction, within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in J.Pharm.Sci., 1977, 66, 1-19.

[0066] The present teachings include pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and salts of organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds of the present teachings having an acidic group, such as a carboxylic acid, can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts), and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0067] Compounds with one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration, or a mixture of both. Stereoisomers are compounds that differ only in spatial configuration. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers that have two or more non-identical chiral centers and are not mirror images of each other.

[0068] When the stereochemical configuration at a chiral center of a compound having one or more chiral centers is represented by its chemical name (e.g., when the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., when the configuration is indicated by a "wedge" bond), the stereoisomeric purity of the named or represented stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0069] When a disclosed compound having a chiral center is represented by a structure that does not indicate the configuration at that chiral center, the structure is meant to encompass compounds having the S configuration at that chiral center, compounds having the R configuration at that chiral center, or compounds having a mixture of R and S configurations at that chiral center. When a disclosed compound having a chiral center is represented by its chemical name without indicating the configuration at that chiral center with "S" or "R," the name is meant to encompass compounds having the S configuration at that chiral center, compounds having the R configuration at that chiral center, or compounds having a mixture of R and S configurations at that chiral center.

[0070] When two stereoisomers are represented by chemical names or structures and the names or structures are connected by "or," either one or the other of the two stereoisomers is intended, but not both.

[0071] A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically pure, enantiomerically enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, as well as diastereomeric mixtures, of the compounds disclosed herein.

[0072] Enantiomeric and diastereomeric mixtures can be separated into their component enantiomers or stereoisomers by well-known methods such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallizing the compounds as chiral salt complexes, or crystallizing the compounds in chiral solvents. Enantiomers and diastereomers can also be obtained by well-known asymmetric synthetic methods from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts.

[0073] In the experimental section, "first eluting compound" or "Peak 1" refers to an intended reaction product compound from a chromatographic separation / purification that elutes earlier than a second intended reaction product compound from the same preceding reaction. The second intended reaction product compound is referred to as the "second eluting compound" or "Peak 2."

[0074] In compounds of the present disclosure, positions specifically designated as "D" or "deuterium" are understood to have a deuterium enrichment of 50, 80, 90, 95, 98, or 99%. "Deuterium enrichment" is a molar percentage and is determined by dividing the number of compounds with deuterium at the indicated position by the total number of all compounds. When a position is designated as "H" or "hydrogen," hydrogen is present at that position at its natural abundance. When the presence or absence of hydrogen or deuterium at a position is not specified, hydrogen is present at that position at its natural abundance. One specific alternative embodiment relates to compounds of the present disclosure having a deuterium enrichment of at least 5, 10, 25, 50, 80, 90, 95, 98, or 99% at one or more positions not specifically designated as "D" or "deuterium."

[0075] As used herein, many components (e.g., alkyl, alkoxy, cycloalkyl, or heterocyclyl) are referred to as "substituted" or "optionally substituted." When a component is modified by one of these terms, this means that, unless otherwise noted, any portion of the component known to those of skill in the art to be available for substitution, including one or more substituents, can be substituted. When multiple substituents are present, each substituent can be independently selected. Such substitution means are well known in the art and / or taught by this disclosure. An optional substituent can be any suitable substituent for attachment to that component.

[0076] The compounds of the present disclosure are selective EGFR inhibitors. As used herein, the term "selective EGFR inhibitor" refers to a compound that selectively inhibits a specific mutant EGFR kinase over wild-type EGFR and the kinome. In other words, a selective EGFR inhibitor has no or low activity against wild-type EGFR and the kinome. The inhibitory activity of a selective EGFR inhibitor against a specific mutant EGFR kinase is measured by an IC2000 or higher when compared to the inhibitory activity against wild-type EGFR and many other kinases. 50 more powerful in terms of value (i.e., IC 50 (Values ​​are subnanomolar.) Potency can be measured using known biochemical assays.

[0077] Some compounds of the present disclosure have the advantage of good brain permeability. The ability of a particular compound to penetrate the brain through the BBB can be evaluated using various known methods or a combination of such methods. One frequently used in vitro method to predict a compound's in vivo brain permeability is the P-gp efflux ratio. P-glycoprotein (P-gp) is expressed at the blood-brain barrier (BBB) ​​and limits the permeability of its substrates into the central nervous system (CNS). Compounds that are found to be good P-gp substrates in vitro (i.e., have a high efflux ratio) are predicted to have poor in vivo brain permeability. To measure the P-gp efflux ratio, the apparent apical-to-basolateral permeability (Papp[AB]) and apparent basolateral-to-apical permeability (Papp[BA]) of a compound are quantified in Madin-Darby canine kidney cells (MDCK-MDR1 cells) overexpressing P-gp. The P-gp efflux ratio is a measure of the ratio of Papp[BA] / Papp[AB]. In some embodiments, compounds of the present disclosure have a P-gp efflux ratio of less than 2, less than 3, less than 4, or less than 5.

[0078] Some compounds of the present disclosure have the advantage of good metabolic stability. One indicator of good metabolic stability is high microsomal stability. The main excretion pathway for small molecule drugs is hepatic metabolism. Compound clearance by hepatic metabolism can be assessed in vitro using human liver microsomes (HLM) or human hepatocytes. The in vitro intrinsic clearance (Clint) is determined by incubating the compound with HLM or human hepatocytes supplemented with appropriate cofactors and measuring the compound depletion. The hepatic extraction ratio (ER) is determined by scaling Clint to the total body clearance (CL) and dividing CL by the standard human hepatic blood flow. Compounds with low hepatic extraction ratios are considered to have good metabolic stability. In some embodiments, compounds of the present disclosure have a calculated ER of less than 0.3, less than 0.4, less than 0.5, or less than 0.6.

[0079] Pharmaceutical Composition Pharmaceutical compositions of the present disclosure (also referred to herein as "disclosed pharmaceutical compositions") comprise one or more pharmaceutically acceptable carrier(s) or diluent(s) and a compound of the present disclosure (e.g., a compound of Formula (A) or (I)) or a pharmaceutically acceptable salt thereof.

[0080] "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to substances that aid in the formulation of an active agent and / or its administration to and / or absorption by a subject, and can be included in the pharmaceutical compositions of the present disclosure without causing significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidine, dyes, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents that do not adversely react with or interfere with the activity of the compounds provided herein. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds, or pharmaceutically acceptable salts thereof.

[0081] Pharmaceutical compositions of the present disclosure optionally include one or more pharmaceutically acceptable carriers and / or diluents therefor, such as lactose, starch, cellulose, and dextrose. Other excipients may also be included, such as flavoring agents, sweeteners, and preservatives, such as methylparaben, ethylparaben, propylparaben, and butylparaben. A more comprehensive list of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 thEd., Pharmaceutical Press (2005). Those skilled in the art will know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences (2003-20th edition) and The United States Pharmacopeia: The National Formulary, published in 1999 (USP 24 NF19). A carrier, diluent, and / or excipient is "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0082] Treatment method The present disclosure provides a method for inhibiting a specific mutant form of epidermal growth factor receptor (EGFR) in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. Mutant forms of EGFR include, for example, EGFR with an LRCS mutation (exon 19 deletion (del19) or exon 21 (L858R) substitution mutation, and a C797X (e.g., C797S) mutation). A subject "in need of EGFR inhibition" is one who has a disease in which inhibition of at least one mutant EGFR can achieve a beneficial therapeutic effect, such as slowing disease progression, alleviating one or more symptoms associated with the disease, or extending the subject's lifespan given the disease.

[0083] In some embodiments, the present disclosure provides a method of treating a disease / condition / cancer associated with or modulated by mutant EGFR, where inhibition of mutant EGFR has a therapeutic benefit, including but not limited to, treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0084] In another embodiment, the present disclosure provides a method for treating a subject with cancer, comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. Cancers that can be treated according to the disclosed methods include lung cancer, colon cancer, urothelial cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, gastric cancer, pancreatic cancer, head and neck cancer, bladder cancer, and mesothelioma, including metastases (particularly brain metastases) of all of the listed cancers. Typically, the cancer is characterized by one or more EGFR mutations described herein. In a specific embodiment, the cancer has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy. In a specific embodiment, the disease has progressed on or after first-line third-generation TKI therapy, such as osimertinib. In a specific embodiment, the cancer has not been previously treated.

[0085] In a specific embodiment, the cancer to be treated is lung cancer. In a more specific embodiment, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is locally advanced or metastatic NSCLC, NSCLC adenocarcinoma, NSCLC with squamous histology, and NSCLC with non-squamous histology. In another embodiment, the lung cancer is NSCLC adenocarcinoma. In another specific embodiment, the lung cancer (or non-small cell lung cancer) has metastasized to the brain.

[0086] In another embodiment, the disease / condition / or cancer associated with or modulated by mutant EGFR is characterized by an EGFR genotype selected from genotypes 1 to 36 according to the table below (del18 = exon 18 deletion, specifically, e.g., del E709_T710 insD; and del19 = exon 19 deletions, specifically, for example, delE746_A750 (most common), delE746_S752insV, del747_A750insP, delL747_P753insS, and delS752_I759; ex20ins - exon 20 insertions, specifically, for example, D761-E762insX, A763-Y764insX, Y764-V765insX, V765-M766insX, A767-S768insX, S768-D769insX, V769-D770insX, N771-P772insX, P772-H773insX, H773-V774insX, and V774-C775insX): [Table 2]

[0087] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR, including EGFR del19.

[0088] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR del19 C797S.

[0089] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 C797X (C797G or C797N or C797Y or C797T or C797D).

[0090] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 L792X (L792F, L792H, or L792Y).

[0091] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 G796R (G796S).

[0092] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 L792R (L792V or L792P).

[0093] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 L718Q (L718V).

[0094] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R.

[0095] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R C797S.

[0096] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R C797X (797G or C797N or C797Y or C797T or C797D).

[0097] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R L792X (L792F, L792H, or L792Y).

[0098] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R G796R (G796S).

[0099] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R L792R (L792V or L792P).

[0100] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR L858R L718Q (L718V).

[0101] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR, including EGFR del18.

[0102] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR containing EGFR G719X (G719A, G719S, G719C, G719R, G719D, or G719V).

[0103] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR containing EGFR E709X (E709K, E709H, or E709A).

[0104] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR containing EGFR E709X (E709K, E709H, or E709A) (G719A, G719S, G719C, G719D, G719R, or G719V).

[0105] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR G719X (G719A, G719S, G719C, G719D, G719R, or G719V) S768I.

[0106] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR that contains EGFR S768I.

[0107] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR containing EGFR ex20ins.

[0108] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR containing the EGFR ex20ins L718Q.

[0109] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR containing the EGFR exon C797S.

[0110] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR genotype selected from genotypes 1-36.

[0111] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to osimertinib.

[0112] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to afatinib.

[0113] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to dacomitinib.

[0114] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to lazertinib.

[0115] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to osimertinib and afatinib.

[0116] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to osimertinib and dacomitinib.

[0117] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to amivantamab.

[0118] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to amivantamab and lazertinib.

[0119] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to aumoretinib (formerly known as almonertinib).

[0120] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to olmutinib.

[0121] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to nazartinib.

[0122] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR mutation that confers resistance to avitinib.

[0123] Another embodiment is the treatment of a subject with metastatic NSCLC with tumors harboring an activating exon 19 deletion or an L858R EGFR mutation, G719X(A,S,C,D,R,V), S768I and L861Q, and resistance mutations disclosed herein, as detected by an approved molecular testing methodology.

[0124] Another embodiment is the disclosed compounds used in combination with a second or third generation TKI indicated for the treatment of subjects with metastatic NSCLC with tumors harboring a C797X mutation as detected by an approved test, and who have disease progression on or after one or two prior EGFR TKI therapies.

[0125] Another embodiment is the disclosed compounds for the treatment of subjects with metastatic NSCLC who have progressed with on-target EGFR-resistant disease on or after any EGFR TKI. In a specific embodiment, the disclosed compounds are used in combination with second- or third-generation TKIs indicated for the treatment of subjects with metastatic NSCLC.

[0126] Another embodiment is a disclosed compound for the treatment of subjects with metastatic EGFR C797X mutation-positive NSCLC as detected by an approved molecular test and who have progressed on or after first- or second-line osimertinib. In a specific embodiment, the disclosed compound is used in combination with a second- or third-generation TKI indicated for the treatment of subjects with metastatic NSCLC.

[0127] In certain embodiments, the deletions, mutations, and insertions disclosed herein are detected by an FDA-approved test.

[0128] One skilled in the art can readily determine whether a subject has a particular EGFR alteration, e.g., one or more of the mutations or deletions described herein, in their cells, cancer, gene, or gene product using a detection method selected from those known in the art, such as hybridization-based methods, amplification-based methods, microarray analysis, flow cytometry analysis, DNA sequencing, next-generation sequencing (NGS), primer extension, PCR, in situ hybridization, fluorescent in situ hybridization, dot blot, and Southern blot.

[0129] To detect one or more EGFR deletions and / or mutations, primary tumor samples, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and / or circulating exosomes may be collected from a subject. The sample is processed and nucleic acids are isolated using techniques known in the art, followed by sequencing using methods known in the art. The sequences are then mapped to individual exons, and a measure of transcriptional expression (e.g., RPKM, or reads per kilobase per million mapped reads) is quantified. Raw sequence and exon array data are available from sources such as TCGA, ICGC, and NCBI Gene Expression Omnibus (GEO). For a given sample, individual exon coordinates are annotated with gene identification information, and exons belonging to the kinase domain are flagged. Exon levels are then z-score normalized across all tumor samples.

[0130] The disclosed compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein can be used to treat subjects who have become refractory to treatment with one or more other EGFR inhibitors. "Refractory" means that the subject's cancer previously responded to the drug but has subsequently become poorly or completely unresponsive. In some embodiments, the subject has become refractory to one or more first-generation EGFR inhibitors, such as erlotinib, gefitinib, icotinib, or lapatinib. In some embodiments, the subject has become refractory to treatment with one or more second-generation EGFR inhibitors, such as afatinib, dacomitinib, poziotinib, or neratinib. In some embodiments, the subject has become refractory to treatment with one or more first-generation inhibitors and one or more second-generation inhibitors. In some embodiments, the subject has become refractory to treatment with one or more third-generation inhibitors, such as osimertinib, nazartinib, or avitinib. In one embodiment, the subject has become refractory to treatment with one or more first-generation EGFR inhibitors and one or more third-generation EGFR inhibitors. In some embodiments, the subject has become refractory to treatment with one or more second-generation EGFR inhibitors and one or more third-generation EGFR inhibitors. In some embodiments, the subject has become refractory to treatment with one or more first-generation inhibitors and one or more third-generation EGFR inhibitors.

[0131] combination The compounds of the present disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein may be used in combination with one or more additional pharmacologically active agents. For example, the present disclosure includes a method of treating a condition / disease / or cancer, comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of the present disclosure or a pharmaceutical composition thereof disclosed herein, in combination with an EGFR (or EGFR mutant) inhibitor such as afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02, alflutinib (AST 2818), aumoretinib (formerly known as almonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilliteritinib, icotinib, JND-3229, lazertinib, nazartinib (EGF 816), avitinib, PCC-0208027, resibertinib (BPI-7711), TQB3804, zolifertinib (AZ-3759), or DZD9008; an EGFR antibody, e.g., cetuximab, panitumumab, necitumumab, HLX07, JMT101; or a bispecific EGFR and MET antibody (e.g., amivantamab ((JNJ-61186372, JNJ-372)). When the disclosed compound or its pharmaceutically acceptable salt, or the pharmaceutical composition disclosed herein is used in combination with first-line therapy to treat cancer such as NSCLC, for example, a first-, second-, or third-generation EGFR inhibitor (i.e., as an initial treatment before the cancer becomes refractory) can prevent or delay the cancer from becoming refractory. Typically, the cancer is characterized by one of the EGFR genotypes described herein.

[0132] In one embodiment, the compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein may be administered in combination with a compound disclosed in International Application Publication No. WO2021 / 133809, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0133] In one embodiment, the compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is a compound presented below, i.e., (3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-ol, (3R,4S)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-ol, N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, N-(2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, N-(2-((3S,4R)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, N-(2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, (3S,4R)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropyl-2,6-naphthyridin-3-ylamino)pyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol, (3S,4R)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropyl-2,7-naphthyridin-3-ylamino)pyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol, 2-((3S,4R)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropylisoquinolin-3-ylamino)pyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol, (3S,4S)-5,5-difluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol, (3R,4R)-5,5-difluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol, (3S,4S)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropylisoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol, (3R,4R)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropylisoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol, It may be administered in combination with a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it.

[0134] Alternatively, the compounds of the present disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein may be used in combination with other anti-cancer agents that are not EGFR inhibitors, such as MEK (including mutant MEK) inhibitors (trametinib, cobimtetinib, binimetinib, selumetinib, refametinib); c-MET (including mutant c-Met) inhibitors (savolitinib, cabozantinib, foretinib, glumetinib, tepotinib) and MET antibodies (emibetuzumab, telisotuzumab vedotin (ABBV)). 339); mitotic kinase inhibitors (CDK4 / 6 inhibitors such as palbociclib, ribociclib, abemaciclib, GIT38, etc.); antiangiogenic agents such as bevacizumab and nintedanib; Bcl-2 inhibitors such as venetoclax, obatoclax, navitoclax, palcitoclax (APG-1252), and Mcl-1 inhibitors such as AZD-5991, AMG-176, and S-6 apoptosis inducers such as 4315; mTOR inhibitors, e.g., rapamycin, temsirolimus, everolimus, lidofololimus; RET inhibitors such as pralsetinib and selpercatinib, and PI3K inhibitors dactolisib (BEZ235), pictilisib (GDC-0941), LY294002, idelalisib (CAL-101); JAK inhibitors (e.g., AZD4205, itacitinib), Aurora A inhibitors (e.g., alisertib); BCR / ABL and / or Src family tyrosine kinase inhibitors (e.g., dasatinib); VEGF inhibitors (e.g., MP0250; ramucirumab); multikinase protein inhibitors (e.g., anlotinib, midostaurin); PARP inhibitors (e.g., niraparib); platinum therapy (e.g., cisplatin (CDDP), carboplatin (CBDCA), or nedaplatin (CDGP)); PD-L1 inhibitors (e.g., durvalumab (MEDI 4736)); HER2 / neu receptor inhibitors (e.g., trastuzumab); anti-HER2 or anti-HER3 antibody-drug conjugates (e.g., patritumab deruxtecan (U3-1402), trastuzumab emtansine); or immunogene therapy (e.g., Oncoplex).

[0135] A "subject" is a human in need of treatment.

[0136] Administration method and dosage form The exact amount of compound administered to provide an "effective amount" to a subject depends on the mode of administration, the type and severity of the cancer, and the subject's characteristics, such as overall health, age, sex, weight, and drug tolerance. One of ordinary skill in the art would be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, e.g., in combination with anti-cancer agents, the "effective amount" of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by one of ordinary skill in the art depending on the subject's condition, the type of condition(s) being treated, and the amount of compound of Formula (A) or (I) being used, for example, by following dosages reported in the literature and recommended in the Physician's Desk Reference (57th Ed., 2003).

[0137] "Treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, which includes partially or substantially achieving one or more of the following results: partially or substantially reducing the extent of the disease, condition, or cancer; alleviating or ameliorating clinical symptoms or indicators associated with the disease, condition, or cancer; delaying, inhibiting, or reducing the likelihood of progression of the disease, condition, or cancer; or reducing the likelihood of recurrence of the disease, condition, or cancer.

[0138] The term "effective amount" means an amount that, when administered to a subject, produces beneficial or desired results, including clinical results, such as inhibiting, suppressing, or reducing the symptoms of the condition being treated in the subject compared to a control. For example, a therapeutically effective amount can be provided in a unit dosage form (e.g., 0.1 mg to about 50 g per day, or 1 mg to about 5 grams per day, or 10 mg to 1 gram per day).

[0139] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that can be used to enable delivery of a composition to a site where a biological effect is desired. These methods include, but are not limited to, intra-articular (into a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon, and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0140] Furthermore, compounds of the present disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present disclosure can be co-administered with other therapeutic agents. As used herein, the terms "co-administration," "administered in combination with," and their grammatical equivalents are meant to encompass the administration of two or more therapeutic agents to a single subject and are intended to include treatment regimens in which these agents are administered by the same or different routes of administration or at the same or different times. In some embodiments, one or more compounds of the present disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present disclosure are co-administered with other agents. These terms encompass administering two or more agents to a subject so that both agents and / or their metabolites are present in the subject at the same time. This includes co-administration in separate compositions, administration at different times in separate compositions, and / or administration in a composition in which both agents are present. Thus, in some embodiments, a compound described herein and other agent(s) are administered in a single composition. In some embodiments, a compound described herein and other agent(s) are admixed in the composition.

[0141] The particular mode of administration and dosing regimen will be selected by the attending physician, taking into account the particulars of the case (e.g., the subject, the disease, the disease state involved, the particular treatment). Treatment may involve daily or multiple daily dosing, or less than daily (such as weekly or monthly), for a period of several days to several months, or even years. However, one of ordinary skill in the art will readily recognize appropriate and / or equivalent doses, having reference to the dosages of approved compositions for treating diseases using EGFR inhibitors disclosed as guidance.

[0142] As will be understood by those skilled in the art, the compounds of the present disclosure or their pharmaceutically acceptable salts can be administered to patients in various forms depending on the selected administration route.The compounds of the present teachings can be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, by patch, pump, or transdermal administration, and the pharmaceutical composition will be formulated accordingly.Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary, intrathecal, rectal, and topical administration modes.Parenteral administration can be performed by continuous infusion over a selected period of time.

[0143] The pharmaceutical composition of the present disclosure is formulated to be suitable for intended administration route.In one embodiment, the composition is formulated according to routine procedures as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans.In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0144] Typically, for oral therapeutic administration, the compounds of the present disclosure or pharmaceutically acceptable salts thereof may be formulated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0145] For parenteral administration, typically, a solution of the compound of the present disclosure or its pharmaceutically acceptable salt can be prepared in water, suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, and oils. These preparations contain preservatives to prevent the growth of microorganisms under normal storage and use conditions.

[0146] Typically, for injectable use, sterile aqueous solutions or dispersions of the compounds of the present disclosure and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion are suitable.

[0147] The compounds of the present disclosure can be prepared according to the following general synthetic methods.

[0148] General synthesis scheme According to the first process, L 1 Compounds of formula (I)(A) in which is a bond can be prepared from compounds of formulas (II), (III) and (IV) as illustrated by Scheme 1A.

[0149] [ka] Scheme 1A LG is a suitable leaving group, typically halo or triflate, preferably Cl or Br or triflate. Compounds of formula (I)(A) can be prepared by reacting compounds of formula (II) and R 1 MgBr can be prepared by Fe-catalyzed cross-coupling reaction with Grignard reagents in the presence of NMP as described in process step (a) by Munoz et al., Angew. Chem. Int. Ed. 2018, 57, 6496. Preferred conditions are to react compound (II) with R in THF at temperatures between 0 °C and room temperature (rt). 1 This involves reacting with MgBr, Fe(III) acetylacetone, and NMP.

[0150] Alternatively, the compound of formula (I)(A) may be a compound of formula (II) and R 1 From Sn(alkyl)3, process step (b) can be prepared by a palladium-catalyzed cross-coupling reaction, i.e., a Stille reaction, with a suitable alkyl or aryl stannane. Typical cross-coupling reaction conditions involve a palladium catalyst containing a suitable phosphine ligand in the presence of an inorganic base in a suitable aqueous solvent between room temperature and the reflux temperature of the reaction. Preferred conditions involve the reaction of a compound of formula (II) with R in the presence of a suitable catalyst such as Pd(PPh3)2Cl2, Pd(PPh3)4, in a suitable solvent such as dioxane at elevated temperatures, such as 90-100°C, optionally in the presence of an additive (typically LiCl). 1 Alternatively, the compound of formula (I)(A) can be prepared by reacting the compound of formula (II) with SnBu3. 1 BPin or R 1 B(OH) can be prepared according to process step (c) a palladium-catalyzed cross-coupling reaction such as the Suzuki reaction. Typical cross-coupling reaction conditions are: 1 BPin or R 1 B(OH)2 and a palladium catalyst containing a suitable phosphine ligand in the presence of an inorganic base in a suitable aqueous solvent between room temperature and the reflux temperature of the reaction. Preferred conditions include reaction of a compound of formula (II) and R with Xphos Pd G3, Pd(dppf)Cl2, Pd2(dppf)3Pd(PPh3)4, cataCXium A Pd G3 or PdCl2(Amphos)2 in the presence of a suitable base, such as K3PO4, KHCO3, K2CO3 or Cs2CO3, in a suitable solvent such as aqueous dioxane, DME or DMSO at 70-100°C. 1 BPin or R 1 This involves the reaction of B(OH)2.

[0151] Alternatively, R 1 Compounds of formula (I)(A) where R is C-C alkyl or C-C cycloalkyl substituted by OH can be prepared by the reaction of compounds of formula (II) and R 1 C(O)Ra or R 1 C(O) by process step (d). Preferred conditions are the reaction of a compound of formula (II) and R in the presence of a strong base such as n-BuLi in a suitable solvent such as THF at low temperature such as -78°C. 1 C(O)R a or R 1 This involves the reaction of C(O).

[0152] R 1 is alkyl, cycloalkyl, or heterocyclyl, and R 1’ is its unsaturated precursor, a compound of formula (III) can be prepared by reacting a compound of formula (II) and R 1’ H can be prepared from H by process step (e), a palladium-catalyzed cross-coupling reaction such as a Heck reaction. Preferred conditions include reacting a compound of formula (II) with R in the presence of a suitable palladium catalyst such as Pd(dppf)Cl or Pd(PPh) in the presence of a suitable base such as KCO or KPO at an elevated temperature such as 80° C. in a suitable solvent such as aqueous dioxane or THF. 1’ This includes reactions with H.

[0153] Compounds of formula (I)(A) can be prepared from compounds of formula (III) by process step (f) reduction reaction. Preferred conditions include reaction of compounds of formula (III) with a suitable reducing agent, such as NaCNBH3, in the presence of AcOH in a suitable alcoholic solvent, such as MeOH, at room temperature.

[0154] Alternatively, R 1 is heteroaryl, the compound of formula (I)(A) can be prepared by combining a compound of formula (II) and R 1 It can be prepared from H by process step (e) described above.

[0155] The compound of formula (IV) can be prepared by reacting a compound of formula (II) with R 1 It can be prepared from (BPin) by process step (c) previously described above. 1Compounds of formula (I)(A), where is a cycloalkyl group substituted with OH, can be prepared from compounds of formula (IV) by process step (g), oxidation reaction. Typical conditions include reaction of compounds of formula (IV) with a suitable oxidizing agent, such as NaBO, in a suitable solvent, such as aqueous THF, at about room temperature.

[0156] According to the second process, L 1 Compounds of formula (I)(A) in which is a bond can be prepared from compounds of formula (II), (V), (VI) and (VII) as illustrated by Scheme 1B.

[0157] [ka] Scheme 1B Compounds of formula (V) may be prepared from compounds of formula (II) and (C-C alkyl)OC(CH)Sn(alkyl) by process step (b) a palladium-catalyzed cross-coupling reaction with a suitable alkylstannane, i.e., a Stille reaction, as previously described in Scheme 1A.

[0158] Compounds of formula (VI) can be prepared from compounds of formula (V) by process step (h), oxidation reaction. Typical conditions include reaction of compounds of formula (V) with KMnO4, NaIO4 in a suitable solvent such as aqueous DCM at room temperature.

[0159] Compounds of formula (I)(A) can be prepared from compounds of formula (VI) following process step (i) ester reduction. Typical conditions include reaction of compounds of formula (VI) with DIBAL-H in a suitable solvent such as THF at low temperature, such as -30°C.

[0160] Compounds of formula (VII) may be prepared from compounds of formula (V) by process step (j). Typical conditions include reaction of compounds of formula (V) with TFA in DCM at room temperature.

[0161] Compounds of formula (I)(A) can be prepared from compounds of formula (VII) by process step (k) reduction of the ketone. Typical conditions include reaction of a compound of formula (VII) with a suitable reducing agent, such as NaBH4, in a suitable solvent, such as MeOH.

[0162] According to the third process, L 1 Compounds of formula (I)(B) where is O can be prepared from compounds of formula (VIII) as illustrated by Scheme 1C.

[0163] [ka] Scheme 1C Compounds of formula (I)(B) can be prepared from compounds of formula (VIII) according to process step (1), the Mitsunobu reaction. Typical conditions include the reaction of an alcohol of formula (VIII) with R in the presence of PPh and a suitable azodicarboxylic acid such as DEAD, DIAD, or DBAD in a suitable solvent such as THF between -10°C and room temperature. 1 This includes reactions with OH.

[0164] Alternatively, the compound of formula (I)(B) may be a compound of formula (VIII) and R 1 OH by process step (m) alkylation reaction. Typical conditions are the reaction of a compound of formula (VIII) with R in the presence of an inorganic base such as NaH, KOtBu, KOH or KCO in a suitable solvent such as DMF or THF at room temperature to an elevated temperature such as 80° C. 1 This includes reactions with OH.

[0165] According to the fourth process, L 1 Compounds of formula (I)(B) where is O can be prepared from compounds of formula (II) as illustrated by Scheme 1D.

[0166] [ka] Scheme 1D The compound of formula (I)(B) is a compound of formula (II) and R 1 It can be prepared from OH by an alkylation reaction as previously described in Scheme 1C above.

[0167] According to the fifth process, L 1 Compounds of formula (I)(C) where is OC(O) can be prepared from compounds of formula (VIII) and (IX) as illustrated by Scheme 1E.

[0168] [ka] Scheme 1E Compounds of formula (IX) can be prepared from compounds of formula (VIII) by process step (o) phosgenation reaction. Typical conditions include reacting compounds of formula (VIII) with phosgene or triphosgene in the presence of a suitable organic base, such as DIPEA, in a suitable solvent, such as THF, at low to room temperature.

[0169] The compound of formula (I)(C) can be prepared by combining a compound of formula (IX) and R 1 H according to process step (p). Typical conditions are the reaction of a compound of formula (IX) with R in the presence of a suitable organic base such as TEA in a suitable organic solvent such as DCM at about room temperature. 1 This includes reactions with H.

[0170] Alternatively, the compound of formula (I)(C) may be a compound of formula (VIII) and R 1 Typical conditions include reacting a compound of formula (VIII) with R in the presence of a suitable inorganic or organic base such as KCO or TEA or pyridine in a suitable solvent such as DMF, THF, MeCN or DCM at room temperature to an elevated temperature such as 80° C. 1 This includes the reaction with COCl.

[0171] According to the sixth process, L 1 is NH or L 1 is a bond and R1 Compounds of formula (I)(D), where is an N-linked heterocycle, can be prepared from compounds of formula (II) as illustrated by Scheme 1F.

[0172] [ka] Scheme 1F The compound of formula (I)(D) is a compound of formula (II) and R 1 NH according to process step (q) Buchwald-Hartwig cross-coupling. Typical conditions include reacting a compound of formula (II) with R in the presence of a suitable inorganic base, a suitable catalyst, in a suitable solvent at elevated temperature. 1 Preferred conditions include reaction with CsCO in a suitable solvent such as toluene, dioxane, or MeCN at 80-120 °C. 3、 a compound of formula (II) and R in the presence of BrettPhos Pd G3, Rockphos Pd, Xantphos Pd G3, RuPhos Pd, E-Phos Pd G4, PEPPSI Pd-Ipent-O-picoline or BINAP Pd G2 or a combination of Xphos or Xphos Pd G3 with Pd2(dba)3 in the presence of a suitable base such as K2CO3, K3PO4, KOAc or NaOtBu; 1 Includes reactions with NH2.

[0173] Alternatively, the compound of formula (I)(D) may be a compound of formula (II) and R 1 NH according to process step (z) amination reaction. Preferred conditions are the reaction of a compound of formula (II) and R in a suitable solvent such as DMSO, optionally in the presence of an organic or inorganic base, at an elevated temperature such as 100° C. 1 Includes reactions with NH2.

[0174] According to the seventh process, L 1 Compounds of formula (I)(E) where is NHC(O) can be prepared from compounds of formula (X) as illustrated by Scheme 1G.

[0175] [ka] Scheme 1G The compound of formula (I)(E) is a compound of formula (X) and R 1 H according to process step (r). Typical conditions include reacting a compound of formula (XX) with a suitable "carbonylating agent" such as 4-nitrophenyl chloroformate, 2,4,6-trichlorobenzoyl chloride or CDI in the presence of a suitable organic base such as pyridine or TEA, optionally in a suitable solvent such as DCM, at between -78°C and 60°C, followed by reaction of R 1 H, optionally in the presence of an organic base such as TEA, in a suitable solvent such as DCM at temperatures between room temperature and about 80°C.

[0176] Alternatively, the compound of formula (I)(E) may be a compound of formula (X) and R 1 Alternatively, compounds of formula (I)(E) can be prepared from compounds of formula (X) and R 1 COH according to process step (s), i.e., an amide bond formation reaction in the presence of a suitable coupling agent and an organic base, optionally in a suitable polar aprotic solvent. Preferred conditions are to couple an amine of formula (X) to R 1 It involves reacting COH in the presence of a coupling agent, preferably T3P®, CDI or HATU in combination with DMAP, in the presence of a suitable organic base such as TEA, DIPEA or pyridine, optionally in a suitable solvent such as DMF, dioxane or THF, at between room temperature and the reflux temperature of the reaction.

[0177] Alternatively, the compound of formula (I)(E) may be a compound of formula (X) and R 1 C(O)imidazole according to process step (t). Preferred conditions are the reaction of a compound of formula (X) with R in the presence of a strong base such as NaH in a suitable solvent such as THF at low temperature (typically 0° C.).1 C(O) involves reaction with imidazole.

[0178] According to an eighth process, compounds of formula (I)(E) can be prepared from compounds of formula (II) as illustrated by Scheme 1H.

[0179] [ka] Scheme 1H The compound of formula (I)(E) is a compound of formula (II) and R 1 It can be prepared from CONH2 according to process step (q) as previously described in Scheme 1F.

[0180] Alternatively, the compound of formula (I)(E) may be a compound of formula (II) and R 1 From CONH2, it can be prepared according to process step (u) Ullmann-type copper-mediated coupling reaction. Preferred conditions are the reaction of compound of formula (II) with R in the presence of CuI, a suitable ligand such as N1,N2-dimethylethane-1,2-diamine or L-proline, and a suitable inorganic base such as K2CO3 or K3PO4 in dioxane or DMSO at 90-120 °C. 1 Including reaction with CONH2.

[0181] According to the ninth process, L 1 Compounds of formula (I)(F), where is NHC(O)O, can be prepared from compounds of formula (X) as illustrated by Scheme 1I.

[0182] [ka] Scheme 1I The compound of formula (I)(F) is a compound of formula (X) and R 1 It can be prepared from OC(O)Cl according to process step (n) as previously described in Scheme 1E above.

[0183] According to the tenth process, L2 Compounds of formula (I)(G) where is O can be prepared from compounds of formula (XI) as illustrated by Scheme 2A.

[0184] [ka] Scheme 2A LG is as previously defined.

[0185] The compound of formula (I)(G) can be prepared by combining a compound of formula (XI) and R 2 From ROH, the compound of formula (XI) can be prepared according to process step (v) Buchwald-Hartwig cross-coupling reaction. Typical conditions are the reaction of a compound of formula (XI) with R in the presence of a suitable inorganic base, a suitable catalyst, in a suitable solvent at elevated temperature. 2 Preferred conditions include reaction of a compound of formula (XI) and R with BrettPhos Pd G3, Rockphos Pd, Xantphos Pd G3, or t-BuXphos and Pd2(dba)3 in the presence of a suitable base such as Cs2CO3 in a suitable solvent such as toluene, DMSO, or aqueous dioxane at about 95°C. 2 This includes the reaction of OH.

[0186] According to the 11th process, L 2 Compounds of formula (I)(G) where is O can be prepared from compounds of formula (XII) as illustrated by Scheme 2B.

[0187] [ka] Scheme 2B The compound of formula (I)(G) can be prepared by reacting a compound of formula (XII) with R 2 Alternatively, compounds of formula (I)(G) can be prepared from compounds of formula (XII) and R 2 OH by process step (m) alkylation reaction as previously described in Scheme 1C above.

[0188] According to the 12th process, L 2 Compounds of formula (I)(H) where is a bond can be prepared from compounds of formula (XI) as illustrated by Scheme 2C.

[0189] [ka] Scheme 2C The compound of formula (I)(H) can be prepared by combining a compound of formula (XI) and R 2 It can be prepared from MgBr by process step (a) as previously described in Scheme 1A above.

[0190] Alternatively, the compound of formula (I)(H) may be a compound of formula (XI) and R 2 It can be prepared from SnBu3 by process step (b) as previously described in Scheme 1A above.

[0191] Alternatively, the compound of formula (I)(H) may be a compound of formula (XI) and R 2 It can be prepared from BPin by process step (c) as previously described in Scheme 1A above.

[0192] Alternatively, the compound of formula (I)(H) may be a compound of formula (XI) and R 2 C(O)R a can be prepared from by process step (d) as previously described in Scheme 1A above.

[0193] Alternatively, the compound of formula (I)(H) may be a compound of formula (XI) and R 2 'H can be prepared by process steps (e) and (f) as previously described in Scheme 1A above.

[0194] Alternatively, R 2 is a C2-C4 alkynyl group, the compound of formula (I)(H) can be prepared by the reaction of a compound of formula (XI) and R 2From H, the compound of formula (XI) can be prepared according to process step (w), a palladium-catalyzed cross-coupling reaction, known as a Sonogashira-type reaction. Typical conditions include the reaction of a compound of formula (XI) with R in the presence of a suitable Cu(I) salt, such as CuI, a suitable palladium catalyst, such as Pd(PPh) in the presence of an organic base, such as TEA, in DMF at elevated temperatures, such as 100°C. 2 This includes reactions with H.

[0195] Alternatively, R 2 is an N-linked heterocycle, the compound of formula (I)(H) can be prepared by combining a compound of formula (XI) and R 2 It can be prepared from H according to process step (q) Buchwald reaction as previously described in Scheme 1F above.

[0196] According to the thirteenth process, compounds of formula (I) can be prepared from compounds of formulae (XIII) and (XIV), as illustrated by Scheme 3.

[0197] [ka] Scheme 3 Hal is a halogen, preferably Cl or Br.

[0198] Compounds of formula (I) may be prepared from compounds of formula (XIII) and (XIV) following process step (c) Suzuki-type cross-coupling reaction as previously described in Scheme 1A above.

[0199] According to the fourteenth process, compounds of formula (II) can be prepared from compounds of formulae (XV), (XVI) and (XIV), as illustrated by Scheme 4.

[0200] [ka] Scheme 4 Compounds of formula (XVI) may be prepared from compounds of formula (XV) by process step (x) halogenation reaction using a suitable halogenating agent. Typical conditions include reacting compounds of formula (XV) with a suitable halogenating agent such as POCl3 or CCl4 or POBr3 in the presence of PPh3, optionally in the presence of an organic base such as DIPEA or N,N-diethylaniline, optionally in a suitable solvent such as DCE or MeCN, at elevated temperatures such as 70-100°C.

[0201] Compounds of formula (II) may be prepared from compounds of formula (XVI) and (XIV) by process step (c) Suzuki-type cross-coupling reaction as previously described in Scheme 1A above.

[0202] According to the fifteenth process, compounds of formula (VIII) can be prepared from compounds of formula (II), (XIV) and (XVII), as illustrated by Scheme 5.

[0203] [ka] Scheme 5 Compounds of formula (VIII) may be prepared from compounds of formula (II) by process step (v) a Buchwald-type cross-coupling reaction as previously described in Scheme 2A above.

[0204] Compounds of formula (VIII) may be prepared from compounds of formula (XVII) and (XIV) by process step (c) Suzuki-type cross-coupling reaction as previously described in Scheme 1A above.

[0205] According to the sixteenth process, compounds of formula (XI) can be prepared from compounds of formulae (XVIII) and (XIX), as illustrated by Scheme 6.

[0206] [ka] Scheme 6 Compounds of formula (XIX) may be prepared from compounds of formula (XVIII) by process step (x), the halogenation reaction, as previously described in Scheme 4.

[0207] Compounds of formula (XI) may be prepared from compounds of formula (XIX) and (XIV) according to process step (c) as previously described in Scheme 1A.

[0208] According to the eighteenth process, compounds of formula (XII) can be prepared from compounds of formulae (XX) and (XIV), as illustrated by Scheme 7.

[0209] [ka] Scheme 7 Compounds of formula (XII) may be prepared from compounds of formula (XX) and (XIV) according to process step (c) as previously described in Scheme 1A.

[0210] According to the nineteenth process, compounds of formula (X) can be prepared from compounds of formulae (XIV), (XXI) and (XXII), as illustrated by Scheme 8.

[0211] [ka] Scheme 8 Compounds of formula (XXII) may be prepared from compounds of formula (XXI) and (XIV) by process step (c) Suzuki cross-coupling reaction as previously described in Scheme 1A.

[0212] Compounds of formula (X) can be prepared from compounds of formula (XXII) by process step (y), reduction of the nitro group. Typical conditions involve reaction of compounds of formula (XXII) with iron in the presence of a weak acid in a suitable alcoholic solvent, such as aqueous EtOH, at elevated temperatures, for example 80°C.

[0213] According to a twentieth process, compounds of formula (XIII) can be prepared from compounds of formulae (XVII) and (XXIII), as illustrated by Scheme 9.

[0214] [ka] Scheme 9 The compound of formula (XIII) can be prepared by reacting a compound of formula (XVII) with R 1 OH according to process step (1) Mitsunobu reaction as previously described in Scheme 1C.

[0215] Alternatively, compounds of formula (XIII) may be prepared from compounds of formula (XXIII) following process step (x) the halogenation reaction as previously described in Scheme 4.

[0216] Compounds of formula (XIV), (XV), (XVII), XVIII), (XX), (XXI) and (XXIII) are either commercially available or may be prepared analogously to methods known in the literature or by methods described in the experimental section below.

[0217] Compounds of formula (I), (II), (VIII), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), and (XXII) can be converted to alternative compounds of formula (I), (II), (VIII), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), and (XXII) by standard chemical transformations known to those skilled in the art. Examples of these transformations include, but are not limited to, reductive amination of an N atom, alkylation or acetylation of a heteroatom such as N or O, Chan-Lam coupling reactions of NH-containing compounds, or reduction of an ester to an alcohol.

[0218] As will be appreciated by those skilled in the art, it may be necessary to utilize a suitable protecting group strategy to prepare compounds of formula (I). Typical protecting groups may include carbamates, and preferably Boc, for protection of amines, TBS or benzyl groups for protection of primary alcohols, benzyl groups, methyl or TBDMS for protection of phenolic OH, or THP groups for protection of pyrazole N atoms.

[0219] Additionally, it will be understood that it may be necessary or desirable to carry out the transformations in a different order than that depicted in the Schemes, or to modify one or more of the transformations, to provide the desired compounds of the invention.

[0220] The following examples are intended to be illustrative and not to limit the scope of the disclosure in any way. [Example]

[0221] Preparation of Exemplary Compounds definition ℃: Celsius CC: Silica column chromatography CAN, MeCN: acetonitrile AcOH: acetic acid DCM: dichloromethane DIEA: Diisopropylethylamine DMF: dimethylformamide DMF-DMA: N,N-dimethylformamide dimethyl acetal DMSO: dimethyl sulfoxide EA: Ethyl acetate EDCI: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide EtOAc: ethyl acetate H, h, hr(s): hour(s) HOBt: 1-hydroxybenzotriazole HPLC: High-performance liquid chromatography I C 50 :50% inhibitory concentration i-PrOH: Isopropyl alcohol IPA: Isopropyl alcohol min:minutes MTBE: Methyl tert-butyl ether MeOH: Methanol Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2.DCM: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex PE: Petroleum ether rt: room temperature TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran RT: retention time Preparative HPLC: Preparative High Performance Liquid Chromatography Preparative TLC: Preparative thin layer chromatography TLC: Thin Layer Chromatography MsCl: methanesulfonyl chloride Bpin: pinacol boronic acid ester BINAP: (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0222] The method for preparing the compound of the present invention can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of two or more solvents.Those skilled in the art can select a suitable solvent for a particular reaction step depending on the specific reaction step.

[0223] The preparation of compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by one skilled in the art. The chemical nature of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 5th ed., John Wiley & Sons: New Jersey, (2014), the entire contents of which are incorporated herein by reference. The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13 C), can be monitored by spectroscopic means such as infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry (MS), or chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Analytical Instruments and Methods for Compound Characterization:

[0224] LC-MS: Liquid chromatography mass spectrometry (LC-MS) data (samples analyzed for purity and identity) were obtained as follows: An Agilent model-1260 LC system equipped with an Agilent Poroshel 120 (EC-C18, 2.7 μm particle size, 3.0 × 50 mm) reversed-phase column was used, utilizing ES-API ionization, and an Agilent model 6120 mass spectrometer at 22.4°C. The mobile phase consisted of a solvent mixture of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient of 95% aqueous / 5% organic to 5% aqueous / 95% organic over 4 minutes was used. The flow rate was constant at 1 mL / min; or A Shimadzu LCMS system was used with an Agilent (Poroshel HPH-C18, 2.7 μm particle size, 3.0 × 50 mm) reversed-phase column at 22.4°C, utilizing ESI ionization, and a Shimadzu LCMS mass spectrometer. The mobile phase consisted of a solvent mixture of water and acetonitrile containing 5 mM NH4HCO3 (or 0.05% TFA). A constant gradient of 90% aqueous / 10% organic to 5% aqueous / 95% organic over 2 minutes was used. The flow rate was constant at 1.5 mL / min.

[0225] Preparative LC-MS: Preparative HPLC was performed on a Shimadzu Discovery VP® preparative system equipped with a Luna 5u C18(2) 100A, AXIA prepacked 250x21.2mm reversed-phase column at 22.4°C. The mobile phase consisted of a solvent mixture of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient of 95% aqueous / 5% organic to 5% aqueous / 95% organic over 25 minutes was used. The flow rate was constant at 20 mL / min.

[0226] Manufacturer: Yantai Xinnuo Chemicals Co., Particle size: 10-40um, pH=6.2-7, Thickness: 1mm, Binder: CMC, Specification: 200 * 200mm.

[0227] Silica gel chromatography: Silica gel chromatography was performed on either a Teledyne Isco CombiFlash® Rf unit, or a Biotage® Isolera Four unit, or a Biotage® Isolera Prime unit.

[0228] Proton NMR: 1 H NMR spectra were obtained as follows: Varian 400 MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.5 seconds with a 1 second delay; scans 16-64). When characterized, all protons were reported as parts per million (ppm) relative to residual DMSO (2.50 ppm) in DMSO-d6 solvent; or Avance 400MHz Unity Inova 400MHz NM instrument (acquisition time = 3.99 seconds with a 1 second delay; number of scans 4-64) or Avance 300MHz Unity Inova 300MHz NMR instrument (acquisition time = 5.45 seconds with a 1 second delay; number of scans 4-64).

[0229] Preparative LC-MS: Preparative HPLC was performed using an XBridge Shield RP18 OBD column, 30 * The analysis was performed on a Waters Preparative system equipped with a 150 mm, 5 μm column. The mobile phase consisted of a mixture of aqueous (10 mmol / L NH4HCO3 + 0.05% NH3.H2O) and organic (acetonitrile) solvents. A constant gradient of 95% aqueous / 5% organic to 5% aqueous / 95% organic was used. The flow rate was constant, typically 60 mL / min.

[0230] Microwave-driven reactions were performed in a Biotage Initiator microwave unit. Those skilled in the art will recognize that gradients, column lengths, and flow rates can be varied and that, depending on the species being analyzed, some conditions may be more suitable for compound characterization than others.

[0231] Preparation of intermediates Preparation 1: 1-ethyl-3-phenyl-1H-pyrazole [ka] Cs2CO3 (441 g, 1.35 mol) was added to a solution of 3-phenyl-1H-pyrazole (65 g, 451 mmol) in DMF (250 mL), and the mixture was warmed to 45-60 °C. Ethyl iodide (141 g, 902 mL) was added dropwise, and the reaction was stirred at 45-60 °C overnight. The cooled mixture was diluted with water (2.5 L) and extracted with EtOAc (700 mL x 3). The combined organic extracts were washed with brine (1 L x 3), dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to give 80.8 g of the title compound. LCMS m / z = 173.1 [M+H] + .

[0232] Preparation 2: 1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazole [ka] To a DMF solution (900 mL) of 3-phenyl-1H-pyrazole (84.0 g, 582 mmol) and CsCO (569 g, 1.75 mol), 1,1-difluoro-2-iodoethane (223 g, 1.17 mol) was added dropwise at 45 °C, and the mixture was stirred at 45 °C for 12 h. The reaction mixture was diluted with HO (1.50 L) and extracted with EtOAc (1.50 L x 3). The combined organic layers were washed with brine (2.00 L x 2), dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, PE:EtOAc = 20:1 to 3:1) to give the title compound (137 g, crude) as a pale yellow oil. LCMS m / z = 209.2 [M+H] + .

[0233] Preparation 3: 1-Ethyl-3-(4-fluorophenyl)-1H-pyrazole [ka] To 3-(4-fluorophenyl)-1H-pyrazole (2 g, 12.3 mmol) in DMF (20 mL) was added NaH (295 mg, 12.3 mmol) and the solution was stirred for 30 minutes. Ethyl iodide (1.91 g, 12.3 mmol) was added and the resulting solution was stirred at room temperature for 1 hour. The reaction was quenched with water (5 mL) and the resulting solution was extracted with DCM (3 x 10 mL). The combined organic extracts were evaporated under reduced pressure to give the title compound as a pale yellow solid (1.5 g, 64.3% yield). LCMS m / z = 191 [M+H] + .

[0234] Preparation 4: 1-Ethyl-3-(2-fluorophenyl)-1H-pyrazole [ka] To 3-(2-fluorophenyl)-1H-pyrazole (2 g, 12.3 mmol) in DMF (10 mL) was slowly added NaH (590 mg, 24.6 mmol) at 0° C. The mixture was stirred for 30 minutes, and then iodoethane (3.83 g, 24.6 mmol) was added to the mixture at 0° C. The mixture was stirred at 60° C. for 16 hours. The solution was diluted with water (500 mL) and extracted with EtOAc (3×200 mL). The combined organics were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by column chromatography (10:1 PE / EtOAc) to give the title compound as a yellow oil (2 g, 85%). LCMS: m / z = 191 [M+H] + .

[0235] Preparation 5: 1-(oxetan-3-yl)-3-phenyl-1H-pyrazole [ka] 3-Iodooxetane (794 μL, 9.02 mmol) was added to a mixture of 3-phenyl-1H-pyrazole (1.0 g, 6.94 mmol) and NaOtBu (727 mg, 7.56 mmol) in DMF (23.1 mL), and the reaction was stirred at room temperature for 24 h. Additional NaOtBu (242 mg) and 3-iodooxetane (0.26 mL) were added, and the reaction was stirred for an additional 24 h. The reaction was diluted with water, the layers were separated, and the aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water (3 × 5 mL), dried over anhydrous NaSO, filtered, and the solvent was removed under reduced pressure. The crude product was purified by ISCO CombiFlash (0–30% EtOAc / hexanes) to afford the title compound as a pale yellow oil (870 mg, 62.6% yield). 1H NMR (500 MHz, CDCl3) δ 7.84 (d, 2H), 7.61 (d, 1H), 7.41 (td, 2H), 7.35 - 7.28 (m, 1H), 6.63 (d, 1H), 5.57 - 5.44 (m, 1H), 5.14 (t, 2H), 5.10 - 5.03 (m, 2H).

[0236] Preparation 6: 3-(2-fluorophenyl)-1-methyl-1H-pyrazole [ka] To a vial containing 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g, 7.21 mmol) and PdCl(dppf):DCM (589 mg, 0.721 mmol) in DME (10.30 mL) was added NaCO (2.29 g, 21.63 mmol) in water (10.30 mL) followed by 1-bromo-2-fluorobenzene (1.183 mL, 10.81 mmol) under N2, and the reaction was stirred at 90 °C for 1 h. The reaction mixture was diluted with water and EtOAc, and the organic layer was separated, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by ISCO Combiflash (0–60% EtOAc / hexanes) to afford the title compound as an orange oil (637 mg, 50% yield).

[0237] Preparation 7: 3-(2,6-difluorophenyl)-1-methyl-1H-pyrazole [ka] Following the procedure described in Preparation 6, 2-bromo-1,3-difluorobenzene and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave the title compound as a yellow oil (1.05 g, 56% yield).

[0238] Preparation 8: 3-(4-fluorophenyl)-1-methyl-1H-pyrazole [ka] A mixture of Pd(dppf)Cl (465 mg, 0.571 mmol), KCO (1.18 g, 8.56 mmol), 1-bromo-4-fluorobenzene (1 g, 5.71 mmol), and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.78 g, 8.56 mmol) in HO (6 mL) and dioxane (24 mL) was stirred at 80 °C for 2 h under N. The reaction mixture was diluted with DCM (100 mL), washed with HO (2 × 50 mL), dried (NaSO), and evaporated to dryness. The residue was purified by column chromatography (20:1 DCM / MeOH) to give the title compound as an off-white solid (800 mg, 80%). LCMS: m / z = 177 [M+H] + .

[0239] Preparation 9: 3-(2,4-difluorophenyl)-1-methyl-1H-pyrazole [ka] Following the procedure described in Preparation 8, 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1-bromo-2,4-difluorobenzene gave the title compound as a yellow oil (990 mg). LCMS m / z = 195 [M+H] + .

[0240] Preparation 10: 1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-1H-pyrazole [ka] A mixture of Pd(dppf)Cl (1.39 g, 1.91 mmol), KCO (3.96 g, 28.7 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4 g, 19.2 mmol), and 2-(3-bromophenoxy)tetrahydro-2H-pyran (7.37 g, 28.7 mmol) in dioxane / HO (120 mL / 30 mL) was stirred at 80 °C for 2 h under N. The reaction mixture was extracted with EtOAc (3 × 150 mL), and the combined organics were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (2:1 PE / EtOAc) to give the title compound as a white solid (3.5 g, 70%). LCMS: m / z = 259 [M+H] + .

[0241] Preparation 11: 3-(2,6-difluorophenyl)-1-methyl-1H-pyrazole [ka] A mixture of 3-bromo-1-methyl-1H-pyrazole (5 g, 31.0 mmol), (2,6-difluorophenyl)boronic acid (7.34 g, 46.5 mmol), Pd(dtbpf)Cl (2.01 g, 3.10 mmol), and KPO (13.1 g, 62.0 mmol) in dioxane (60 mL) and water (10 mL) was stirred at 100 °C for 16 h. The reaction mixture was extracted with EtOAc, and the combined organics were evaporated to dryness. The residue was purified by column chromatography (20% EtOAc / PE) to give the title compound as a white solid (3 g, 50%). LCMS: m / z = 195 [M+H] + .

[0242] Preparation 12: 4-Bromo-1-ethyl-3-phenyl-1H-pyrazole [ka] NBS (87.2 g, 490 mmol) was added to a solution of 1-ethyl-3-phenyl-1H-pyrazole (Preparation 1, 80.8 g, 466 mmol) in MeCN (850 mL), and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was dissolved in EtOAc (100 mL) and washed with aqueous NaHCO (700 mL). The aqueous solution was extracted with EtOAc (200 mL x 3), and the combined organic phases were washed with brine (250 mL x 5), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc 20 / 1 to 10 / 1) to give 115 g of a brown oil. This was purified by SFC column: DAICEL CHIRALCEL OJ (250 mm * Further purification by HPLC using a 50 mm, 10 μm column chromatography on a 500 MHz column in IPA (0.05% DEA) afforded the title compound as a yellow oil (40 g, 35% yield). 1H NMR (400 MHz, CDCl3) δ: 7.90 (q, 2H), 7.49 (s, 1H), 7.46 - 7.44 (m, 2H), 7.42 - 7.37 (m, 1H), 4.22 - 4.17 (m, 2H), 1.55 - 1.51 (t, 3H).

[0243] Preparation 13: 4-Bromo-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole [ka] A mixture of 1-ethyl-3-(4-fluorophenyl)-1H-pyrazole (Preparation 3, 2 g, 10.5 mmol), NBS (1.86 g, 10.5 mmol) and MeCN (5.00 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography with DCM / MeOH (20 / 1) to give the title compound (1.5 g, 53%) as a pale yellow solid. LCMS m / z = 269 [M+H] + .

[0244] Preparation 14: 4-Bromo-1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazole [ka] To a solution of 1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazole (Preparation 2, 137 g, 658 mmol) in MeCN (1.50 L) was added NBS (117 g, 658 mmol), and the reaction was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO, PE: EtOAc = 20:1 to 3:1) to give the title compound (165 g, 87.3% yield) as a brown oil. LCMS m / z = 287.0 [M+H] + .

[0245] Preparation 15: 4-Bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazole [ka] To 3-(4-fluorophenyl)-1-methyl-1H-pyrazole (Preparation 8, 800 mg, 4.54 mmol) in DMF (15 mL) was added NBS (968 mg, 5.44 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (2×50 mL). The combined organics were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by column chromatography (25:1 DCM / MeOH) to give the title compound as a yellow solid (720 mg, 90%). LCMS: m / z = 255 [M+H] + .

[0246] Preparation 16: 5-Bromo-2-methyl-4-phenylthiazole [ka] Using a method similar to that described for Preparation 15, the title compound was prepared from 2-methyl-4-phenylthiazole as a white solid (1.3 g, 90%). LCMS: m / z = 254 [M+H] + .

[0247] Preparation 17: 4-Bromo-3-(2-fluorophenyl)-1-methyl-1H-pyrazole [ka] To a solution of 3-(2-fluorophenyl)-1-methyl-1H-pyrazole (Preparation 6, 637 mg, 3.62 mmol) in DMF (9 mL) was added NBS (643 mg, 3.62 mmol) in small portions over 10 minutes, and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with EtOAc. The combined organic extracts were washed with brine, then dried over anhydrous Na2SO4, filtered, and the solvent removed under reduced pressure. The crude product was purified by Combiflash ISCO (0-50% EtOAc / hexanes) to afford the title compound as a light brown oil (428 mg, 46% yield). LCMS m / z = 255 [M+H] + .

[0248] Preparations 18-22 The compounds in the table below were prepared from the appropriate pyrazole following a procedure similar to that described in Preparation 17. [Table 3]

[0249] Preparation 23: 3-(4-bromo-1-methyl-1H-pyrazol-3-yl)phenol [ka] NBS (2.63 g, 14.8 mmol) was added to 1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-1H-pyrazole (Preparation 10, 3.5 g, 13.5 mmol) in THF (60 mL) at 0° C., and the mixture was stirred at room temperature for 2 h. The resulting solution was extracted with EtOAc (3×100 mL), and the combined organics were dried (NaSO) and evaporated to dryness. The residue was purified by silica gel chromatography (33% EtOAc / PE) to give the title compound as a white solid (2.6 g, 76%). LCMS: m / z = 253 [M+H]+ .

[0250] Preparation 24: 4-Bromo-3-(2-fluorophenyl)-1H-pyrazole [ka] Pyridinium tribromide (1.67 g, 5.24 mmol) was added to 3-(2-fluorophenyl)-1H-pyrazole (850 mg, 5.24 mmol) in MeOH (9 mL), and the reaction mixture was stirred at room temperature for 2 hours. The resulting solution was concentrated in vacuo. The residue was purified by preparative TLC (30:1 DCM / MeOH) to give the title compound as a pale yellow liquid (1.2 g, 93%). LCMS m / z = 241 [M+H] + .

[0251] Preparation 25: 4-Bromo-3-(3-chlorophenyl)-1H-pyrazole [ka] Following a procedure similar to that described in Preparation 24, 3-(3-chlorophenyl)-1H-pyrazole gave the title compound as an off-white solid (1.36 g, 95%). LCMS m / z = 257, 259 [M+H] + .

[0252] Preparation 26: 4-Bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole [ka] To a mixture of 4-bromo-3-phenyl-1H-pyrazole (500 mg, 2.24 mmol) in DCM (30 mL) was added dihydropyran (942 mg, 11.2 mmol) and para-toluenesulfonate (385 mg, 2.24 mmol). The reaction mixture was stirred at 50 °C for 2 h. The solvent was removed in vacuo. The residue was purified by column chromatography (SiO, 25% EtOAc / PE) to give the title compound as an off-white solid (480 mg, 70%). LCMS m / z = 307, 309 [M+H] + .

[0253] Preparation 27: 4-Bromo-3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole [ka] Following a procedure similar to that described for Preparation 26, 4-bromo-3-(2-fluorophenyl)-1H-pyrazole gave the title compound as a colorless liquid (750 mg, 47% yield). LCMS m / z = 325 [M+H] + .

[0254] Preparation 28: 4-Bromo-3-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole [ka] Following a procedure similar to that described in Preparation 26, 4-bromo-3-(3-chlorophenyl)-1H-pyrazole (Preparation 25) and dihydropyran gave the title compound as an off-white solid (900 mg, 68% yield). LCMS m / z = 341, 343 [M+H] + .

[0255] Preparation 29: 4-Bromo-3-(2,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole [ka] Using a procedure similar to that described in Preparation 26, 4-bromo-3-(2,5-difluorophenyl)-1H-pyrazole (Preparation 21) gave the title compound as a colorless liquid (570 mg, 67% yield). LCMS m / z = 343, 345 [M+H] + .

[0256] Preparation 30: 4-Bromo-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole [ka] A mixture of 4-bromo-3-phenyl-1H-pyrazole (1.0 g, 4.48 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.775 mL, 5.60 mmol), DMF (9 mL), and CsCO (2.92 g, 8.97 mmol) was stirred at room temperature overnight. The reaction was diluted with water and extracted with EtOAc (2x). The combined organic layers were washed with water (4x) and brine, dried over MgSO, filtered, and concentrated. The residue was purified by silica column chromatography (DCM) to give the title compound (894 mg, 65.4% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 7.83 - 7.78 (m, 2H), 7.53 - 7.46 (m, 2H), 7.46 - 7.41 (m, 1H), 5.21 (q, 2H).

[0257] Preparation 31: 4-Bromo-3-(3-((tert-butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-pyrazole [ka] Imidazole (2.07 g, 30.5 mmol) was added to 3-(4-bromo-1-methyl-1H-pyrazol-3-yl)phenol (2.6 g, 10.2 mmol) and TBSCl (4.60 g, 30.5 mmol) in DMF (50 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The resulting solution was extracted with EtOAc (3 × 100 mL), and the combined organics were dried (Na SO ) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (50% DCM / PE) to give the title compound as a white solid (3 g, 80%). LCMS: m / z = 367 [M+H] + .

[0258] Preparation 32: 4-Bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazole [ka] To a solution of 4-bromo-3-phenyl-1H-pyrazole (2 g, 8.96 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (3.20 g, 13.4 mmol), and DMF (25 mL) was added NaH (321 mg, 13.4 mmol), and the resulting mixture was stirred at 50° C. for 2 hours. The reaction was quenched with water and evaporated to dryness in vacuo. The residue was purified by column chromatography (5% EtOAc / PE) to give the title compound as a yellow liquid (3.2 g, 85%). LCMS: m / z = 383 [M+H] + .

[0259] Preparation 33: 1-Ethyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] A solution of 4-bromo-1-ethyl-3-phenyl-1H-pyrazole (Preparation 12, 40 g, 159 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (59.3 g, 319 mmol) in THF (400 mL) was cooled to −78 °C, and n-BuLi (127 mL, 2.5 M) was added dropwise. The reaction was stirred at −60 °C for 1 h, then allowed to warm to room temperature and stirred for an additional 30 min. The mixture was poured into saturated NH4Cl(aq) solution (500 mL) at 0 °C, and the solution was extracted with EtOAc (500 mL × 3). The combined organic extracts were washed with brine (500 mL), dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column (PE / EtOAc 1 / 0 to 4 / 1) to give the title compound as a yellow solid (22.3 g, 47% yield). LCMS m / z = 299 [M+H] + .

[0260] Preparation 34: 3-(2,6-difluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] Following a procedure similar to that described in Preparation 33, 4-bromo-3-(2,6-difluorophenyl)-1-methyl-1H-pyrazole (Preparation 19) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane gave the title compound as a white solid (364 mg, 49%). 1H NMR (500 MHz, CDCl3) δ 7.75 (t, 1H), 7.32 - 7.24 (m, 1H), 6.92 (td, 2H), 3.98 (t, 3H), 1.21 (t, 12H).

[0261] Preparation 35: 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] To a solution of 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazole (Preparation 32, 3 g, 7.76 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.15 g, 11.6 mmol) in THF (20 mL) was added BuLi with stirring at −70° C. and stirring was continued at −10° C. for 1 h. The reaction was quenched with water and evaporated to dryness in vacuo. The residue was purified by column chromatography to give the title compound as a yellow solid (500 mg, 13%). LCMS: m / z = 429 [M+H] + .

[0262] Preparation 36: 2-methyl-4-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole [ka] nBuLi (1.5 mL) was added to 5-bromo-2-methyl-4-phenylthiazole (Preparation 16, 1.2 g, 4.72 mmol) in THF (50 mL) at −78° C., and the resulting mixture was stirred for 1 h under N. To this was added 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (878 mg, 4.72 mmol) at −78° C., and the reaction mixture was allowed to warm to room temperature and stirred at 25° C. for 2 h. The resulting solution was extracted with EtOAc (3×100 mL), and the combined organics were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by column chromatography (25:1 DCM / MeOH) to give the title compound as an off-white solid (400 mg, 28%). LCMS: m / z = 254 [M+H] + .

[0263] Preparation 37: 3-(2-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] A mixture of 4-bromo-3-(2-fluorophenyl)-1-methyl-1H-pyrazole (Preparation 17, 428 mg, 1.68 mmol), KOAc (494 mg, 5.03 mmol), B(Pin) (469 mg, 1.846 mmol), and PdCl(dppf)DCM (68.5 mg, 0.084 mmol) in dioxane (1.86 mL) was purged with N and stirred at 100 °C for 3 h. The reaction mixture was filtered through Celite®, washing with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified on a silica gel column (0–30% EtOAc / hexanes) to afford the title compound as a white sticky solid (220 mg, 43% yield). 1H NMR (500 MHz, CDCl3) δ 7.71 (s, 1H), 7.62 - 7.55 (m, 1H), 7.31 (q, 1H), 7.16 (t, 1H), 7.12 - 7.05 (m, 1H), 3.96 (s, 3H), 1.26 (t, 12H)

[0264] Preparation 38: 1-(oxetan-3-yl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] Following the procedure described in Preparation 37, 4-bromo-1-(oxetan-3-yl)-3-phenyl-1H-pyrazole (Preparation 22) gave the title compound as a white solid (281 mg, 40% yield). 1H NMR (500 MHz, CDCl3) δ 8.06-7.94 (m, 3H), 7.44-7.29 (m, 3H), 5.53 (p, 1H), 5.17-5.09 (m, 2H), 5.05 (t, 2H), 1.32 (d, 12H).

[0265] Preparation 39: 3-(3-((tert-butyldimethylsilyl)oxy)phenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] A mixture of KOAc (1.39 g, 14.1 mmol), Pd(dppf)Cl2 (517 mg, 0.707 mmol), 4-bromo-3-(3-((tert-butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-pyrazole (Preparation 31, 2.6 g, 7.07 mmol), and B(Pin)2 (3.58 g, 14.1 mmol) in dioxane (60 mL) was stirred at 100 °C for 2 h under N2. The reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (10:1 EtOAc / PE) to give the title compound as a white solid (500 mg, 17%). LCMS: m / z = 415 [M+H] + .

[0266] Preparation 40: 1-Ethyl-3-(2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] Pd(dppf)Cl2 (544 mg, 0.743 mmol) and KOAc (1.45 g, 14.8 mmol) were added to a DMSO solution of 4-bromo-1-ethyl-3-(2-fluorophenyl)-1H-pyrazole (Preparation 20, 2 g, 7.43 mmol) and B(Pin)2 (3.75 g, 14.8 mmol), and the mixture was stirred at 80 °C overnight. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3 × 200 mL). The combined extracts were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography (10:1 PE / EtOAc) to give the title compound as an oil (2.1 g, 89%). LCMS: m / z = 317 [M+H] + .

[0267] Preparation 41: 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] A mixture of 4-bromo-1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazole (Preparation 14, 160 g, 557 mmol), (BPin) (283 g, 1.11 mol), Pd(dppf)Cl. DCM (45.5 g, 55.7 mmol), and KOAc (164 g, 1.67 mol) in DMSO (1.80 L) was degassed and purged with N (x3), and the mixture was stirred at 90 °C for 4 h under N. The reaction mixture was filtered, then diluted with H2O (3.60 L), and extracted with EtOAc (2.0 L x 3). The combined organic layers were washed with brine (3.0 L x 2), dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EtOAc = 20:1 to 3:1). The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250 mm * 100mm *Further purification with 10 μm; mobile phase: [water (0.225% FA)-MeCN]; B%: 50%-70%, 25 min) afforded the title compound (60.0 g, 31.4% yield) as a pale yellow solid. LCMS m / z = 335.2 [M+H] + .

[0268] Preparation 42: 3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] To a mixture of 4-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 26, 440 mg, 1.43 mmol) in DMSO (4 mL) was added B(Pin) (726 mg, 2.86 mmol), KPO (607 mg, 2.86 mmol), and Pd(dppf)Cl.DCM (116 mg, 0.143 mmol), and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was extracted with EtOAc, and the organic phase was concentrated in vacuo. The residue was purified by column chromatography (SiO, 10% MeOH / DCM) to give the title compound as a pale yellow solid (400 mg, 79%). LCMS m / z = 355 [M+H] + .

[0269] Preparation 43: 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] A mixture of Pd(PPh3)4 (216 mg, 0.282 mmol), KOAc (414 mg, 4.23 mmol), 4-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazole (Preparation 15, 720 mg, 2.82 mmol), and B(Pin)2 (986 mg, 3.29 mmol) in HO (4 mL) and DMSO (16 mL) was stirred at 100 °C for 2 h under N2. The mixture was diluted with EtOAc (150 mL), washed with brine (2 x 75 mL), dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by column chromatography (15:1 DCM / MeOH) to give the title compound as a pale yellow solid (600 mg, 83%). LCMS: m / z = 303 [M+H] + .

[0270] Preparation 44: 1-Ethyl-3-(4-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] Following the procedure described in Preparation 43, 4-bromo-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole (Preparation 13) gave the title compound as an off-white solid (1 g, 56.8% yield). LCMS m / z = 317 [M+H] +

[0271] Preparation 45: 3-(2,4-difluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] Following a procedure similar to that described in Preparation 43, 3-(2,4-difluorophenyl)-1-methyl-1H-pyrazole (Preparation 18) gave the title compound as an off-white solid (900 mg). LCMS m / z = 321 [M+H] +

[0272] Preparation 46: 3-(2-Fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] Following a procedure similar to that described in Preparation 43, 4-bromo-3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 27) gave the title compound as a colorless liquid (650 mg, 76% yield). LCMS m / z = 373 [M+H] + .

[0273] Preparation 47: 3-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] Following a procedure similar to that described in Preparation 43, 4-bromo-3-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 28) gave the title compound as a yellow solid (380 mg, 84%). LCMS m / z = 389 [M+H] + .

[0274] Preparation 48: 3-(2,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] A mixture of 4-bromo-3-(2,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 29, 300 mg, 0.874 mmol) in DMSO (3 mL), B(Pin) (441 mg, 1.74 mmol), Pd(PPh) (20.1 mg, 0.0174 mmol), and NaOAc (142 mg, 1.74 mmol) was stirred at 100° C. for 16 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative TLC (4:1 PE / EtOAc) to give the title compound as a pale yellow oil (130 mg, 38%). LCMS m / z = 391 [M+H] + .

[0275] Preparation 49: 1,4-Dioxepan-6-ol [ka] To a mixture of 1,4-dioxepan-6-one (200 mg, 1.72 mmol) in MeOH (10 mL) was added NaBH (130 mg, 3.44 mmol) in ice water, and the solution was stirred for 10 minutes. The resulting solution was diluted with water (30 mL), extracted with EtOAc (2 x 20 mL), and the organic layers were combined. The resulting organic solution was washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo to give the title compound (150 mg, 85% yield) as a white solid.

[0276] Preparation 50: 1-(5-methylthiazol-4-yl)ethan-1-ol [ka] Methylmagnesium bromide (3 M in EtO, 2 mL) was added to 5-methyl-1,3-thiazole-4-carbaldehyde (250 mg, 1.96 mmol) in THF (5 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of 1 M HCl (5 mL), and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over NaSO and evaporated under reduced pressure to give the title compound (250 mg, 89% yield) as a clear liquid. LCMS: m / z = 144 [M+H] + .

[0277] Preparation 51: 1-(5-methyl-1,3,4-thiadiazol-2-yl)ethan-1-ol [ka] The title compound was prepared from 5-methyl-1,3,4-thiadiazole-2-carbaldehyde according to the procedure described in Preparation 50. LCMS m / z = 145 [M+H] + .

[0278] Preparation 52: 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one [ka] A mixture of 8-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-one (300 mg, 1.31 mmol), (BPin) (497 mg, 1.96 mmol), Pd(dppf)Cl (96.0 mg, 1.96 mmol), and KOAc (192 mg, 1.96 mmol) in DMSO (15 mL) was stirred at 80 °C for 3 h under N. The solution was diluted with H0 (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over NaSO and concentrated in vacuo. The crude product was purified by preparative TLC with PE:EtOAc = 2:1 to give the title compound (120 mg) as a brown solid. LCMS: m / z = 276 [M+H] + .

[0279] Preparation 53: (S)-2,4-Dimethylpiperazine-1-carbonyl chloride [ka] To a solution of triphosgene (59 mg, 0.20 mmol) in DCM (1 mL) at 0 °C under N was added pyridine (0.142 mL, 1.75 mmol), followed by (S)-1,3-dimethylpiperazine (0.067 mL, 0.5 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The solvent was removed under reduced pressure to give the title compound.

[0280] Preparations 54-58 The compounds in the table below were obtained from the appropriate amine and phosgene according to the procedures described in the preparations above. [Table 4]

[0281] Preparation 59: (S)-4-Ethyl-2-methylpiperazine-1-carbonyl chloride [ka] Triphosgene (115 mg, 0.389 mmol) was added in portions to pyridine (184 mg, 2.33 mmol) and (3S)-1-ethyl-3-methylpiperazine (100 mg, 0.779 mmol) in DCM (10 mL) at 0 °C, and the reaction was stirred at room temperature for 2 h. The mixture was diluted with DCM (50 mL) and washed with brine (20 mL × 2), and the organic layer was dried over Na SO and concentrated in vacuo. The residue was purified by preparative TLC with PE: EtOAc = 2:1 to give the title compound (100 mg) as a white solid.

[0282] Preparation 60: Tetrahydro-1H-pyrrolidine-7a(5H)-carboxamide [ka] Methyl hexahydro-1H-pyrrolidine-7a-carboxylate (200 mg, 1.18 mmol) was added to the ammonia methanol solution, and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by preparative TLC (20:1 DCM / MeOH=20:1) to give the title compound as a white solid (150 mg, 82%). LCMS: m / z = 155 [M+H] + .

[0283] Preparation 61: Ethyl 1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-carboxylate [ka] Ethyl 1H-pyrazole-4-carboxylate (300 mg, 2.14 mmol), (2-bromoethyl)dimethylamine (976 mg, 6.42 mmol), and CsCO (2.09 g, 6.42 mmol) were added to DMF, and the reaction was stirred at 60 °C for 5 h. The solution was diluted with water (500 mL) and then extracted with EtOAc (3 x 200 mL). The organic layer was dried over NaSO and concentrated in vacuo. The crude product was purified by column chromatography with DCM:MeOH = 10:1 to give the title compound (200 mg) as a yellow oil. LCMS m / z = 212 [M+H] + .

[0284] Preparation 62: 1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-carboxamide [ka] Ethyl 1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-carboxylate (Preparation 61, 100 mg, 0.473 mmol) in NH4OH (5 mL) was heated to 80°C for 4 hours. The mixture was concentrated under reduced pressure to give the title compound as a yellow oil (50 mg, 58%), which was used without further purification. LCMS: m / z = 183 [M+H] + .

[0285] Preparation 63: tert-butyl (3-carbamoylbicyclo[1.1.1]pentan-1-yl)carbamate [ka] A mixture of ethyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (2 g, 8.28 mmol) in NH4OH was stirred for 16 h at 60° C. The solution was evaporated to dryness to give tert-butyl (3-carbamoylbicyclo[1.1.1]pentane-1-yl)carbamate as a white solid (1.5 g), which was used without further purification.

[0286] Preparation 64: 3-Oxabicyclo[3.1.0]hexane-1-carboxamide [ka] To a solution of 3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acid (200 mg, 1.56 mmol) in DCM (10 mL) were added EDCI (450 mg, 2.34 mmol) and HOBt (316 mg, 4.00 mmol), and the solution was stirred at room temperature for 2 hours. 35% aqueous NH3 (3 mL) was added, and the reaction was stirred at room temperature for 1 hour before being concentrated to dryness. The residue was purified by preparative TLC (5% MeOH / DCM) to afford the title compound (140 mg, yield = 70%) as a white solid. LCMS: m / z = 128 [M+H] + .

[0287] Preparation 65: tert-Butyl 1-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate [ka] To a mixture of 3-((tert-butoxy)carbonyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (200 mg, 0.88 mmol) in DCM (15 mL) was added EDCI (275 mg, 1.75 mmol) and HOBt (236 mg, 1.75 mmol), and the solution was stirred at 25 °C for 2 h. 35% aqueous NH3 (3 mL) was added, and the reaction was stirred at 25 °C for 1 h before being concentrated to dryness. The residue was purified by preparative TLC with DCM:MeOH = 15:1 to give the title compound (160 mg, yield: 80.4%) as a white solid. LCMS m / z = 171 [M+H] + .

[0288] Preparation 66: 2-Methyltetrahydrofuran-2-carboxamide [ka] Following a procedure similar to that described in Preparation 65, 2-methyltetrahydrofuran-2-carboxylic acid gave the title compound as a white solid (150 mg, 76% yield). LCMS: m / z =130 [M+H] + .

[0289] Preparation 67: (R)-2-methyltetrahydrofuran-2-carboxamide [ka] Using a method similar to that described for Preparation 65, the title compound was prepared from (R)-2-methyltetrahydrofuran-2-carboxylic acid as a white solid (70 mg, 71%). LCMS: m / z =130 [M+H] + .

[0290] Preparation 68: 1-(trifluoromethyl)cyclopropane-1-carboxamide [ka] To a mixture of 1-(trifluoromethyl)cyclopropanecarboxylic acid (10 g, 64.9 mmol) in DCM (150 mL) was added HOBt (10.5 g, 77.9 mmol) and EDCI (15.0 g, 77.9 mmol) in several portions. The solution was stirred at room temperature for 2 hours, and then 35% aqueous NH3 (5 mL) was added. The reaction was stirred at room temperature for 1 hour and then concentrated to dryness. The residue was purified on a silica gel column with 5% MeOH / DCM to give the title compound (9.1 g, 91% yield) as a white solid. LCMS: m / z = 154 [M+H] + .

[0291] Preparations 69-75 The compounds in the table below were prepared from the appropriate carboxylic acid following a procedure similar to that described in Preparation 68. [Table 5-1] [Table 5-2]

[0292] Preparation 76: 1-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] A mixture of 1-(trifluoromethyl)pyrazole-4-carboxylic acid (200 mg, 1.11 mmol), HOBT (225 mg, 1.67 mmol), EDCI (319 mg, 1.67 mmol), and NHOH (77.8 mg, 2.22 mmol) in DCM (5 mL) was stirred at room temperature for 3 h. The reaction was quenched by the addition of water, and the resulting solution was extracted with DCM (3 × 10 mL). The combined organics were evaporated to dryness in vacuo, and the residue was purified by column chromatography (SiO, 20:1 DCM / MeOH) to give the title compound as an off-white solid (150 mg, 75%).

[0293] Preparation 77: 1-Isopropyl-3-methyl-1H-pyrazole-4-carboxamide [ka] Following the procedure described in Preparation 76, 1-isopropyl-3-methylpyrazole-4-carboxylic acid gave the title compound as a white solid (90 mg). LCMS: m / z = 168 [M+H] + .

[0294] Preparation 78: 2-(trifluoromethyl)pyrrolidine-2-carboxamide [ka] LiOH.HO (267 mg, 6.36 mmol), HO (2 mL), and 30% HO (1 mL) were added to a solution of 2-(trifluoromethyl)pyrrolidine-2-carbonitrile (300 mg, 1.82 mmol) in MeOH (6 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by column chromatography (2:1 EtOAc / PE) to give the title compound as a colorless oil (140 mg, 42%). LCMS: m / z = 183 [M+H] + .

[0295] Preparations 79 and 80: Methyl 1-(bromodifluoromethyl)-1H-pyrazole-3-carboxylate and methyl 1-(bromodifluoromethyl)-1H-pyrazole-5-carboxylate [ka] To a mixture of methyl 1H-pyrazole-3-carboxylate (3 g, 23.7 mmol) in DMF (45 mL) was added NaH (1.42 g, 59.2 mmol) at 0° C., and the reaction mixture was stirred at 0° C. for 15 minutes. Dibromodifluoromethane (14.9 g, 71.1 mmol) was added, and the reaction mixture was stirred at 25° C. for 16 hours. The reaction mixture was added to ice water and extracted with EtOAc. The combined organics were evaporated to dryness in vacuo, and the residue was purified by column chromatography (14% EtOAc / PE) to give the title compound.

[0296] Peak 1, Preparation 79; Methyl 1-(bromodifluoromethyl)-1H-pyrazole-3-carboxylate (colorless oil, 3 g, 50%). LCMS: m / z = 255 [M+H] + ; 1 H NMR (300 MHz, DMSO-d6) δ: 8.61 (dt, 1H), 7.06 (d, 1H), 3.87 (s, 4H).

[0297] Peak 2, Preparation 80; Methyl 1-(bromodifluoromethyl)-1H-pyrazole-5-carboxylate (colorless oil, 400 mg, 7%). LCMS: m / z = 255 [M+H] + ; 1 H NMR (300 MHz, DMSO-d6) δ 8.02 (d, 1H), 7.26 (dt, 1H), 3.89 (s, 3H).

[0298] Preparation 81: Methyl 1-(trifluoromethyl)-1H-pyrazole-5-carboxylate [ka] To a mixture of methyl 1-(bromodifluoromethyl)-1H-pyrazole-5-carboxylate (Preparation 80, 400 mg, 1.56 mmol) in DCM (20 mL) was added AgBF (912 mg, 4.68 mmol) at −78° C. under a N atmosphere, and the reaction was stirred at room temperature overnight. The resulting solution was diluted with water (40 mL) and extracted with DCM (2×50 mL). The combined organics were washed with brine (30 mL), dried (NaSO), and evaporated to dryness in vacuo. The residue was purified by column chromatography (10% EtOAc / PE) to give the title compound as a yellow oil (300 mg, 99%). LCMS: m / z = 195 [M+H] + .

[0299] Preparation 82: 1-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid [ka] To a solution of methyl 1-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Preparation 81, 300 mg, 1.54 mmol) in THF / HO was added LiOH (110 mg, 4.62 mmol) and the mixture was stirred for 4 h at 25° C. The resulting solution was evaporated to dryness in vacuo to give the title compound as a white solid (150 mg, 54%), which was used without further purification.

[0300] Preparation 83: Methyl 1-(bromodifluoromethyl)-3-methyl-1H-pyrazole-4-carboxylate and methyl 1-(bromodifluoromethyl)-5-methyl-1H-pyrazole-4-carboxylate [ka] To methyl 3-methyl-1H-pyrazole-4-carboxylate (2 g, 14.2 mmol) in DMF (10 mL) was added NaH (567 mg, 14.2 mmol) at 0 °C, followed by stirring at 0 °C for 30 minutes. CFBr (4.43 g, 21.3 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was evaporated to dryness in vacuo, and the residue was purified by preparative TLC (2:1 PE / EtOAc) to give the title compound mixture as a pale yellow solid (1.9 g, 50%). LCMS: m / z = 269 [M+H] + .

[0301] Preparation 84: Methyl 3-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylate and methyl 5-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylate [ka] To a mixture of methyl 1-(bromodifluoromethyl)-3-methyl-1H-pyrazole-4-carboxylate and methyl 1-(bromodifluoromethyl)-5-methyl-1H-pyrazole-4-carboxylate (Preparation 83, 2 g, 7.43 mmol) in DCM (30 mL) was added AgBF (2.88 g, 14.8 mmol), and the resulting mixture was stirred at room temperature for 16 hours under N at −78° C. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (50% EtOAc / PE) to give the mixture of title compounds as an off-white oil (540 mg). LCMS: m / z = 209 [M+H] + .

[0302] Preparation 85: 3-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid and 5-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [ka] LiOH (343 mg, 14.3 mmol) was added to a mixture of 3-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylate and methyl 5-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Preparation 84, 500 mg, 2.40 mmol) in THF / HO (15 mL / 5 mL) at room temperature, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water, the pH adjusted to pH 6-7 with HCl (1 M), and extracted with EtOAc (100 mL). The combined organics were washed with water (3 x 100 mL) and brine (100 mL), then dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by column chromatography (20:1 DCM / MeOH) to give the title compound as a white solid (430 mg, 92%). LCMS: m / z = 195 [M+H] + .

[0303] Preparation 86: 7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol [ka] A mixture of 4-chloro-7-methoxyquinazolin-6-ol (2.0 g, 9.49 mmol), 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.21 g, 11.3 mmol), Pd(dppf)Cl (1.38 g, 1.89 mmol), and KPO (4.0 g, 18.9 mmol) in dioxane and HO was stirred at 100 °C under N for 2 h. The cooled mixture was partitioned between EtOAc and water, the layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over NaSO and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound as a yellow solid (2.20 g, 69.8%). LCMS m / z = 333 [M+H] + .

[0304] Preparation 87: 6-Bromo-7-fluoroquinazolin-4(3H)-one [ka] A mixture of 2-amino-5-bromo-4-fluorobenzoic acid (2 g, 8.54 mmol) and formamidine acetate (4.43 g, 42.6 mmol) in EtOH (20 mL) was stirred at 100 °C for 16 h. The mixture was concentrated to dryness, and the residue was diluted with water and extracted with DCM. The combined organic layers were dried over Na SO , filtered, and the filtrate was evaporated under reduced pressure to give the title compound (2 g, yield = 96%) as an off-white solid. LCMS m / z = 243, 245 [M+H] + .

[0305] Preparation 88: 6-Bromo-7-ethoxyquinazolin-4(3H)-one [ka] To a solution of EtONa in EtOH (21%, 10 mL) was added 6-bromo-7-fluoroquinazolin-4(3H)-one (Preparation 87, 2 g, 8.22 mmol) and the reaction was stirred at 80° C. for 16 hours. The reaction was concentrated to dryness, the residue was diluted with water, and the mixture was filtered. The solid was dried in vacuo to give the title compound (2.1 g, yield=90%) as a white solid. LCMS m / z = 271 [M+H] + .

[0306] Preparation 89: 6-Bromo-4-chloro-7-ethoxyquinazoline [ka] A solution of 6-bromo-7-ethoxyquinazolin-4(3H)-one (Preparation 88, 2.2 g, 8.17 mmol) in POCl (10 mL) was stirred at 100 °C for 3 h. The cooled mixture was concentrated to dryness and the residue was diluted with DCM (5 mL). The resulting solution was added dropwise to saturated NaCO (aq) (30 mL) and the mixture was extracted with DCM. The organic layer was dried over NaSO, filtered and concentrated to dryness to give the title compound (2.4 g, yield = 90%) as a brown solid. LCMS m / z = 289 [M+H] + .

[0307] Preparation 90: 6-Bromo-7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline [ka] A mixture of 6-bromo-4-chloro-7-ethoxyquinazoline (Preparation 89, 300 mg, 1.04 mmol), 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (443 mg, 1.56 mmol), KPO (331 mg, 1.56 mmol), and Pd(PPh) (48 mg, 0.0416 mmol) in dioxane (15 mL) and water (5 mL) was stirred at 80 °C for 3 h. The reaction mixture was evaporated to dryness, and the residue was purified by preparative TLC (20:1 DCM / MeOH) to give the title compound as a yellow solid (225 mg, 53%). LCMS: m / z = 409, 411 [M+H] + .

[0308] Preparation 91: 6-Bromo-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline [ka] Following a procedure similar to that described in Preparation 90, 6-bromo-4-chloro-7-methoxyquinazoline and 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave the title compound as a white solid (1.0 g, 49%). LCMS m / z = 397 [M+H] + .

[0309] Preparation 92: 6-Bromo-4-(3-(2,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazoline [ka] Using a method similar to that described for Preparation 90, the title compound was prepared from 6-bromo-4-chloro-7-methoxyquinazoline and 3-(2,6-difluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 34) as an off-white solid (160 mg, 88%). LCMS: m / z = 397 [M+H] + .

[0310] Preparation 93: 6-Bromo-7-ethoxy-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazoline [ka] Following a procedure similar to that described in Preparation 90, 6-bromo-4-chloro-7-ethoxyquinazoline (Preparation 89) and 1-ethyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 33) gave the title compound as an off-white solid (180 mg, 61% yield). LCMS m / z = 423,425 [M+H] + .

[0311] Preparation 94: 6-Bromo-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline [ka] Following the procedure described in Preparation 90, 6-bromo-4-chloro-7-methoxyquinazoline and 1-ethyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 33) gave the title compound as a yellow solid (200 mg, 57% yield). LCMS m / z = 409,411 [M+H] +. .

[0312] Preparation 95: 6-Bromo-7-ethoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinazoline [ka] Following a procedure similar to that described in Preparation 90, 6-bromo-4-chloro-7-ethoxyquinazoline (Preparation 89) and 3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 42) gave the title compound as a yellow solid (560 mg, 56% yield). LCMS m / z = 479,481 [M+H] + .

[0313] Preparation 96: 6-Bromo-4-(3-(2,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazoline [ka] Pd(PPh) (95.2 mg, 0.124 mmol) and KPO (394 mg, 1.86 mmol) were added to a solution of 3-(2,4-difluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 45, 400 mg, 1.24 mmol) and 6-bromo-4-chloro-7-methoxyquinazoline (404 mg, 1.48 mmol) in HO (4 mL) and dioxane (16 mL), and the reaction mixture was stirred at 80 °C for 2 h under N. The mixture was diluted with DCM (100 mL) and washed with brine (50 mL × 2), and the organic layer was dried over NaSO and concentrated in vacuo. The residue was purified on a silica gel column with DCM:MeOH = 20:1 to give 400 mg of the title compound as a white solid. LCMS m / z = 431 [M+H] + .

[0314] Preparation 97: 6-Bromo-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazoline [ka] A mixture of Pd(dppf)Cl (465 mg, 0.571 mmol), KPO (419 mg, 1.98 mmol), 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 43, 400 mg, 1.32 mmol), and 6-bromo-4-chloro-7-methoxyquinazoline (432 mg, 1.58 mmol) in HO (6 mL) and dioxane (24 mL) was stirred at 80° C. for 2 h under N. The mixture was diluted with EtOAc (150 mL), washed with brine (2×75 mL), dried (NaSO), and evaporated to dryness in vacuo. The residue was purified by column chromatography (15:1 DCM / MeOH) to give the title compound as an off-white solid (205 mg, 51%). LCMS: m / z = 413 [M+H] + .

[0315] Preparation 98: 6-Bromo-4-(1-ethyl-3-(2-fluorophenyl)-1H-pyrazol-4-yl)-7-methoxyquinazoline [ka] Pd(dppf)Cl (133 mg, 1.82 mmol) and KCO (251 mg, 1.82 mmol) were added to a solution of 6-bromo-4-chloro-7-methoxyquinazoline (500 mg, 1.82 mmol) and 1-ethyl-3-(2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 40, 575 mg, 1.82 mmol) in dioxane / HO, and the mixture was stirred at 80 °C for 3 h. The resulting solution was extracted with EtOAc (3 × 20 mL), dried (NaSO), and evaporated to dryness in vacuo. The residue was purified by preparative TLC (30:1 DCM / MeOH) to give the title compound as a yellow solid (290 mg, 37%). LCMS: m / z = 427 [M+H] + .

[0316] Preparation 99: 6-Bromo-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-ol [ka] A mixture of 6-bromo-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline (Preparation 94, 400 mg, 0.977 mmol) and pyridine hydrochloride (2.25 g, 19.5 mmol) was stirred at 140° C. for 8 hours. The mixture was diluted with DCM (100 mL), washed with brine (2×50 mL), dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by preparative TLC (25:1 DCM / MeOH) to give the title compound as a yellow solid (200 mg, 52%). LCMS: m / z = 395 [M+H] + .

[0317] Preparation 100: 6-Bromo-7-(difluoromethoxy)-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazoline [ka] Sodium 2-chloro-2,2-difluoroacetate (76.9 mg, 0.505 mmol) was added to a mixture of KCO (69.6 mg, 0.505 mmol), 6-bromo-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-ol (Preparation 99, 200 mg, 0.505 mmol) in DMF (10 mL) and HO (1 mL) at room temperature, and the resulting mixture was heated to 100 °C for 16 h. The mixture was diluted with EtOAc (100 mL) and washed with brine (2 × 50 mL). The combined organics were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by preparative TLC (25:1 DCM / MeOH) to give the title compound as a white solid (120 mg, 53%). LCMS: m / z = 395 [M+H] + .

[0318] Preparation 101: 6-Bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-ol [ka] A solution of 6-bromo-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 91, 300 mg, 0.759 mmol) in BBr3 (10.40 g, 41.51 mmol) was stirred at 80 °C for 6 h. This mixture was added dropwise to HO (30 mL) at 0 °C, the pH was adjusted to pH 8-9 with NaCO3, and the mixture was extracted with DCM (20 mL x 3). The combined organic layers were dried over NaSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc = 1 / 1) to give the title compound (74 mg, 25.6%) as a yellow solid.

[0319] Preparation 102: 6-Bromo-7-isopropoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline [ka] To a solution of 6-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-ol (Preparation 101, 45 mg, 0.118 mmol) and 2-iodopropane (30.1 mg, 0.177 mmol) in DMF (3 mL) was added K2CO3 (32.63 mg, 0.236 mmol), and the reaction was stirred at 80 °C for 2 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (0-100% EtOAc / PE) to afford the title compound (27 mg, 54%) as a white solid.

[0320] Preparation 103: 7-Isopropoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol [ka] To a solution of 6-bromo-7-isopropoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 102, 37 mg, 0.087 mmol) in dioxane (1 mL) and HO (0.25 mL) was added Pd(dba) (8.0 mg, 0.009 mmol), t-BuXphos (7.42 mg, 0.0175 mmol), and KOH (9.81 mg, 0.175 mmol), and the reaction was stirred at 80 °C for 2 h under N. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (EtOAc / MeOH = 10 / 1) to give the title compound (16.0 mg, 50.8%) as a yellow solid.

[0321] Preparation 104: tert-butyl (2-((6-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-yl)oxy)ethyl)carbamate [ka] A mixture of 6-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-ol (Preparation 101, 150 mg, 0.393 mmol), tert-butyl N-(2-bromoethyl)carbamate (176 mg, 0.786 mmol), and CsCO (257 mg, 0.786 mmol) in DMF (5 mL) was stirred at 100 °C for 16 h. The reaction was diluted with water and extracted with EtOAc (3 x 50 mL). The combined organics were dried (NaSO) and evaporated to dryness in vacuo, and the residue was purified by preparative TLC (10:1 DCM / MeOH) to give the title compound as a pale yellow solid (180 mg, 87%). LCMS: m / z = 523 [M+H] + .

[0322] Preparation 105: 2-((6-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-yl)oxy)-N,N-dimethylethan-1-amine [ka] Part 1. To tert-butyl (2-((6-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-yl)oxy)ethyl)carbamate (Preparation 104, 200 mg, 0.381 mmol) in DCM was added TFA and the mixture was stirred at room temperature for 4 hours. The reaction was evaporated to dryness in vacuo to give 2-((6-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-yl)oxy)ethan-1-amine, which was used in Part 2 without purification.

[0323] Part 2. HCHO solution (173 μL, 1.76 mmol) was added to a solution of 2-((6-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-yl)oxy)ethan-1-amine (Part 2, 150 mg, 0.354 mmol) in DCM, followed by Na(OAc)BH (224 mg, 1.06 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with NHCl solution and extracted with DCM. The combined organics were evaporated to dryness and the residue was purified by preparative TLC (10:1 DCM / MeOH) to afford the title compound as a white solid (70 mg, 41%). LCMS: m / z = 454 [M+H] + .

[0324] Preparation 106: 6-Bromo-4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline [ka] A mixture of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 35, 390 mg, 0.774 mmol), 6-bromo-4-chloro-7-methoxyquinazoline (317 mg, 1.16 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol), and K3PO4 (326 mg, 1.54 mmol) in dioxane (12 mL) and HO (3 mL) was stirred at 80 °C for 2 h. The reaction mixture was evaporated to dryness and the residue was purified by preparative TLC (35:1 DCM / MeOH) to give the title compound as a yellow solid (240 mg, 52%). LCMS: m / z = 541 [M+H] + .

[0325] Preparation 107: 6-Bromo-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)quinazoline [ka] To a solution of 6-bromo-4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline (Preparation 106, 570 mg, 1.10 mmol) in DCM (20 mL) was added TFA (5 mL) and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated to dryness and the residue was diluted with DCM and washed with saturated aqueous Na2CO3. The organic layer was separated, dried over Na2SO4, filtered and concentrated to dryness to give the title compound (480 mg, 84.9% yield) as a yellow solid. LCMS m / z = 381, 383 [M+H] + Preparation 108: 6-Bromo-7-methoxy-4-(3-phenyl-1-propyl-1H-pyrazol-4-yl)quinazoline [ka] NaH (31.3 mg, 0.786 mmol) was added to a solution of 6-bromo-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 107, 150 mg, 0.393 mmol), 1-bromopropane (96.6 mg, 0.786 mmol), and DMF (5 mL), and the mixture was stirred at 50° C. for 2 hours. The reaction was quenched with water and evaporated to dryness. The residue was purified by preparative TLC (20:1 DCM / MeOH) to give the title compound as a yellow solid (120 mg, 38%). LCMS: m / z = 425 [M+H] + .

[0326] Preparation 109: 7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol [ka] A mixture of 6-bromo-7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 90, 500 mg, 1.22 mmol), BrettPhos Pd G3 (111 mg, 0.122 mmol), and CsCO3 (598 mg, 1.83 mmol) in HO (2 mL) and dioxane (10 mL) was stirred at 100 °C for 16 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine (2 x 50 mL). The organic layer was dried over NaSO4 and concentrated in vacuo. The residue was purified by preparative TLC (15:1 DCM / MeOH) to give the title compound as a yellow solid (350 mg, 83%). LCMS m / z = 347 [M+H] + .

[0327] Preparation 110: 7-Methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinazolin-6-ol [ka] A mixture of 4-chloro-7-methoxyquinazolin-6-ol (315 mg, 1.5 mmol), 3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 42, 634 mg, 1.79 mmol), Pd(dppf)Cl (109 mg, 0.150 mmol), and KPO (1.27 g, 6.0 mmol) in dioxane (9 mL) and HO (3 mL) was heated to 80 °C for 3 h. The reaction mixture was concentrated to dryness, and the residue was purified by column chromatography to give the title compound as a light brown syrup (400 mg, 66%). LCMS m / z = 403 [M+H] + .

[0328] Preparation 111: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-ol [ka] A mixture of 4-chloro-7-methoxyquinazolin-6-ol (3 g, 14.2 mmol), 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 41, 5.68 g, 17.0 mmol), Pd(PPh3)4 (1.64 g, 1.42 mmol), and K3PO4 (3.60 g, 17.0 mmol) in dioxane / HO was stirred at 80 °C for 16 h. The resulting solution was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 3% MeOH / DCM) to give the title compound as a yellow solid (2.4 g, 44%). LCMS m / z = 383 [M+H] + .

[0329] Preparation 112: 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-ol [ka] To a mixture of 4-chloro-7-methoxyquinazolin-6-ol (70 mg, 0.332 mmol), KCO (92 mg, 0.665 mmol), and 3-(2-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 37, 151 mg, 0.499 mmol) in water (0.317 mL), dioxane (1.266 mL), and DME (0.633 mL) was added Pd(PPh) (38.4 mg, 0.033 mmol), and the reaction was stirred at 100° C. for 5 h under N. The mixture was filtered through Celite® eluting with DCM / MeOH, and the mixture was concentrated in vacuo. The residue was purified by Combiflash Isco, 12 g gold column, 0-20% MeOH / DCM to give the title compound as a viscous yellow oil (92.4 mg, 63.5% yield).

[0330] Preparation 113: 4-(3-(2,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-ol [ka] Following the procedure described in Preparation 112, 4-chloro-7-methoxyquinazolin-6-ol and 3-(2,6-difluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 34) gave the title compound as an off-white solid (40.6 mg, 46.4% yield).

[0331] Preparation 114: 7-Methoxy-4-(1-(oxetan-3-yl)-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol [ka] Following the procedure described in Preparation 112, 1-(oxetan-3-yl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 38) and 4-chloro-7-methoxyquinazolin-6-ol gave the title compound as a pale yellow solid (89.6 mg, 36% yield).

[0332] Preparation 115: 7-Methoxy-4-(3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)quinazolin-6-ol [ka] A mixture of 4-bromo-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (Preparation 30, 250 mg, 0.819 mmol), (BPin) (250 mg, 0.983 mmol), KOAc (241 mg, 2.458 mmol), and PdCl(dppf)-DCM (100 mg, 0.123 mmol) in dioxane (4 mL) was sparged with N for 5 minutes, and the reaction was heated at 90 °C overnight. The mixture was cooled to room temperature, and 4-chloro-7-methoxyquinazolin-6-ol (86 mg, 0.410 mmol), 2 M aqueous KCO (1.229 mL, 2.46 mmol), and additional PdCl(dppf)-DCM (100 mg, 0.123 mmol) were added, and the reaction was heated at 90 °C overnight. The reaction was diluted with water (1 mL) and mixed vigorously. The resulting solution was added to an Isolute HMN SPE tube (5 mL size) and gravity eluted with EtOAc. The filtrate was concentrated and dried under vacuum. The residue was purified by silica column chromatography (DCM to 20% MeOH / DCM) to give the title compound (142 mg, 39.0%). LCMS m / z = 401.1 [M+H] + .

[0333] Preparation 116: 7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl trifluoromethanesulfonate [ka] To a solution of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 86, 1 g, 3.0 mmol) and TEA (1.21 g, 12.0 mmol) in anhydrous DCM (20 mL) at −60° C., TfO (2.11 g, 7.50 mmol) was added dropwise, and the reaction was stirred for 1 h. The solution was extracted with DCM (2×50 mL), and the combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography (SiO, 1:1 DCM / EtOAc) to give the title compound as a yellow solid (1.0 g, 72%). LCMS m / z = 465 [M+H]+ .

[0334] Preparation 117: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl trifluoromethanesulfonate [ka] TEA (116 mg, 1.15 mmol) was added to an ice-cold solution of 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-ol (Preparation 111, 220 mg, 0.575 mmol) in DCM (20 mL). TfO was added dropwise and the reaction was stirred for 1 h. The reaction was neutralized with aqueous NaHCO and extracted with DCM (60 mL x 3), and the combined organic extracts were concentrated in vacuo. The crude compound was purified by TLC PE: EtOAc = 1:1 to give 250 mg of the title compound as a red solid. LCMS m / z = 515 [M+H] + .

[0335] Preparation 118: 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl trifluoromethanesulfonate [ka] To a solution of 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-ol (Preparation 112, 200 mg, 0.570 mmol) in DCM (15 mL) was added TEA (230 mg, 2.28 mmol) and the solution was cooled to −50° C. TfO (482 mg, 1.71 mmol) was added and the reaction was stirred at −50° C. for 1 h. The mixture was concentrated in vacuo, the residue diluted with water (100 mL), the mixture extracted with EtOAc (2×100 mL), and the organic layers combined. The organic solution was washed with brine (50 mL), dried over anhydrous NaSO, and concentrated in vacuo. The product was purified by chromatography with DCM:MeOH (10:1) to give the title compound (240 mg, 87.5%) as a yellow solid. LCMS m / z = 483 [M+H] + .

[0336] Preparation 119: tert-butyl (3R,4R)-3-fluoro-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)oxy)piperidine-1-carboxylate [ka] To a solution of PPh3 (789 mg, 3.0 mmol), 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 86, 200 mg, 0.60 mmol), and tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (526 mg, 2.40 mmol) in THF at −10° C., DIAD (484 mg, 2.40 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 8 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (50 mL×2). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC eluting with PE:EtOAc = 1:1 to give 250 mg of the title compound as a yellow solid. LCMS m / z = 534 [M+H] + .

[0337] Preparation 120-124 The compounds in the table below were prepared from the appropriate quinazolin-6-ol and alcohol following a procedure similar to that described in Preparation 119. [Table 6-1] [Table 6-2]

[0338] Preparation 125: 4-chloro-7-methoxy-6-((tetrahydrofuran-3-yl)oxy)quinazoline [ka] A mixture of 4-chloro-7-methoxyquinazolin-6-ol (200 mg, 0.949 mmol), PPh3 (495 mg, 1.89 mmol), and tetrahydrofuran-3-ol (166 mg, 1.89 mmol) in THF (20 mL) was stirred at room temperature for 10 minutes. DIAD (382 mg, 1.89 mmol) was added, and the reaction was stirred at room temperature for 4 hours. The reaction was quenched with water, and the mixture was concentrated to dryness. The residue was purified by preparative TLC eluting with PE:EtOAc = 1:1 to give the title compound (200 mg, yield: 75%) as an off-white solid. LCMS m / z = 281 [M+H] + .

[0339] Preparation 126: 4-chloro-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline [ka] Following the procedure described in Preparation 125, 4-chloro-7-methoxyquinazolin-6-ol and tetrahydro-2H-pyran-4-ol gave the title compound as a colorless oil (240 mg, 86% yield). LCMS m / z = 295 [M+H] + .

[0340] Preparation 127: trans-rac-4-chloro-6-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-7-methoxyquinazoline [ka] PPh3 (1.24 g, 4.74 mmol) and DIAD (773 mg, 3.79 mmol) were added to 4-chloro-7-methoxyquinazolin-6-ol (200 mg, 0.949 mmol) and cis-rac-(3S,4SR)-3-fluorotetrahydro-2H-pyran-4-ol (569 mg, 4.74 mmol) in THF (5 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h under N2. The mixture was extracted with EtOAc (3 x 40 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by preparative TLC with DCM:MeOH = 25:1 to give the title compound as a yellow solid (110 mg, 37%). LCMS: m / z = 313 [M+H] + .

[0341] Preparation 128: 6-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-ol [ka] Pd(dppf)Cl (173 mg, 0.237 mmol) and KCO (489 mg, 3.55 mmol) were added to a solution of 4-chloro-6-methoxyquinazolin-7-ol (500 mg, 2.37 mmol) and 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in dioxane / HO (4 / 1 v / v). The reaction was stirred at 80 °C under N overnight. The resulting solution was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over NaSO and concentrated in vacuo. The crude product was purified by preparative TLC (25:1 DCM / MeOH) to give the title compound as a yellow solid (209 mg, 27%). LCMS m / z = 333 [M+H] + .

[0342] Preparation 129: 4-chloro-7-ethoxy-6-methoxyquinazoline [ka] To a solution of PPh3 (1.86 g, 7.10 mmol), 4-chloro-6-methoxyquinazolin-7-ol (300 mg, 1.42 mmol) in EtOH (327 mg, 7.10 mmol) and THF (15 mL) at 0 °C, DIAD (1.15 g, 5.68 mmol) was added dropwise, and the reaction was stirred at room temperature for 2 h. The resulting solution was extracted with EtOAc (3 × 50 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by preparative TLC with DCM:MeOH = 25:1 to afford 200 mg (59%) of the title compound as a yellow solid. LCMS m / z = 239 [M+H] + .

[0343] Preparation 130: 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline [ka] Following the procedure described in Preparation 129, 4-chloro-6-methoxyquinazolin-7-ol and 2-methoxyethan-1-ol gave the title compound as a yellow solid (500 mg, 56% yield). LCMS m / z = 269 [M+H] + .

[0344] Preparation 131: 6-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-ol [ka] To a solution of 4-chloro-6-methoxyquinazolin-7-ol (350 mg, 1.66 mmol) in dioxane / HO (4 / 1 v / v) was added 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (565 mg, 1.99 mmol), KCO (458 mg, 3.32 mmol), and Pd(dppf)Cl (121 mg, 0.166 mmol) under N, and the reaction was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature and then diluted with water (20 mL). The resulting solution was extracted with EtOAc (2 × 20 mL), and the organic layers were combined, washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo. The crude product was purified by preparative TLC (DCM:MeOH=10:1) to give the title compound (270 mg, 49.0%) as a yellow solid. LCMS m / z = 333 [M+H] + .

[0345] Preparation 132: 4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline-6,7-diol [ka] To a solution of 6-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-ol (Preparation 131, 140 mg, 0.421 mmol) in DCE (5 mL) was added BBr (1.06 g, 4.21 mmol) dropwise at 0 °C. The mixture was stirred at 25 °C for 1 h, then quenched with HO (10 mL) and extracted with DCM (10 mL × 2). The aqueous layer was diluted with MeOH (20 mL), the mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (150 mg, crude) as a yellow solid.

[0346] Preparation 133: 6-(benzyloxy)-7-bromopyrido[3,2-d]pyrimidin-4-ol [ka] To a solution of benzyl alcohol (177.26 mg, 1.64 mmol) in DMF (2.0 mL) was added NaH (98.35 mg, 2.46 mmol, 60% purity), and the mixture was stirred at 25 °C for 5 minutes. 7-Bromo-6-fluoropyrido[3,2-d]pyrimidin-4-ol (400 mg, 1.64 mmol) was added, and the reaction was stirred at 25 °C for 20 minutes. The reaction was diluted with HO (8 mL) at 0 °C, and then 1 M HCl was added dropwise until pH = 3. The reaction mixture was filtered, and the filter cake was concentrated under reduced pressure to provide the title compound as a white solid.

[0347] Preparation 134: 6-(benzyloxy)-7-methoxypyrido[3,2-d]pyrimidin-4-ol [ka] To a solution of 6-(benzyloxy)-7-bromopyrido[3,2-d]pyrimidin-4-ol (Preparation 133, 200 mg, 0.602 mmol) in MeOH (5.0 mL) and DMSO (5.0 mL) was added t-BuXphos (25.57 mg, 0.06 mmol), CsCO (392.37 mg, 1.20 mmol), and Pd(dba) (55.14 mg, 0.06 mmol), and the mixture was stirred at 80 °C for 2 h under N. The crude product was diluted with HO (8 mL) at 0 °C, and then 1 M HCl was added dropwise until pH = 3. The reaction mixture was filtered, and the filtrate was freeze-dried. The crude product was purified by recrystallization from HO (2 mL) to give the title compound as an off-white solid.

[0348] Preparation 135: 6-(benzyloxy)-4-chloro-7-methoxypyrido[3,2-d]pyrimidine [ka] To a solution of 6-(benzyloxy)-7-methoxypyrido[3,2-d]pyrimidin-4-ol (Preparation 134, 100 mg, 0.353 mmol) in CCl (1.0 mL) and DCE (2.0 mL) was added PPh (277.8 mg, 1.06 mmol), and the reaction was stirred at 75 °C for 2 h under N. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EtOAc = 1 / 0 to 1 / 1) to give the title compound (150 mg, crude) as a yellow gum.

[0349] Preparation 136: 6-(benzyloxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine [ka] To a solution of 6-(benzyloxy)-4-chloro-7-methoxypyrido[3,2-d]pyrimidine (Preparation 135, 150 mg, 0.497 mmol) and 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (70.63 mg, 0.249 mmol) in HO (0.10 mL), DME (1.00 mL), and dioxane (2.00 mL) was added Pd(PPh) (57.45 mg, 0.05 mmol) and KCO (137.41 mg, 0.994 mmol). The mixture was stirred at 100 °C for 1 h under N. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (PE / EtOAc = 0 / 1) to give the title compound (40 mg, 19.0% yield) as a white solid. H-NMR (400 MHz, CDCl) δ ppm 9.05 (s, 1H), 7.97 (s, 1H), 7.49-7.47 (m, 2H), 7.41 (s, 1H), 7.37-7.34 (m, 5H), 7.26-7.24 (m, 3H), 5.06 (s, 2H), 4.03 (s, 3H), 4.01 (s, 3H).

[0350] Preparation 137: 7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-ol [ka] To a solution of 6-(benzyloxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Preparation 136, 40.0 mg, 0.095 mmol) in 5.0 mL of EtOAc was added Pd / C (40.0 mg, 10% purity, 50% in HO), and the reaction was stirred under H (15 psi) at 25° C. for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (40.0 mg, crude) as a yellow solid.

[0351] Preparation 138: 7-Methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinazolin-6-yl (2S)-2,4-dimethylpiperazine-1-carboxylate [ka] A mixture of 7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 110, 100 mg, 0.248 mmol), (2S)-2,4-dimethylpiperazine-1-carbonyl chloride (43 mg, 0.248 mmol) and K2CO3 (68 mg, 0.497 mmol) in MeCN (5.0 mL) was stirred at 0 °C for 2 hours. The reaction mixture was concentrated to dryness. The residue was purified on a silica gel column with 5% MeOH / DCM to give the title compound (100 mg, yield = 74%) as a pale yellow solid. LCMS m / z = 543 [M+H] + .

[0352] Preparation 139: 7-Methoxy-4-(3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (S)-2,4-dimethylpiperazine-1-carboxylate [ka] To a solution of 7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinazolin-6-yl(2S)-2,4-dimethylpiperazine-1-carboxylate (Preparation 138, 100 mg, 0.184 mmol) in DCM (5 mL) was added TFA (2 mL) at 0° C. and the reaction was stirred at room temperature for 3 hours. The mixture was concentrated to dryness and the residue was diluted with DCM and washed with saturated aqueous Na2CO3. The organic layer was separated, dried over Na2SO4, filtered and concentrated to dryness to give the title compound (100 mg, crude) as a pale yellow solid. LCMS m / z = 459 [M+H] + .

[0353] Preparation 140: 1-(tert-butyl) 4-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)(2S,5S)-2,5-dimethylpiperazine-1,4-dicarboxylate [ka] To a mixture of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 86, 100 mg, 0.301 mmol) and tert-butyl (2S,5S)-4-(chlorocarbonyl)-2,5-dimethylpiperazine-1-carboxylate (Preparation 58, 166.54 mg, 0.602 mmol) in DMF (2 mL) was added KCO (83.17 mg, 0.602 mmol) and the reaction was stirred for 1 hour at 80° C. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (150 mg, crude) as a yellow solid.

[0354] Preparation 141: 4-(tert-butyl) 1-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)(S)-2-methylpiperazine-1,4-dicarboxylate [ka] Following the procedure described in Preparation 140, 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 86) and tert-butyl (2S)-4-(chlorocarbonyl)-2,5-dimethylpiperazine-1-carboxylate gave the title compound as a yellow solid (100 mg, crude).

[0355] Preparation 142: 1-(tert-butyl) 4-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)(2R,3S)-2,3-dimethylpiperazine-1,4-dicarboxylate [ka] Part 1: To a solution of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 86, 500 mg, 1.50 mmol) and DIPEA (291.65 mg, 2.26 mmol) in THF (20 mL) was added triphosgene (1.050 g, 3.54 mmol) dropwise at 0° C., and the reaction was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure to give 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl carbonochloridate (500 mg, crude) as a yellow solid, which was used directly in the next step.

[0356] Part 2: To a solution of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl carbonochloridate (200 mg, 0.507 mmol) and (2R,3S)-tert-butyl 2,3-dimethylpiperazine-1-carboxylate (54.28 mg, 0.253 mmol) in DCM (2 mL) was added TEA (102.52 mg, 1.01 mmol), and the reaction was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 * 30mm *10 um; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 30%-60%, 10 min) to afford the title compound (80 mg, 27.6% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ ppm 9.18 (s, 1H), 7.79 (s, 1H), 7.45 (s, 1H), 7.40-7.34 (m, 3H), 7.23-7.18 (m, 3H), 6.80-6.73 (m, 1H), 4.06 (s, 3H), 4.05-4.01 (m, 1H), 3.98 (s, 3H), 3.97-3.92 (m, 1H), 3.72-3.63 (m, 2H), 3.57-3.44 (m, 2H), 1.50 (s, 9H), 1.36 (d, 3H), 1.29 (d, 3H).

[0357] Preparation 143: 7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (2S,5S)-2,5-dimethylpiperazine-1-carboxylate [ka] 1-(tert-butyl) 4-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)(2S,5S)-2,5-dimethylpiperazine-1,4-dicarboxylate (Preparation 140, 150 mg, 0.262 mmol) in a HCl / EtOAc mixture (5.0 mL) was stirred at 20° C. for 20 min. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 * 30mm *3 um; mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-MeCN]; B%: 20%-45%, 8 min) to give the title compound (66.30 mg, 53.6% yield) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 9.20 (s, 1H), 7.82 (s, 1H), 7.52 (s, 1H), 7.43-7.40 (m, 3H), 7.25-7.23 (m, 3H), 4.33-4.27 (m, 1H), 4.09 (s, 3H), 4.02 (s, 3H), 3.92-3.84 (m, 1H), 3.13-3.07 (m, 1H), 2.89 (br d, 1H, J = 12.4 Hz), 2.84-2.67 (m, 2H), 1.35 (br dd, 3H, J = 18.0, 6.8 Hz), 1.14-1.13 (m, 3H).

[0358] Preparation 144: 7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (2S,3R)-2,3-dimethylpiperazine-1-carboxylate [ka] Following a procedure similar to that described in Preparation 143, 1-(tert-butyl) 4-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)(2R,3S)-2,3-dimethylpiperazine-1,4-dicarboxylate (Preparation 142) gave the title compound as a yellow solid (36.2 mg, 58% yield).

[0359] Preparation 145: 7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (S)-2-methylpiperazine-1-carboxylate trifluoroacetate [ka] To a mixture of 4-(tert-butyl) 1-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)(S)-2-methylpiperazine-1,4-dicarboxylate (Preparation 141, 100 mg, 0.179 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) and the reaction was stirred at 20° C. for 0.5 h. The mixture was concentrated under reduced pressure to give the title compound (120 mg, crude) as a yellow oil.

[0360] Preparation 146: Methyl 5-(benzyloxy)-4-bromo-2-nitrobenzoate [ka] To a mixture of phenylmethanol (7.76 g, 71.8 mmol) in THF (200 mL) was added NaH (1.72 g, 71.8 mmol) at 0° C. The solution was stirred at 0° C. for 15 minutes, and then methyl 4-bromo-5-fluoro-2-nitrobenzoate (10 g, 35.9 mmol) was added, and the reaction mixture was stirred at 25° C. for 16 hours. The mixture was poured into ice water and extracted with EtOAc. The organic phase was concentrated in vacuo, and the residue was purified by column chromatography (50% EtOAc / PE) to give the title compound (6 g, yield: 45.8%) as a yellow solid. LCMS m / z = 366 [M+H] + .

[0361] Preparation 147: Methyl 2-amino-5-(benzyloxy)-4-bromobenzoate [ka] A mixture of methyl 5-(benzyloxy)-4-bromo-2-nitrobenzoate (Preparation 146, 6 g, 16.3 mmol), Fe (13.6 g, 244 mmol), and HCl (8.54 g, 244 mmol) in EtOH (100 mL) and water (10 mL) was stirred at 80 °C for 2 h. The cooled mixture was filtered, and the filtrate was evaporated under reduced pressure. The crude solid was diluted with DCM (100 mL), basified with NaHCO and extracted with DCM. The organic phase was dried over NaSO, filtered, and concentrated to give the title compound (5 g, 91.4% yield) as a yellow solid. LCMS m / z = 336 [M+H] + .

[0362] Preparation 148: 2-Amino-5-(benzyloxy)-4-bromobenzoic acid [ka] To a solution of methyl 2-amino-5-(benzyloxy)-4-bromobenzoate (Preparation 147, 5 g, 14.8 mmol) in THF / HO was added LiOH (1.06 g, 44.4 mmol) and the reaction was stirred at 25 °C for 4 h. The resulting solution was diluted with water (100 mL), extracted with EtOAc (2 x 50 mL), and the organic layers were combined. The resulting solution was washed with brine (20 mL), dried over anhydrous NaSO, and evaporated under reduced pressure to give the title compound (4 g, 84.0%) as a yellow solid. LCMS m / z = 322 [M+H] + .

[0363] Preparation 149: 6-(benzyloxy)-7-bromoquinazolin-4(3H)-one [ka] To a solution of 2-amino-5-(benzyloxy)-4-bromobenzoic acid (Preparation 148, 4 g, 12.4 mmol) in EtOH (100 mL) was added ethanimidamide (3.60 g, 62.0 mmol) and the reaction was stirred at 80° C. for 16 hours. The solution was concentrated in vacuo, water was added, and the resulting solid was filtered off to give the title compound as a yellow solid (3.5 g, 85.3% as a yellow solid). LCMS m / z = 322 [M+H] + .

[0364] Preparation 150: 6-(benzyloxy)-7-bromo-4-chloroquinazoline [ka] To a solution of 6-(benzyloxy)-7-bromo-3,4-dihydroquinazolin-4-one (Preparation 149, 3.5 g, 10.5 mmol) in MeCN (100 mL) was added TEA (6.36 g, 63.0 mmol), followed by phosphoroyl trichloride (8.04 g, 52.5 mmol), and the reaction was stirred at 80° C. for 3 h. The cooled mixture was poured into sodium bicarbonate solution and extracted with EtOAc. The organic layer was dried (MgSO), filtered, and the solvent evaporated to dryness. The crude product was purified by silica gel column chromatography (PE:EtOAc=2:1) ​​to give the title compound (2.0 g, 54.4%) as a yellow solid. LCMS m / z = 350 [M+H] + .

[0365] Preparation 151: 6-(benzyloxy)-7-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline [ka] A mixture of 6-(benzyloxy)-7-bromo-4-chloroquinazoline (Preparation 150, 699 mg, 2 mmol), 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (625 mg, 2.20 mmol), Pd(PPh3)4 (346 mg, 0.30 mmol), and K3PO4 (805 mg, 3.80 mmol) in DMSO (20 mL) was heated to 80 °C for 3 h. After cooling to room temperature, the mixture was quenched with 5% NaOH (aq) (50 mL). The mixture was extracted with EtOAc (20 mL x 3), and the organic layers were combined and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / EtOAc = 1:1 to DCM / MeOH = 15:1) to afford 300 mg of the title compound as a yellow solid.

[0366] Preparation 152: 7-Bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol [ka] A solution of 6-(benzyloxy)-7-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 151, 282 mg, 0.6 mmol) in TFA (20 mL) was heated to 80° C. for 3 hours. After cooling to room temperature, the mixture was evaporated under reduced pressure to give the title compound (190 mg, 83%) as a yellow syrup.

[0367] Preparation 153: 7-Bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (S)-2,4-dimethylpiperazine-1-carboxylate [ka] A mixture of 7-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 152, 190 mg, 0.5 mmol), (2S)-2,4-dimethylpiperazine-1-carbonyl chloride (176 mg, 1 mmol), and KCO (207 mg, 1.5 mmol) in MeCN (5 mL) was heated to 80 °C for 3 h. The cooled mixture was concentrated in vacuo, and the residue was purified by preparative TLC (DCM / MeOH = 15:1) to give the title compound (200 mg, 76.9%) as a yellow syrup. LCMS m / z = 521 [M+H] + .

[0368] Preparation 154: (S)-6-Bromo-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4(3H)-one [ka] To a solution of 6-bromo-7-fluoroquinazolin-4(3H)-one (200 mg, 0.826 mmol) and (S)-tetrahydrofuran-3-ol (145 mg, 1.65 mmol) in DMF (10 mL) was added NaH (60%, 66 mg, 1.65 mmol) at room temperature, and the reaction was stirred at 80° C. for 3 hours. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated to dryness. The residue was purified by preparative TLC with DCM:MeOH=25:1 to give the title compound (180 mg, yield: 70%) as a white solid. LCMS: m / z = 311, 313 [M+H] + .

[0369] Preparation 155: (S)-6-Bromo-4-chloro-7-((tetrahydrofuran-3-yl)oxy)quinazoline [ka] A solution of (S)-6-bromo-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4(3H)-one (Preparation 154, 180 mg, 0.579 mmol) in POCl (5 mL) was stirred at 100 °C for 3 h. The cooled reaction was concentrated to dryness and the residue was then diluted with DCM (5 mL). The resulting solution was diluted with saturated NaCO (aq) (30 mL) and extracted with DCM. The organic layer was dried over NaSO, filtered and concentrated to dryness to give the title compound (200 mg, crude) as a brown solid. LCMS: m / z = 330 [M+H] +

[0370] Preparation 156: (S)-6-Bromo-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-((tetrahydrofuran-3-yl)oxy)quinazoline [ka] Following the procedure described in Preparation 90, (S)-6-bromo-4-chloro-7-((tetrahydrofuran-3-yl)oxy)quinazoline (Preparation 155) and 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 41) gave the title compound as a yellow solid (150 mg, 50% yield). LCMS: m / z = 501, 503 [M+H] + .

[0371] Preparation 157: 6-Bromo-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline [ka] Following a procedure similar to that described in Preparation 90, 6-bromo-4-chloro-7-methoxyquinazoline and 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 41) gave the title compound (400 mg, 90% yield). LCMS: m / z = 445, 447 [M+H] + .

[0372] Preparation 158: 6-Bromo-4-(1-ethyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-7-methoxyquinazoline [ka] Following a procedure similar to that described in Preparation 90, 1-ethyl-3-(4-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 44) and 6-bromo-4-chloro-7-methoxyquinazoline gave the title compound as a pale yellow solid (50 mg, 37% yield). LCMS m / z = 427 [M+H] + .

[0373] Preparation 159: 6-Bromo-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-ethoxyquinazoline [ka] Pd(dppf)Cl (76.0 mg, 0.104 mmol) and KCO (215 mg, 1.56 mmol) were added to 6-bromo-4-chloro-7-ethoxyquinazoline (Preparation 89, 300 mg, 1.04 mmol) and 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 41, 380 mg, 1.14 mmol) in dioxane / HO (10 mL / 2.5 mL), and the reaction mixture was heated at 80 °C for 16 h. The reaction mixture was diluted with EtOAc (100 mL) and washed successively with water (100 mL x 3) and brine (100 mL). The organic layer was dried over NaSO, filtered, and evaporated under reduced pressure. The crude product was purified by preparative TLC eluting with PE: EtOAc = 1:1 to give 360 ​​mg (75.4%) of the title compound as a pale yellow solid. LCMS m / z = 458 [M+H] + .

[0374] Preparation 160: 6-Bromo-7-ethoxy-4-(3-phenyl-1H-pyrazol-4-yl)quinazoline [ka] To a solution of 6-bromo-7-ethoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinazoline (Preparation 95, 600 mg, 1.25 mmol) in DCM (9 mL) was added TFA (3 mL) and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated to dryness and the residue was diluted with saturated aqueous Na2CO3 and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness to give the title compound (400 mg, yield=80%) as a pale yellow solid. LCMS: m / z =395, 397 [M+H] + .

[0375] Preparation 161: 6-Bromo-7-ethoxy-4-(1-isopropyl-3-phenyl-1H-pyrazol-4-yl)quinazoline [ka] To a mixture of 6-bromo-7-ethoxy-4-(3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 160, 200 mg, 0.505 mmol) and 2-iodopropane (171 mg, 1.01 mmol) in DMF (10 mL) was added NaH (24.2 mg, 1.01 mmol), and the reaction was stirred at 50° C. for 1 hour. The reaction was quenched with ice water and then concentrated to dryness. The residue was purified by preparative TLC with DCM:MeOH=20:1 to give the title compound (150 mg, yield=68%) as a pale yellow solid. LCMS: m / z = 437, 439 [M+H] + .

[0376] Preparation 162: 6-Bromo-4-(1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7-ethoxyquinazoline [ka] A mixture of Cu(OAc) (92 mg, 0.760 mmol) and bipyridine (118 mg, 0.760 mmol) in DCE (15 mL) was stirred at 80 °C for 30 min and then allowed to cool. 6-Bromo-7-ethoxy-4-(3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 160, 150 mg, 0.380 mmol), cyclopropylboronic acid (65 mg, 0.760 mmol), and NaCO (80 mg, 0.760 mmol) were added, and the reaction was stirred at 80 °C under an atmosphere of O for 4 h. The mixture was concentrated to dryness, and the residue was purified by preparative TLC with DCM:MeOH = 25:1 to give the title compound (80 mg, 48% yield) as a pale yellow solid. LCMS: m / z = 435, 437 [M+H] + .

[0377] Preparation 163: 6-(1-ethoxyvinyl)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline [ka] To a solution of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl trifluoromethanesulfonate (Preparation 116, 1 g, 2.15 mmol) in dioxane / HO (20 mL / 5 mL) was added tributyl(1-ethoxyethenyl)stannane (776 mg, 2.15 mmol), KCO (593 mg, 4.30 mmol), and Pd(PPh)Cl (171 mg, 0.21 mmol) under N, and the reaction was stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature and then diluted with water (25 mL). The resulting solution was extracted with EtOAc (2 × 40 mL), and the organic layers were combined. The resulting mixture was washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo. The product was purified by chromatography with PE: EtOAc (1:1) to give 600 mg (72.2%) of the title compound as a yellow solid. LCMS m / z = 387 [M+H] + .

[0378] Preparation 164: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6-(1-ethoxyvinyl)-7-methoxyquinazoline [ka] Following the procedure described in Preparation 163, 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl trifluoromethanesulfonate (Preparation 117) gave the title compound as a white solid (211 mg, 48%). LCMS m / z = 437 [M+H] + .

[0379] Preparation 165: 7-ethoxy-6-(1-ethoxyvinyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline [ka] A mixture of 6-bromo-7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 90, 200 mg, 0.488 mmol), (1-ethoxyethenyl)triethylstannane (270 mg, 0.976 mmol), Pd(PPh)Cl (30 mg, 0.043 mmol), and CsCO (317 mg, 0.976 mmol) in dioxane (15 mL) was stirred at 100 °C for 4 h, and then the reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC with DCM:MeOH = 15:1 to give the title compound (160 mg, yield: 75.8%) as a gray-yellow solid. LCMS: m / z = 401 [M+H] + .

[0380] Preparation 166: 7-ethoxy-6-(1-ethoxyvinyl)-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazoline [ka] A mixture of 6-bromo-7-ethoxy-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 93, 180 mg, 0.425 mmol), tributyl(1-ethoxyethenyl)stannane (230 mg, 0.637 mmol), and Pd(PPh)Cl (29.8 mg, 0.0425 mmol) in dioxane (15 mL) was stirred at 100 °C for 2 h and concentrated to dryness. The residue was purified by preparative TLC with DCM:MeOH = 20:1 to give the title compound (130 mg, 74%) as a pale yellow solid. LCMS: m / z = 415 [M+H] + .

[0381] Preparations 167-171 The compounds in the table below were prepared from the appropriate 6-bromoquinazoline and tributyl(1-ethoxyethenyl)stannane following a procedure similar to that described in Preparation 166. [Table 7-1] [Table 7-2]

[0382] Preparation 172: 1-(7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-one [ka] A mixture of 6-(1-ethoxyvinyl)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 163, 150 mg, 0.388 mmol) in TFA (3.0 mL) and DCM (3.0 mL) was stirred at 25° C. for 1 hour. The mixture was evaporated under reduced pressure to give the title compound as a yellow solid (120 mg, 86.3%). LCMS m / z = 359 [M+H] + .

[0383] Preparation 173: 1-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl)ethan-1-one [ka] 1-(4-(1-(2,2-Difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl)ethan-1-one was obtained from 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6-(1-ethoxyvinyl)-7-methoxyquinazoline (Preparation 164) according to the procedure described in Preparation 172. LCMS m / z = 409 [M+H] + .

[0384] Preparation 174: 1-(7-isopropoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-one [ka] Obtain the title compound as a pale yellow solid from 6-(1-ethoxyvinyl)-7-isopropoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 171) following the procedure described in Preparation 172. LCMS m / z = 387 [M+H] + .

[0385] Preparation 175: (S)-1-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)ethan-1-one [ka] A mixture of (S)-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6-(1-ethoxyvinyl)-7-((tetrahydrofuran-3-yl)oxy)quinazoline (Preparation 168, 110 mg, 0.223 mmol) in DCM (12 mL) and TFA (4 mL) was stirred at room temperature for 1 hour and then concentrated to dryness. The residue was purified by preparative TLC with DCM:MeOH=30:1 to give the title compound (90 mg, yield=86%) as a pale yellow solid. LCMS: m / z = 465 [M+H] + .

[0386] Preparation 176: 1-(4-(1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7-ethoxyquinazolin-6-yl)ethan-1-one [ka] Following the procedure described in Preparation 175, 4-(1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7-ethoxy-6-(1-ethoxyvinyl)quinazoline (Preparation 170) gave the title compound as an off-white solid (95 mg, 81% yield). LCMS m / z = 399 [M+H] + .

[0387] Preparation 177: 1-(7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-one [ka] A mixture of 7-ethoxy-6-(1-ethoxyvinyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 165, 260 mg, 0.601 mmol) in TFA (2 mL) and DCM (10 mL) was stirred at 25 °C for 2 h, and the mixture was concentrated in vacuo. The residue was diluted with saturated aqueous Na2CO3 and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness to give the title compound (240 mg, 99.1% yield) as a yellow solid. LCMS m / z = 373 [M+H] + .

[0388] Preparation 178: 1-(7-ethoxy-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-one [ka] Obtain the title compound as an off-white solid (100 mg, 82% yield) from 7-ethoxy-6-(1-ethoxyvinyl)-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 166) following the procedure described in Preparation 177. LCMS: m / z = 387 [M+H] + .

[0389] Preparation 179: 1-(4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl)ethan-1-one [ka] Following the procedure described in Preparation 177, 6-(1-ethoxyvinyl)-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline (Preparation 167) gave the title compound as a yellow solid (140 mg, 68% yield). LCMS m / z = 373 [M+H] + .

[0390] Preparation 180: 1-(7-ethoxy-4-(1-isopropyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-one [ka] A solution of 7-ethoxy-6-(1-ethoxyvinyl)-4-(1-isopropyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 169, 120 mg, 0.238 mmol) in DCM (10 mL) and TFA (2 mL) was stirred at 25 °C for 2 h and then concentrated to dryness. The residue was diluted with saturated aqueous Na2CO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated to dryness, and purified by preparative TLC with DCM:MeOH = 40:1 to give the title compound (76 mg, yield: 57.3%) as a yellow solid. LCMS: m / z = 401 [M+H] + .

[0391] Preparation 181: Ethyl 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline-6-carboxylate [ka] To a solution of 6-(1-ethoxyvinyl)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 163, 150 mg, 0.388 mmol) in dioxane (6 mL) was added a solution of NaIO (166 mg, 0.776 mmol) in water (2 mL), followed by the addition of KMnO (12.2 mg, 0.078 mmol) in several portions. The resulting solution was stirred at 25 °C for 2 h, then extracted with DCM (2 × 20 mL) and the organic layers combined. The resulting mixture was washed with HO (2 × 20 mL) and brine (10 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by TLC DCM:MeOH = 10:1 to afford 100 mg (66.6%) of the title compound as a white solid. LCMS m / z = 389 [M+H] + .

[0392] Preparation 182: Ethyl 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline-6-carboxylate [ka] Following a procedure similar to that described in Preparation 181, 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6-(1-ethoxyvinyl)-7-methoxyquinazoline (Preparation 164) gave ethyl 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline-6-carboxylate as a white solid (100 mg, 66.6% yield). LCMS m / z = 439 [M+H] + .

[0393] Preparation 183: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxy-6-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)quinazoline [ka] To a solution of cataCXium A Pd G3 (389 mg, 0.524 mmol), 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl trifluoromethanesulfonate (Preparation 117, 2.7 g, 5.24 mmol), and 2,2'-(cyclopropane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (4.61 g, 15.7 mmol) in dioxane / HO (50 mL / 5 mL) was added CsCO3 (5.11 g, 15.7 mmol), and the reaction was stirred at 100 °C for 16 h. The mixture was diluted with EtOAc (300 mL) and washed with brine (100 mL x 2), and the organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column eluting with DCM:MeOH=25:1 to give 2.4 g of the title compound as a yellow solid. LCMS: m / z =533 [M+H] + .

[0394] Preparation 184: tert-butyl 6-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate [ka] Pd(dppf)Cl (36.9 mg, 0.051 mmol) and KCO (104 mg, 0.757 mmol) were added to a solution of 6-bromo-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 91, 200 mg, 0.505 mmol) and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (188 mg, 0.606 mmol) in HO (1 mL) and dioxane (4 mL) at room temperature, and the reaction mixture was heated at 80 °C for 2 h under N. The resulting solution was extracted with EtOAc (3 × 50 mL), and the combined organic layers were dried (NaSO) and concentrated in vacuo. The crude product was purified by preparative TLC with DCM:MeOH=25:1 to give 150 mg (59%) of the title compound as a yellow solid. LCMS: m / z = 500 [M+H] + .

[0395] Preparation 185: 6-(7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-3,4-dihydro-2H-1,4-oxazine trifluoroacetate [ka] To tert-butyl 6-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (Preparation 184, 60 mg, 0.12 mmol) in DCM (5 mL) was added TFA (2 mL) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give 40 mg (83%) of the title compound as a yellow oil. LCMS: m / z = 400 [M+H] + .

[0396] Preparation 186: 6-(2,5-dihydro-1H-pyrrol-3-yl)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline trifluoroacetate [ka] A mixture of 6-bromo-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 91, 50 mg, 0.126 mmol), Pd(PPh3)4 (14.62 mg, 0.013 mmol), THF (0.5 mL), K3PO4 (126 μL, 0.253 mmol), and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (56 mg, 0.19 mmol) was stirred at 80 °C. The cooled mixture was diluted with water and DCM, the layers were separated, and the organic phase was concentrated in vacuo. The residue was purified by silica gel column (MeOH:DCM) to give tert-butyl 3-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate. This was dissolved in TFA (1 mL) and the solution was stirred at room temperature overnight. The solution was evaporated under reduced pressure to give the title compound.

[0397] Preparation 187: (7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)methyl methanesulfonate [ka] To an ice-cold solution of (7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)methanol (Example 99, 300 mg, 0.832 mmol) and TEA (251 mg, 2.49 mmol) in DCM (10 mL) was added methanesulfonyl chloride (155 mg, 1.25 mmol) dropwise, and the reaction was stirred at room temperature for 1 hour. The reaction was extracted with EtOAc (3×50 mL), and the combined organic layers were dried over NaSO and concentrated in vacuo. The crude product was purified by preparative TLC with DCM:MeOH=20:1 to give the title compound (200 mg) as a yellow solid. LCMS: m / z = 439 [M+H] + .

[0398] Preparation 188: tert-butyl (S)-4-(7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-3-methylpiperazine-1-carboxylate [ka] PEPPSI Pd-Ipent-O-picoline (40.9 mg, 0.049 mmol) and CsCO (318 mg, 0.976 mmol) were added to 6-bromo-7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 90, 200 mg, 0.488 mmol) and tert-butyl (3S)-3-methylpiperazine-1-carboxylate (195 mg, 0.976 mmol) in dioxane (10 mL), and the reaction was heated to 80 °C under N for 16 h. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with water (100 mL x 3) and saturated brine (100 mL). The organic layer was dried over NaSO, filtered, and evaporated under reduced pressure. The crude product was purified by preparative TLC with DCM:MeOH=20:1 to give the title compound (220 mg, 85.6%) as a pale yellow solid. LCMS m / z = 529 [M+H] + .

[0399] Preparation 189: 4-Bromo-7-methoxy-6-nitroquinazoline [ka] To 7-methoxy-6-nitro-3,4-dihydroquinazolin-4-one (1 g, 4.52 mmol) in MeCN (10 mL) was added phosphoroyl tribromide (2.59 g, 9.04 mmol) at room temperature, and the resulting mixture was heated to 90 °C for 1 h. The reaction mixture was poured into 100 g of crushed ice and extracted with EtOAc (3 × 50 mL). The combined organics were dried (Na SO ) and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO , 33% EtOAc / PE) to afford the title compound as a pale yellow solid (350 mg), which was used without further purification.

[0400] Preparation 190: 7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine [ka] Part 1: A mixture of 4-bromo-7-methoxy-6-nitroquinazoline (Preparation 189, 350 mg, 1.23 mmol), 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (417 mg, 1.47 mmol), KCO (344 mg, 2.46 mmol), and Pd(dppf)Cl (100 mg, 0.123 mmol) in dioxane / water (10 mL / 2.5 mL) was heated at 80° C. for 16 h under N. The reaction mixture was extracted with EtOAc (3×30 mL), and the combined organics were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by preparative TLC (15:1 DCM / MeOH) to give 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-nitroquinazoline as a pale yellow solid (300 mg). LCMS: m / z = 362 [M+H] + .

[0401] Part 2: A mixture of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-nitroquinazoline (Part 1, 300 mg, 0.830 mmol), iron (463 mg, 8.30 mmol), and NH4Cl (448 mg, 8.30 mmol) in EtOH / HO (10 mL / 2.5 mL) was heated to 80 °C for 1 h. The reaction mixture was filtered through a Celite® pad, and the filtrate was evaporated to dryness in vacuo. The residue was purified by preparative TLC (12:1 DCM / MeOH) to give the title compound as a pale yellow solid (250 mg). LCMS: m / z = 332 [M+H] + .

[0402] Preparation 191: tert-butyl (2S,5S)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-2,5-dimethylpiperazine-1-carboxylate [ka] To a solution of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190, 70.0 mg, 0.211 mmol) in DCM (2 mL) was added pyridine (33.42 mg, 0.422 mmol) and 4-nitrophenyl chloroformate (63.87 mg, 0.317 mmol) at 0° C., and the reaction was stirred for 1 hour at 25° C. This mixture was added dropwise to a solution of tert-butyl (2S,5S)-2,5-dimethylpiperazine-1-carboxylate (226.35 mg, 1.06 mmol) and TEA (64.13 mg, 0.634 mmol) in DCM (2 mL), and the reaction was stirred at 45° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (PE / EtOAc=0:1) to give the title compound (70 mg, 58%) as a yellow gum. 1H-NMR (400 MHz, CDCl3) δ ppm 9.08-9.02 (m, 1H), 8.72 (s, 1H), 7.86 (s, 1H), 7.41-7.38 (m, 2H), 7.34 (s, 1H), 7.22-7.14 (m, 4H), 4.28 (d, 1H), 4.08 (d, 6H), 4.00-3.94 (m, 1H), 2.98 (d, 2H), 2.89-2.82 (m, 2H), 1.25 (d, 6H), 1.20 (s, 9H).

[0403] Preparation 192: tert-butyl (S)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-3-methylpiperazine-1-carboxylate [ka] Following a procedure similar to that described in Preparation 191, 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190), 4-nitrophenyl chloroformate, and tert-butyl (3S)-3-methylpiperazine-1-carboxylate gave the title compound as a yellow solid (50 mg, 30% yield).

[0404] Preparation 193: tert-butyl (2R,5S)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-2,5-dimethylpiperazine-1-carboxylate [ka] Following a procedure similar to that described in Preparation 191, 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190), 4-nitrophenyl chloroformate and tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate gave the title compound as a yellow solid (190 mg, 55% yield).

[0405] Preparation 194: tert-butyl (2S,3R)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-2,3-dimethylpiperazine-1-carboxylate or tert-butyl (2S,3R)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-2,3-dimethylpiperazine-1-carboxylate [ka] Following a procedure similar to that described in Preparation 191, 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190), 4-nitrophenyl chloroformate, and cis-tert-butyl 2,3-dimethylpiperazine-1-carboxylate gave the racemic title compound as a yellow solid. LCMS m / z = 486 [M+H] + This was then used in a preparative chiral SFC column: DAICEL CHIRALCEL OJ (250 mm * Further purification using 30 mm, 10 um; mobile phase: A for CO, B for IPA (0.1% NHOH); gradient: isocratic elution mode with B%=15%; flow rate: 60 g / min to give peak 1 (10.0 mg, 6%) and peak 2 (10.0 mg, 6%) of preparation 194, i.e., tert-butyl (2S,3R)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-2,3-dimethylpiperazine-1-carboxylate or tert-butyl (2S,3R)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-2,3-dimethylpiperazine-1-carboxylate. 1H-NMR (400 MHz, CDCl3) δ ppm 8.99 (s, 1H), 8.63 (s, 1H), 7.80 (s, 1H), 7.31-7.34 (m, 2H), 7.16-7.22 (m, 2H), 7.10-7.13 (m, 3H), 4.21-4.25 (m, 1H), 4.03 (s, 1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.72-3.90 (m, 2H), 3.55-3.63 (m, 1H), 3.36-3.47 (m, 2H), 1.41 (s, 9H), 1.27 (d, 3H), 1.23 (d, 3H).

[0406] Preparation 195: (2S,5S)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2,5-dimethylpiperazine-1-carboxamide formate [ka] tert-Butyl (2S,5S)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-2,5-dimethylpiperazine-1-carboxylate (Preparation 191, 70.0 mg, 0.122 mmol) in HCl / EtOAc (10 mL) was stirred at 25° C. for 5 h. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex Luna C18 200 * 40mm * 10 μm; Mobile phase: [water (0.2% FA)-MeCN]; B%: 1% to 50%, 8 min) to give the title compound as a pale yellow solid (11.7 mg, 18%). LCMS m / z = 472 [M+H] + . 1H-NMR (400 MHz, CDCl3) δ ppm 9.07 (s, 1H), 8.67 (s, 1H), 7.87 (s, 1H), 7.38-7.44 (m, 2H), 7.36 (s, 1H), 7.25 (s, 2H), 7.19 (d, 3H), 4.15-4.26 (m, 1H), 4.10 (s, 3H), 4.08 (s, 3H), 3.83 (d, 1H), 2.98-3.15 (m, 2H), 2.75-2.96 (m, 2H), 1.38 (d, 3H), 1.27 (d, 3H).

[0407] Preparation 196: (2R,3S)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2,3-dimethylpiperazine-1-carboxamide or (2S,3R)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2,3-dimethylpiperazine-1-carboxamide [ka] A solution of tert-butyl (2S,3R)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-2,3-dimethylpiperazine-1-carboxylate or tert-butyl (2S,3R)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-2,3-dimethylpiperazine-1-carboxylate (Preparation 194) (10.0 mg, 0.0175 mmol) in HCl / EtOAc (2 mL) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 * 30mm *3 μm; mobile phase: [water-(0.05% NH3H2O ​​+ 10 mM NH4HCO3)-MeCN]; B%: 20%-45%, 8 min) to give the title compound as a white solid (2.60 mg, 30%). LCMS m / z = 472 [M+H] + . 1 H-NMR (400 MHz, CDCl3) δ ppm 9.04 (s, 1H), 8.67 (s, 1H), 7.84 (s, 1H), 7.37-7.41 (m, 2H), 7.31 (s, 1H), 7.22-7.24 (m, 1H), 7.15-7.18 (m, 3H), 4.06 (s, 3H), 3.99-4.05 (m, 5H), 3.63-3.74 (m, 1H), 2.98-3.17 (m, 3H), 2.81-2.88 (m, 1H), 1.18 (d, 3H, J = 6.8 Hz), 1.10 (d, 3H, J = 7.2 Hz).

[0408] Preparation 197: (S)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2-methylpiperazine-1-carboxamide trifluoroacetate [ka] A mixture of tert-butyl (S)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-3-methylpiperazine-1-carboxylate (Preparation 192, 50 mg, 0.090 mmol) in TFA (0.2 mL) and DCM (1 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow oil (20 mg, crude).

[0409] Preparation 198: (2S,5R)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2,5-dimethylpiperazine-1-carboxamide [ka] A mixture of tert-butyl (2R,5S)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-2,5-dimethylpiperazine-1-carboxylate (Preparation 193, 190 mg, 0.332 mmol) in DCM (2 mL) and TFA (0.4 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 * 30mm * 10 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 12% to 42%, 10 min) to give the title compound as a yellow solid (22.1 mg, 13% yield). LCMS m / z = 472 [M+H] + . 1 H-NMR (400 MHz, CDCl3) δ ppm 9.10 (s, 1H), 8.69 (s, 1H), 8.17 (d, 1H,), 7.90 (s, 1H), 7.41 (dd, 2H), 7.38 (s, 1H), 7.22-7.20 (m, 3H), 6.89 (d, 1H), 4.23 (s, 1H), 4.11 (d, 6H), 3.62 (d, 1H), 3.52-3.47 (m, 1H). 3.44 (s, 1H), 3.37 (dd, 1H), 2.79 (dd, 1H), 1.40 (d, 3H), 1.34 (d, 3H).

[0410] Preparation 199: N-(7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl)cyclopropanecarboxamide [ka] To a solution of 6-amino-7-methoxy-3,4-dihydroquinazolin-4-one (4 g, 20.9 mmol) and TEA (11.9 g, 104 mmol) in DCM (35 mL) at 0° C., cyclopropanecarbonyl chloride (6.54 g, 62.6 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 1 hour. The resulting solid was filtered and washed with EtOAc (20 mL) to give the title compound (3.9 g, 97% yield) as a yellow solid. LCMS m / z = 260 [M+H] + .

[0411] Preparation 200: N-(7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl)propionamide [ka] Part 1. Fe (804 mg, 14.4 mmol) and NH4Cl (163 mg, 14.4 mmol) were added to 7-methoxy-6-nitroquinazolin-4(3H)-one (400 mg, 1.8 mmol) in EtOH / HO (10 mL / 2 mL), and the resulting mixture was heated to 80° C. for 2 h. The reaction was filtered, the filtrate was concentrated in vacuo, and the residue was purified by preparative TLC (15:1 DCM / MeOH) to afford 6-amino-7-methoxyquinazolin-4(3H)-one as a white solid (300 mg), which was used without further purification.

[0412] Part 2. A solution of 6-amino-7-methoxyquinazolin-4(3H)-one (Part 1, 300 mg, 1.56 mmol) in propionic anhydride (5 mL) was heated to 120° C. for 2 hours. The reaction was evaporated to dryness in vacuo and the residue was purified by preparative TLC (15:1 DCM / MeOH) to afford the title compound as a white solid (180 mg, 40%). LCMS: m / z = 248 [M+H] + .

[0413] Preparation 201: N-(4-chloro-7-methoxyquinazolin-6-yl)cyclopropanecarboxamide [ka] POCl3 (1.46 g, 9.60 mmol) and TEA (1.17 g, 11.5 mmol) were added to N-(7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl)cyclopropanecarboxamide (Preparation 199, 500 mg, 1.92 mmol) in MeCN (15 mL) at room temperature. The reaction mixture was heated to 80 °C for 2 h and then poured into ice water. Na2CO3 (1 M) was added to achieve a pH of 8. The resulting solution was extracted with EtOAc and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 5:1 DCM / EtOAc) to give the title compound as a yellow solid (400 mg, 75%). LCMS m / z = 278 [M+H] + .

[0414] Preparation 202: N-(4-chloro-7-methoxyquinazolin-6-yl)propionamide [ka] POCl3 (167 mg, 1.09 mmol) was added to N-(7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl)propionamide (Preparation 200, 180 mg, 0.727 mmol) in MeCN (5 mL) and heated to 100 °C for 1 h. The reaction was quenched with HO (2 mL) at 0 °C and extracted with EtOAc (3 x 15 mL). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by preparative TLC (15:1 DCM / MeOH) to give the title compound as a pale yellow solid (60 mg, 31%). LCMS: m / z = 266 [M+H] + .

[0415] Preparation 203: 4-chloro-7-methoxy-6-nitroquinazoline [ka] 7-Methoxy-6-nitroquinazolin-4-ol (10 g, 45.2 mmol) was suspended in POCl (165 g, 1.08 mol) and the mixture was heated to 110 °C for 4 h. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in a mixture of DCM (50 mL) and aqueous NaHCO (50 mL). The organic layer was dried and evaporated to dryness to give the title compound as a yellow solid (7 g, 58%), which was used without further purification.

[0416] Preparation 204: 7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-nitroquinazoline [ka] To a mixture of 4-chloro-7-methoxy-6-nitroquinazoline (Preparation 203, 1.07 g, 3.76 mmol), 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 3.76 mmol), and CsCO (2.45 g, 7.51 mmol) in dioxane (10 mL) and HO (2 mL) was added Pd-118 (122.40 mg, 0.188 mmol), and the mixture was stirred at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ISCO®; 0–30% EtOAc / PE) to give the title compound (1 g, 66%) as a yellow solid.

[0417] Preparation 205: 4-(1-ethyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-7-methoxy-6-nitroquinazoline [ka] To a mixture of 4-bromo-7-methoxy-6-nitroquinazoline (Preparation 189, 200 mg, 0.704 mmol) and 1-ethyl-3-(4-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 44, 222 mg, 0.704 mmol) in dioxane (8 mL) and HO (2 mL) was added Pd(dppf)Cl (25.7 mg, 0.0352 mmol) and KCO (193 mg, 1.40 mmol) at 25 °C, and the mixture was stirred at 80 °C for 4 h under N. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organics were washed with brine (20 mL), dried (NaSO), and evaporated to dryness in vacuo. The residue was purified by preparative TLC (20:1 DCM / MeOH) to give the title compound as a yellow solid (120 mg, 43%). LCMS: m / z =394 [M+H] + .

[0418] Preparation 206: N-(7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinazolin-6-yl)propionamide [ka] A solution of N-(4-chloro-7-methoxyquinazolin-6-yl)propionamide (Preparation 202, 60 mg, 0.225 mmol), 3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 42, 87.5 mg, 0.247 mmol), KCO (63 mg, 0.450 mmol), and Pd(dppf)Cl (18.3 mg, 0.0225 mmol) in dioxane / water (3 mL / 0.8 mL) was heated at 80° C. for 2 hours under N. The reaction was evaporated to dryness in vacuo, and the residue was purified by preparative TLC (15:1 DCM / MeOH) to give the title compound as a yellow solid (20 mg, 19%). LCMS: m / z = 458 [M+H] + .

[0419] Preparation 207: N-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl)-2-fluorobenzamide [ka] A mixture of 6-bromo-4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline (Preparation 106, 100 mg, 0.167 mmol), 2-fluorobenzamide (34.7 mg, 0.250 mmol), Pd(dba) (20 mg, 0.0193 mmol), XPhos (20 mg, 0.0345 mmol), and CsCO (108 mg, 0.334 mmol) in toluene (10 mL) was stirred at 100° C. for 2 hours. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by preparative TLC (35:1 DCM / MeOH) to give the title compound as a yellow solid (84 mg, 73%). LCMS: m / z = 598 [M+H] + .

[0420] Preparation 208: N-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl)bicyclo[1.1.1]pentane-1-carboxamide [ka] Using a method similar to that described for Preparation 207, the title compound was prepared from 6-bromo-4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline (Preparation 106) and bicyclo[1.1.1]pentane-1-carboxamide (Preparation 70) as a yellow solid (159 mg, 86%). LCMS: m / z = 570 [M+H] + .

[0421] Preparation 209: 6-chloro-7-methoxypyrido[3,2-d]pyrimidin-4(3H)-one [ka] To 3-amino-6-chloro-5-methoxypicolinic acid (220 g, 1.01 mol) in EtOH (2.0 L) was added formamidine acetate (420 g, 4.04 mol) at room temperature, and the resulting mixture was heated to 90° C. for 24 hours. The solid was collected by filtration to give the title compound as a brown solid (201 g, 94%). LCMS: m / z = 212 [M+H] + .

[0422] Preparation 210: 7-Methoxy-6-((4-methoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4(3H)-one [ka] To 6-chloro-7-methoxypyrido[3,2-d]pyrimidin-4(3H)-one (Preparation 209, 10 g, 47.2 mmol) in DMSO (50 mL) was added 1-(4-methoxyphenyl)methanamine (45.2 g, 330 mmol) at room temperature, and the resulting mixture was stirred at 100° C. for 2 h. The mixture was diluted with EtOAc (100 mL) and washed with brine (2×50 mL). The combined organics were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO, 25:1 DCM / MeOH) to give the title compound as a yellow solid (8 g, 54%). LCMS: m / z = 313 [M+H] + .

[0423] Preparation 211: 4-chloro-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine [ka] To 7-methoxy-6-((4-methoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4(3H)-one (Preparation 210, 8 g, 25.6 mmol) in MeCN (15 mL) was added POCl (15.7 g, 102 mmol) and N,N-diethylaniline (25.7 g, 153 mmol) at room temperature, and the reaction was stirred at 80 °C for 2 h. The resulting mixture was added to ice water, the pH was adjusted to pH 8 using aqueous NaCO (1 M), and extracted with EtOAc (2 x 500 mL). The combined organic extracts were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (10:1 DCM / EtOAc) to give the title compound as a yellow solid (7 g, 83%). LCMS: m / z = 331 [M+H] + .

[0424] Preparation 212: 7-Methoxy-N-(4-methoxybenzyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-amine [ka] A mixture of Pd(dppf)Cl (1.76 g, 2.11 mmol), KCO (4.36 g, 31.6 mmol), 4-chloro-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 211, 7 g, 21.1 mmol), and 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.97 g, 31.6 mmol) in HO (30 mL) and dioxane (120 mL) was stirred at 80 °C for 2 h under N. The mixture was diluted with EtOAc (200 mL) and washed with water (2 × 50 mL). The combined organics were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (20:1 DCM / MeOH) to give the title compound as a yellow oil (6.5 g, 68%). LCMS: m / z = 453 [M+H] + .

[0425] Preparation 213: 4-(3-(2,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine [ka] Using a method similar to that described for Preparation 212, the title compound was prepared from 4-chloro-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 211) and 3-(2,4-difluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 45) as an off-white solid (550 mg, 80%). LCMS: m / z = 489 [M+H] + .

[0426] Preparation 214: 4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine [ka] Using a method similar to that described for Preparation 212, prepare the title compound from 4-chloro-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 211) and 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 43) as a yellow solid (600 mg, 85%). LCMS: m / z = 471 [M+H] + .

[0427] Preparation 215: 4-(3-(3-((tert-butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine [ka] A mixture of Pd(PPh) (138 mg, 0.120 mmol), KPO (381 mg, 1.79 mmol), 4-chloro-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 211, 396 mg, 1.20 mmol), and 3-(3-((tert-butyldimethylsilyl)oxy)phenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 39, 500 mg, 1.20 mmol) in dioxane / HO (8 mL / 2 mL) was stirred at 80 °C for 2 h under N. The resulting solution was extracted with EtOAc (3 × 50 mL), and the combined organic extracts were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (25:1 DCM / MeOH) to give the title compound as a yellow solid (370 mg, 52%). LCMS: m / z = 583 [M+H] + .

[0428] Preparation 216: 7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-amine [ka] TFA (5 mL) was added to 7-methoxy-N-(4-methoxybenzyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 212, 3 g, 5.49 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The mixture was diluted with EtOAc (100 mL), washed with brine (2×50 mL), dried (NaSO), and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (18:1 DCM / MeOH) to give the title compound as a yellow solid (2.5 g). LCMS: m / z = 333 [M+H] + .

[0429] Preparation 217: 4-(3-(2,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidin-6-amine [ka] A mixture of 4-(3-(2,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 213, 550 mg, 1.12 mmol) and TFA (5 mL) was stirred at 60° C. for 3 h under N. The mixture was diluted with EtOAc (100 mL) and washed with NaHCO (aq) (2×50 mL). The combined organics were dried (NaSO), evaporated to dryness in vacuo, and the residue was purified by silica gel chromatography (18:1 DCM / EtOAc) to give the title compound as a yellow solid (320 mg, 78%). LCMS: m / z = 369 [M+H] + .

[0430] Preparation 218: 4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidin-6-amine [ka] Using a method similar to that described for Preparation 217, the title compound was prepared from 4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 214) as a yellow solid (400 mg, 90%). LCMS: m / z = 351 [M+H] + .

[0431] Preparation 219: 3-(4-(6-amino-7-methoxypyrido[3,2-d]pyrimidin-4-yl)-1-methyl-1H-pyrazol-3-yl)phenol [ka] A solution of 4-(3-(3-((tert-butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 215, 370 mg, 0.634 mmol) in TFA (5 mL) was stirred at 60° C. for 2 h. The resulting solution was extracted with EtOAc (3×50 mL) and the combined extracts were dried (NaSO) and evaporated to dryness. The residue was purified by preparative TLC (15:1 DCM / MeOH) to give the title compound as a yellow solid (140 mg, 63%). LCMS: m / z = 349 [M+H] + .

[0432] Preparation 220: 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine [ka] A mixture of 4-chloro-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 211, 800 mg, 2.4 mmol), KCO (672 mg, 4.8 mmol), Pd(dppf)Cl (174 mg, 0.24 mmol), and 3-(2-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 37, 724 mg, 2.4 mmol) in dioxane / HO (10 mL / 2 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (SiO, 5% MeOH / DCM) to give the title compound as an off-white solid (800 mg, 71%). LCMS m / z = 471 [M+H] + .

[0433] Preparation 221: 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidin-6-amine trifluoroacetate [ka] To a solution of 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 220, 800 mg, 1.70 mmol) in DCM (5 mL) was added TFA (2 mL) at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. The solution was concentrated to dryness to give the title compound as a yellow oil (600 mg, 90%). LCMS m / z = 351 [M+H] + .

[0434] Preparation 222: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine [ka] Following the procedure described in Preparation 220, 4-chloro-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 211) and 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 41) gave the title compound as a pale yellow solid (560 mg, 43%). LCMS m / z = 503 [M+H] + .

[0435] Preparation 223: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidin-6-amine trifluoroacetate [ka] Following the procedure described in Preparation 221, 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 222) gave the title compound as a pale yellow oil (400 mg, crude). LCMS m / z = 383 [M+H] + .

[0436] Preparation 224: 4,6-Dichloro-7-methoxypyrido[3,2-d]pyrimidine [ka] N,N-Diethylaniline (986 g, 6.61 mol) was added to 6-chloro-7-methoxypyrido[3,2-d]pyrimidin-4(3H)-one (Preparation 209, 200 g, 945 mmol) and POCl3 (722 g, 4.72 mol) in MeCN (2000 mL) at room temperature, and the resulting mixture was heated to 80 °C for 2 h. The reaction mixture was poured into ice water, and Na2CO3 (5 M) was added until pH = 8. The solution was extracted with EtOAc, and the combined organics were concentrated in vacuo. The residue was purified by silica gel chromatography (5:1 DCM / EtOAc) to give the title compound as a yellow solid (178 g, 82%). LCMS: m / z = 230 [M+H] + .

[0437] Preparation 225: 2-Bromo-5-ethoxypyridin-3-amine [ka] NaOEt (45 mL) was added to a solution of 2-bromo-5-fluoropyridin-3-amine (6 g, 31.4 mmol) in EtOH (45 mL) at room temperature, and the mixture was heated at 120° C. for 16 h. After cooling to 25° C., the mixture was evaporated to dryness and the residue was purified by column chromatography (SiO, 5:1 PE / EtOAc) to give the title compound as an off-white solid (5.1 g, 75%). LCMS: m / z = 217 [M+H] + .

[0438] Preparation 226: Methyl 3-amino-5-ethoxypicolinate [ka] A mixture of 2-bromo-5-ethoxypyridin-3-amine (Preparation 225, 5.5 g, 25.3 mmol), TEA (7.65 g, 75.8 mmol), and Pd(dppf)Cl (1.84 g, 2.53 mmol) in MeOH (100 mL) was stirred at 80 °C under an atmosphere of CO (10 atm) for 16 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (3 x 200 mL) and saturated brine (200 mL). The organic layer was dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (20% EtOAc / PE) to give the title compound as a yellow solid (1.5 g, 30%). LCMS: m / z = 197 [M+H] + .

[0439] Preparation 227: Methyl 3-amino-6-chloro-5-ethoxypicolinate [ka] NCS (1.48 g, 11.1 mmol) was added to a solution of methyl 3-amino-5-ethoxypicolinate (Preparation 226, 2 g, 10.1 mmol) in MeCN (50 mL) at room temperature, and the resulting mixture was heated to 80° C. for 16 h. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (3×150 mL) and saturated brine (150 mL). The organic layer was dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (2:1 PE / EtOAc) to give the title compound as a pale yellow solid (1.6 g, 69%). LCMS: m / z = 231 [M+H] + .

[0440] Preparation 228: 3-amino-6-chloro-5-ethoxypicolinic acid [ka] LiOH (996 mg, 41.5 mmol) was added to methyl 3-amino-6-chloro-5-ethoxypicolinate (Preparation 227, 1.6 g, 6.93 mmol) in THF / HO (15 mL / 5 mL) at room temperature, and the resulting mixture was stirred at room temperature for 16 hours. The pH was adjusted to pH 3 with HCl (1 mmol). The reaction mixture was diluted with DCM (200 mL) and washed with water (3 x 200 mL) and saturated brine (200 mL). The combined organics were dried (NaSO) and evaporated to dryness in vacuo to give the title compound as an off-white solid (1.4 g, 93%). LCMS: m / z = 217 [M+H] + .

[0441] Preparation 229: 6-chloro-7-ethoxypyrido[3,2-d]pyrimidin-4(3H)-one [ka] To 3-amino-6-chloro-5-ethoxypicolinic acid (Preparation 228, 1.5 g, 6.92 mmol) in EtOH (50 mL) was added formamidine acetate (5.75 g, 55.3 mmol) at room temperature, and the resulting mixture was heated to 80° C. for 16 hours. The reaction mixture was diluted with water (200 mL), and the solid was collected by filtration to give the title compound as a white solid (1.5 g, 96%). LCMS: m / z = 226 [M+H] + .

[0442] Preparation 230: 4,6-Dichloro-7-ethoxypyrido[3,2-d]pyrimidine [ka] To a solution of 6-chloro-7-ethoxypyrido[3,2-d]pyrimidin-4(3H)-one (Preparation 229, 1.5 g, 6.64 mmol) and N,N-diethylaniline (6.92 g, 46.4 mmol) in MeCN (50 mL) was added POCl3 (5.11 g, 33.2 mmol) at room temperature, and the resulting mixture was heated to 80 °C for 2 h. The solution was poured into ice water, and the pH was adjusted to pH 8 by the addition of aqueous NaHCO3 (1.00 M). The solution was extracted with EtOAc and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (3:1 DCM:EtOAc) to give the title compound as an off-white solid (1.4 g, 86%). LCMS: m / z = 244 [M+H] + .

[0443] Preparation 231: 6-chloro-7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine [ka] Pd(PPh) (235 mg, 0.204 mmol) and KPO (864 mg, 4.08 mmol) were added to a solution of 4,6-dichloro-7-ethoxypyrido[3,2-d]pyrimidine (Preparation 230, 500 mg, 2.04 mmol) and 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (579 mg, 2.04 mmol) in dioxane / HO (16 mL / 4 mL) at room temperature, and the resulting mixture was heated to 80 °C under N for 2 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (3 × 100 mL) and saturated brine (100 mL). The combined organics were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (20:1 DCM / MeOH) to give the title compound as an off-white solid (290 mg, 39%). LCMS: m / z = 366 [M+H] + .

[0444] Preparation 232: 6-chloro-7-ethoxy-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine [ka] Following a procedure similar to that described in Preparation 97, 4,6-dichloro-7-ethoxypyrido[3,2-d]pyrimidine (Preparation 230) and 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 43) gave the title compound as a yellow solid (1 g, 32%). LCMS: m / z = 385 [M+H] + .

[0445] Preparation 233: 6-chloro-7-ethoxy-4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine [ka] Following a procedure similar to that described in Preparation 231, 4,6-dichloro-7-ethoxypyrido[3,2-d]pyrimidine (Preparation 230) and 3-(2-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 37) gave the title compound as a yellow solid (500 mg, 20%). LCMS: m / z = 384 [M+H] + .

[0446] Preparation 234: 6-chloro-7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine [ka] Following a procedure similar to that described in Preparation 231, 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine (Preparation 224) and 3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 42) gave the title compound as a yellow solid (4.2 g, 42% yield). LCMS: m / z = 442 [M+H] + .

[0447] Preparation 235: 6-chloro-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine [ka] A mixture of 6-chloro-7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Preparation 234, 2 g, 4.73 mmol) in TFA (10 mL) and DCM (30 mL) was stirred at room temperature for 3 hours under N. The reaction mixture was diluted with EtOAc (120 mL) and washed with H0 (60 mL). The combined organics were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by preparative TLC (50% DCM / EtOAc) to give the title compound as a yellow solid (1.5 g, 94%). LCMS: m / z = 338 [M+H] + .

[0448] Preparation 236: 6-chloro-7-methoxy-4-(1-(methyl-d3)-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine and 6-chloro-7-methoxy-4-(1-(methyl-d3)-5-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine [ka] A mixture of D3I (1.96 g, 14.8 mmol), K2CO3 (2.04 g, 14.8 mmol), and 6-chloro-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Preparation 235, 1 g, 2.96 mmol) in DMF (10 mL) was stirred at room temperature for 3 h under N2. The reaction mixture was diluted with EtOAc (120 mL) and washed with water (60 mL). The combined organics were dried (Na2SO4) and evaporated to dryness. The residue was purified by preparative TLC (2:1 DCM / EtOAc) to give a mixture of 6-chloro-7-methoxy-4-(1-(methyl-d3)-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine and 6-chloro-7-methoxy-4-(1-(methyl-d3)-5-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine as a yellow solid (700 mg, 67%), which was not further purified. LCMS: m / z = 355 [M+H] + .

[0449] Preparation 237: 6-chloro-4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidine [ka] Following a procedure similar to that described in Preparation 231, 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine (Preparation 224) and 3-(2-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 37) gave the title compound as a white solid (150 mg, 47%). LCMS: m / z = 370 [M+H] + .

[0450] Preparation 238: 6-chloro-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidine [ka] Following a procedure similar to that described in Preparation 231, 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine (Preparation 224, 500 mg, 2.17 mmol) and 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 43) gave the title compound as a yellow solid (300 mg, 37%). LCMS: m / z =370 [M+H] + .

[0451] Preparation 239: 6-chloro-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidine [ka] To a solution of Pd(dppf)Cl.DCM (1.41 g, 1.73 mmol), 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine (Preparation 224, 5.0 g, 21.6 mmol), and 1-ethyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 33, 5.79 g, 19.4 mmol) in dioxane / HO at room temperature was added KPO (5.0 g, 23.6 mmol), and the reaction was stirred at 60 °C for 16 h. The reaction mixture was diluted with EtOAc (300 mL) and washed with brine (2 x 100 mL). The organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 5:1 DCM / EtOAc) to give the title compound as a yellow solid (1.6 g, 23%). LCMS m / z = 366 [M+H]+.

[0452] Preparation 240: 6-chloro-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidine [ka] Following the procedure described in Preparation 239, 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine (Preparation 224) and 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 41) gave the title compound as a yellow solid (852 mg, 24% yield). LCMS m / z = 402 [M+H] + .

[0453] Preparation 241: 5-(6-chloro-7-methoxypyrido[3,2-d]pyrimidin-4-yl)-2-methyl-4-phenylthiazole [ka] Following a procedure similar to that described in Preparation 231, 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine (Preparation 224) and 2-methyl-4-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole gave the title compound as a yellow solid (40 mg, 16% yield). LCMS: m / z =369 [M+H] + .

[0454] Preparation 242: 6-chloro-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine [ka] To a mixture of Pd(dppf)Cl.DCM (70.5 g, 86.4 mmol), 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine (Preparation 224, 250 g, 1.08 mol), and 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (276 g, 972 mmol) in dioxane / HO at room temperature was added KPO (250 g, 1.18 mol), and the resulting mixture was stirred at 60 °C for 16 h. The reaction was diluted with EtOAc (3 L) and washed with brine (2 × 1 L). The combined organics were dried (NaSO) and evaporated to dryness in vacuo, and the residue was purified by silica gel chromatography (5:1 DCM / EtOAc) to give the title compound as a yellow solid (66 g, 17%). LCMS: m / z = 352 [M+H] + .

[0455] Preparation 243: 6-chloro-4-(3-(2,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidine [ka] A mixture of 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine (Preparation 224, 600 mg, 2.60 mmol), 3-(2,6-difluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 34, 915 mg, 2.86 mmol), Pd(PPh) (300 mg, 0.260 mmol), and KPO (1.10 g, 5.20 mmol) in dioxane (10 mL) and HO (2 mL) (mixture under N) was stirred at 80 °C for 3 h. The reaction mixture was extracted with EtOAc, and the combined organics were dried and evaporated to dryness in vacuo. The residue was purified by preparative TLC (15:1 DCM / MeOH) to give the title compound as a white solid (200 mg, 20%). LCMS: m / z = 388 [M+H] + .

[0456] Preparation 244: 6-chloro-4-(1-(difluoromethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidine [ka] A mixture of 6-chloro-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Preparation 235, 200 mg, 0.592 mmol), diethyl(bromodifluoromethyl)phosphonate (315 mg, 1.18 mmol), KF (68.5 mg, 1.18 mmol), and KI (195 mg, 1.18 mmol) in MeCN (10 mL) was stirred at 60° C. for 16 hours. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by preparative TLC (30:1 DCM / MeOH) to give the title compound as a yellow solid (60 mg, 26%). LCMS: m / z = 487 [M+H] + .

[0457] Preparation 245: 6-chloro-4-(1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidine [ka] A mixture of Cu(OAc) (192 mg, 0.592 mmol), 2,2'-bipyridine (92.4 mg, 0.592 mmol), and DCE (15 mL) was stirred at 80 °C for 0.5 h. 6-Chloro-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Preparation 235, 100 mg, 0.296 mmol), cyclopropylboronic acid (50.8 mg, 0.592 mmol), and NaCO (62.7 mg, 0.592 mmol) were added, and the resulting mixture was stirred at 80 °C for 4 h under N. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by preparative TLC (30:1 DCM / MeOH) to give the title compound as a yellow solid (60 mg, 86%). LCMS: m / z = 378 [M+H] + .

[0458] Preparation 246: 6-chloro-4-(1-(cyclopropylmethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidine [ka] A mixture of 6-chloro-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Preparation 235, 200 mg, 0.592 mmol), (bromomethyl)cyclopropane (159 mg, 1.18 mmol), and CsCO (384 mg, 1.18 mmol) in MeCN (8 mL) was stirred at 60 °C for 6 h. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by preparative TLC (40:1 DCM / MeOH) to give the title compound as a yellow solid (80 mg, 35%). LCMS: m / z = 392 [M+H] + .

[0459] Preparation 247: 4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4-yl)-6-chloro-7-methoxypyrido[3,2-d]pyrimidine [ka] Using a method similar to that described for Preparation 246, prepare the title compound from 6-chloro-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Preparation 235) and (2-bromoethoxy)(tert-butyl)dimethylsilane as a yellow solid (120 mg, 41%). LCMS: m / z = 496 [M+H] + .

[0460] Preparation 248: N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)propionamide [ka] To a solution of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190, 5 g, 15.0 mmol) and propanoic acid (1.66 g, 22.6 mmol) in THF (50 mL) was added T3P® (10 mL, 50% solution in EtOAc) and pyridine (1.18 g, 15.0 mmol). The reaction was stirred at room temperature for 2 hours and quenched with water. The reaction mixture was extracted with EtOAc, and the organic layer was dried over NaSO and then concentrated in vacuo. The residue was purified by column chromatography (SiO, 20:1 DCM / MeOH) to give the title compound as a yellow solid (5.81 g, 99%). LCMS m / z = 388 [M+H] + .

[0461] Preparation 249: N-(7-hydroxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)propionamide [ka] To N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)propionamide (Preparation 248, 400 mg, 1.03 mmol) in pyridine (4 mL) was added pyridine-HCl (1.18 g, 10.3 mmol) and the reaction was stirred at 100° C. overnight. The reaction was concentrated in vacuo and adjusted to pH 8 with TEA. The residue was purified by preparative TLC (10:1 DCM / MeOH) to give the title compound as a yellow oil (200 mg, 52%). LCMS m / z = 374 [M+H] + .

[0462] Preparation 250: 4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-propanamidoquinazolin-7-yl trifluoromethanesulfonate [ka] To N-(7-hydroxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)propionamide (Preparation 249, 200 mg, 0.535 mmol) and TEA (226 mg, 0.802 mmol) in DCM (2 mL) was added TfO (226 mg, 0.802 mmol) dropwise at 0 °C under N and the reaction was stirred at room temperature for 2 h. The reaction was quenched with water / ice and extracted with DCM. The combined organics were concentrated in vacuo and the residue was purified by preparative TLC (5:1 DCM / MeOH) to give the title compound as a yellow solid (100 mg, 37%). LCMS m / z = 506 [M+H] + .

[0463] Preparation 251: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-amine [ka] Using a two-part process similar to that described for Preparation 190, the title compound was prepared from 4-bromo-7-methoxy-6-nitroquinazoline (Preparation 189) and 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 41) as a yellow solid (300 mg, 56%). LCMS: m / z = 382 [M+H] + .

[0464] Preparation 252: 4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-amine [ka] Using a two-part process similar to that described for Preparation 190, the title compound was prepared from 4-bromo-7-methoxy-6-nitroquinazoline (Preparation 189) and 1-ethyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 33) as a white solid (120 mg). LCMS: m / z = 346 [M+H] + .

[0465] Preparation 253: 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-amine [ka] Using a two-part process similar to that described for Preparation 190, the title compound was prepared from 7-methoxy-6-nitro-3,4-dihydroquinazolin-4-one and 3-(2-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 37) as a white solid (80 mg, 77%). LCMS: m / z = 350 [M+H] + .

[0466] Preparation 254: 4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-amine [ka] Using a two-part process similar to that described for Preparation 190, the title compound was prepared from 7-methoxy-6-nitro-3,4-dihydroquinazolin-4-one and 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 43) as a yellow solid (100 mg, 54%). LCMS: m / z = 380 [M+H] + .

[0467] Preparation 255: 4-(1-ethyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-amine [ka] To a mixture of 4-(1-ethyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-7-methoxy-6-nitroquinazoline (Preparation 205, 120 mg, 0.305 mmol) in EtOH (5 mL) and HO (0.5 mL) was added Fe (341 mg, 6.10 mmol) and HCl (0.2 mL), and the reaction mixture was stirred at 80 °C for 3 h. The cooled reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by preparative TLC (20:1 DCM / MeOH) to give the title compound as a yellow solid (80 mg, 73%). LCMS: m / z = 364 [M+H] + .

[0468] Preparation 256: 5-Fluoro-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine [ka] Selectfluor (266 mg, 0.754 mmol) was added to 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190, 250 mg, 0.754 mmol) in MeCN (15 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (2 x 50 mL). The combined organics were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO, 15:1 DCM / MeOH) to give the title compound as a yellow solid (180 mg, 37%). LCMS: m / z = 350 [M+H] + .

[0469] Preparation 257: tert-butyl 1-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate [ka] Using a method similar to that described for Example 205, the title compound was prepared from 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190) and tert-butyl 1-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (Preparation 65) as a yellow solid (310 mg, 95%). LCMS: m / z = 541 [M+H] + .

[0470] Preparation 258: tert-butyl 1-((4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate [ka] A mixture of BINAP Pd G3 (35.2 mg, 0.0378 mmol), Cs2CO3 (184 mg, 0.567 mmol), 6-chloro-4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidine (Preparation 237, 140 mg, 0.378 mmol), and tert-butyl 1-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (Preparation 65, 128 mg, 0.567 mmol) in dioxane (10 mL) was stirred at 100 °C for 3 h under N2. The reaction mixture was diluted with water and extracted with EtOAc (3 × 50 mL), and the combined extracts were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by preparative TLC (25:1 DCM / MeOH) to give the title compound as a yellow solid (100 mg, 47%). LCMS: m / z = 560 [M+H] + .

[0471] Preparation 259: tert-butyl 1-((7-ethoxy-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate [ka] Using a method similar to that described for Preparation 258, the title compound was prepared from 6-chloro-7-ethoxy-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Preparation 232) and tert-butyl 1-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (Preparation 65) as a yellow solid (320 mg, 71%). LCMS: m / z = 574 [M+H] + .

[0472] Preparation 260: tert-Butyl 6,6-difluoro-1-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate [ka] A mixture of 6-chloro-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Preparation 242, 110 mg, 0.312 mmol), tert-butyl 1-carbamoyl-6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate (Preparation 73, 81.8 mg, 0.312 mmol), Pd(dba) (5 mg, 5.46 μmol), XantPhos (180 mg, 0.312 mmol), and CsCO (101 mg, 0.312 mmol) in toluene (15 mL) was stirred at 100 °C for 3 h. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by preparative TLC (30:1 DCM / MeOH) to give the title compound as a yellow solid (70 mg, 39%). LCMS: m / z = 578 [M+H] + .

[0473] Preparation 261: N-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)bicyclo[1.1.1]pentane-1-carboxamide [ka] Using a method similar to that described for Preparation 260, the title compound was prepared from 4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4-yl)-6-chloro-7-methoxypyrido[3,2-d]pyrimidine (Preparation 247) and bicyclo[1.1.1]pentane-1-carboxamide (Preparation 70) as a yellow solid (80 mg, 58%). LCMS: m / z = 571 [M+H] + .

[0474] Preparation 262: N-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)-1-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] Using a method similar to that described for Preparation 260, prepare the title compound from 4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4-yl)-6-chloro-7-methoxypyrido[3,2-d]pyrimidine (Preparation 247) and 1-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Preparation 76) as a yellow solid (60 mg, 47%). LCMS: m / z = 639 [M+H] + .

[0475] Preparation 263: tert-butyl (1R,3S,5R)-3-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate [ka] Using a method similar to that described for Preparation 260, the title compound was prepared from tert-butyl (1R,3S,5R)-3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (Preparation 74) and 6-chloro-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Preparation 242) as a yellow solid (100 mg, 43%). LCMS: m / z = 542 [M+H] + .

[0476] Preparation 264: tert-butyl (1R,3R,5R)-3-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate [ka] Using a method similar to that described for Preparation 260, the title compound was prepared from tert-butyl (1R,3R,5R)-3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (Preparation 75) and 6-chloro-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Preparation 242) as a yellow solid (100 mg, 43%). LCMS: m / z = 542 [M+H] + .

[0477] Preparation 265: 7-(1-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one [ka] 7-Bromoquinazolin-4(3H)-one (3.00 g, 13.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3.33 g, 16.0 mmol), KHCO (3.71 mg, 26.7 mmol), and Pd(dppf)Cl (975 mg, 1.33 mmol) in dioxane (100 mL) and HO (20 mL) were placed in a round-bottom flask under N, and the resulting solution was stirred at 100 °C for 1 h. The reaction mixture was diluted with HO (50 mL), the solids were removed by filtration, and the resulting solution was extracted with EtOAc (3 × 50 mL). The organic layer was concentrated in vacuo. The residue was purified by column chromatography (SiO, 20:1 DCM / MeOH) to afford the title compound (1.70 g, 56%) as a pale yellow solid. LCMS m / z = 227 [M+H] + .

[0478] Preparation 266: 4-chloro-7-(1-methyl-1H-pyrazol-4-yl)quinazoline [ka] 7-(1-Methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one (Preparation 265, 1.70 mg, 7.51 mmol), POCl3 (10.0 mL), and DIPEA (2.91 g, 22.5 mmol) were placed in a 40 mL pressure tank reactor under N2, and the resulting solution was stirred at 100 °C for 2 h. The mixture was concentrated in vacuo, and the residue was diluted with water (10 mL). The resulting solution was extracted with DCM (3 x 10 mL), and the combined organic layers were concentrated in vacuo to give the title compound as a pale yellow solid (1.30 g, 71%). LCMS m / z = 245 [M+H] + .

[0479] Preparation 267: 7-(1-methyl-1H-pyrazol-4-yl)-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinazoline [ka] 3-Phenyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 42, 289 mg, 0.816 mmol), 4-chloro-7-(1-methyl-1H-pyrazol-4-yl)quinazoline (Preparation 266, 100 mg, 0.408 mmol) in DMSO (1 mL), Pd(PPh) (47.1 mg, 0.0408 mmol), and KPO (173 mg, 0.816 mmol) were placed in an 8 mL sealed tube. The reaction mixture was stirred at 100 °C for 2 h. The resulting solution was extracted with EtOAc (3 × 10 mL). The organic phase was concentrated under reduced pressure. The residue was purified by preparative TLC (20:1 DCM / MeOH) to give the title compound as a white solid (65 mg, 36%). LCMS m / z = 437 [M+H] + .

[0480] Preparation 268: 4-(3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol-4-yl)quinazoline [ka] Following the procedure described in Preparation 267, 3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 46) and 4-chloro-7-(1-methyl-1H-pyrazol-4-yl)quinazoline (Preparation 266) gave the title compound as a pale yellow solid (80 mg, 54% yield). LCMS m / z = 455 [M+H] + .

[0481] Preparation 269: 4-(3-(2,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol-4-yl)quinazoline [ka] Following a procedure similar to that described in Preparation 267, 4-chloro-7-(1-methyl-1H-pyrazol-4-yl)quinazoline (Preparation 266) and 3-(2,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 48) gave the title compound as a white solid (60 mg).

[0482] Preparation 270: 4-chloro-7-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)quinazoline [ka] 7-Bromo-4-chloroquinazoline (100 mg, 0.410 mmol) in DMF (1.2 mL), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine (238 mg, 0.820 mmol), Pd(dppf)Cl.DCM (33.4 mg, 0.041 mmol), and KCO (113 mg, 0.820 mmol) were placed in a 20 mL sealed tube. The reaction mixture was stirred at 100 °C for 16 h. The resulting solution was concentrated in vacuo. The residue was purified by preparative TLC (20:1 DCM / MeOH) to give the title compound (80 mg, 60%) as a white solid.

[0483] Preparation 271: 7-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinazoline [ka] Following a procedure similar to that described in Preparation 267, 3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 42) and 4-chloro-7-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)quinazoline (Preparation 270) gave the title compound as a yellow solid (25 mg, 16% yield). LCMS m / z = 437 [M+H] + .

[0484] Preparation 272: 5-Fluoro-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one [ka] Following a procedure similar to that described in Preparation 265, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 7-bromo-5-fluoroquinazolin-4(3H)-one gave the title compound as a white solid (400 mg, 80% yield). LCMS m / z = 245 [M+H] + .

[0485] Preparation 273: 4-chloro-5-fluoro-7-(1-methyl-1H-pyrazol-4-yl)quinazoline [ka] Following a procedure similar to that described in Preparation 266, 5-fluoro-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one (Preparation 272) gave the title compound as a white solid (200 mg, 47% yield). LCMS m / z = 263 [M+H] + .

[0486] Preparation 274: 6-(benzyloxy)-7-bromo-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)quinazoline [ka] To a mixture of 6-(benzyloxy)-7-bromo-4-chloroquinazoline (Preparation 150, 1 g, 2.86 mmol) and 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 41, 955 mg, 2.86 mmol) in dioxane (20 mL) and HO (5 mL) was added Pd(dppf)Cl (209 mg, 0.286 mmol) and KCO (789 mg, 5.72 mmol) under N, and the reaction was stirred at 80 °C for 4 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated under reduced pressure. The crude product was purified by preparative TLC (10:1 DCM / MeOH) to give the title compound as a yellow solid (700 mg, 74%). LCMS m / z = 521 [M+H] + .

[0487] Preparation 275: 6-(benzyloxy)-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol-4-yl)quinazoline [ka] Following a procedure similar to that described in Preparation 274, 6-(benzyloxy)-7-bromo-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 274) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave the title compound as a white solid (550 mg, 79% yield). LCMS m / z = 523 [M+H] + .

[0488] Preparation 276: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-6-ol [ka] To a mixture of 6-(benzyloxy)-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol-4-yl)quinazoline (Preparation 275, 550 mg, 1.05 mmol) in MeOH (10 mL) was added Pd / C (150 mg) and the reaction was stirred at 25° C. for 4 h under an atmosphere of H. The mixture was filtered and the filtrate evaporated to dryness to give the title compound as a yellow solid (400 mg, 88.1%).

[0489] Preparation 277: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-6-yl trifluoromethanesulfonate [ka] A solution of 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 276, 400 mg, 0.925 mmol) in DCM (10 mL) and TEA (233 mg, 2.31 mmol) was cooled to −50 °C. TfO (467 mg, 1.84 mmol) was added dropwise and the reaction was stirred for 1 h. The reaction was quenched with water and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO, 1:1 DCM / EtOAc) to afford the title compound (500 mg, 96%) as a yellow solid. LCMS m / z = 565 [M+H] + .

[0490] Preparation 278: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6-(1-ethoxyvinyl)-7-(1-methyl-1H-pyrazol-4-yl)quinazoline [ka] To a solution of 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-6-yl trifluoromethanesulfonate (Preparation 277, 500 mg, 0.886 mmol) in dioxane / HO was added tributyl(1-ethoxyvinyl)stannane (319 mg, 0.885 mmol), KCO (244 mg, 1.77 mmol), and Pd(PPh)Cl (57.5 mg, 0.089 mmol) under N. The reaction mixture was stirred at 100 °C for 4 h, then cooled to room temperature, diluted with water (25 mL), and extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with brine (20 mL), then dried over NaSO, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 1:1 PE / EtOAc) to give the title compound as a yellow solid (400 mg, 93%). LCMS m / z = 487 [M+H] + .

[0491] Preparation 279: 1-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-one [ka] A solution of 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6-(1-ethoxyvinyl)-7-(1-methyl-1H-pyrazol-4-yl)quinazoline (Preparation 278, 400 mg, 0.822 mmol) in TFA (3 mL) and DCM (9 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (220 mg, 58%), which was used in the next step without further purification. LCMS m / z = 489 [M+H] + .

[0492] Preparation 280: 7-Bromo-4-chloro-6-methoxyquinazoline [ka] To a solution of POCl3 (599 mg, 3.92 mmol) and 7-bromo-6-methoxyquinazolin-4(3H)-one (200 mg, 0.784 mmol) in MeCN (1 mL) was added TEA (479 mg, 4.70 mmol) at room temperature. The reaction mixture was heated to 80 °C for 2 h. The resulting solution was added to ice water, and then the pH was adjusted to 8 with Na2CO3 (1 M). The solution was extracted with EtOAc and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 100% DCM) to give the title compound as a yellow solid (60 mg, 28%). LCMS m / z = 273 [M+H] + .

[0493] Preparation 281: 7-Bromo-6-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline [ka] Following the procedure described in Preparation 231, 7-bromo-4-chloro-6-methoxyquinazoline (Preparation 280) and 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave the title compound as a yellow solid (40 mg, 46%). LCMS m / z = 395 [M+H] + .

[0494] Preparation 282: 7-(1-methyl-1H-pyrazol-3-yl)-6-nitroquinazolin-4(3H)-one [ka] To a solution of 7-bromo-6-nitro-3,4-dihydroquinazolin-4-one (500 mg, 1.85 mmol) in dioxane and water, 1-methyl-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazole (389 mg, 1.85 mmol), K2CO3 (511 mg, 3.70 mmol), and Pd(dppf)Cl2 (270 mg, 0.370 mmol) were added, and the reaction was stirred at 100 °C for 2 h. The mixture was extracted with EtOAc (20 mL × 3) and washed with brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to afford the title compound (400 mg, 80%) as a yellow solid. LCMS: m / z = 272 [M+H] + .

[0495] Preparation 283: 4-Bromo-7-(1-methyl-1H-pyrazol-3-yl)-6-nitroquinazoline [ka] A solution of 7-(1-methyl-1H-pyrazol-3-yl)-6-nitroquinazolin-4(3H)-one (Preparation 282, 400 mg, 1.47 mmol), DIPEA (400 mg, 1.47 mmol), and POBr (400 mg, 2.20 mmol) in MeCN (5 mL) was stirred at 80 °C for 2 h. The mixture was poured into ice-NaHCO and extracted with EtOAc (3 × 20 mL) and washed with brine (10 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (10:1 DCM / MeOH) to give the title compound as a yellow solid (280 mg, 57%). LCMS m / z = 334 [M+H] + .

[0496] Preparation 284: 4-(3-(2,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]-7-(1-methyl-1H-pyrazol-3-yl)-6-nitroquinazoline [ka] Following a procedure similar to that described in Preparation 274, 4-bromo-7-(1-methyl-1H-pyrazol-3-yl)-6-nitroquinazoline (Preparation 283) and 3-(2,6-difluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 34) gave the title compound as a yellow solid (40 mg, 25% yield). LCMS m / z = 448 [M+H] + .

[0497] Preparation 285: 4-(3-(2,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol-3-yl)quinazolin-6-amine [ka] To a solution of 4-(3-(2,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]-7-(1-methyl-1H-pyrazol-3-yl)-6-nitroquinazoline (Preparation 284, 40 mg, 0.089 mmol) was added iron (49.9 mg, 0.894 mmol) and NH4Cl (47.8 mg, 0.894 mmol) in EtOH (3 mL) and HO (1 mL). The reaction mixture was stirred at 80 °C for 2 h, then filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (10:1 DCM / MeOH) to give the title compound as a yellow solid (30 mg, 80%).

[0498] Preparation 286: Methyl 3-amino-5,6-dichloropicolinate [ka] NCS (749 mg, 5.59 mmol) was added to methyl 3-amino-5-chloropyridine-2-carboxylate (950 mg, 5.09 mmol) in MeCN (10 mL) at room temperature. The resulting mixture was heated to 80° C. for 16 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL×3) and saturated brine (100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. This was purified on a silica gel column eluted with PE:EtOAc = 4:1 to give the title compound (1.1 g, yield: 98.2%) as a yellow solid. LCMS m / z = 221 [M+H] + .

[0499] Preparation 287: 6,7-Dichloropyrido[3,2-d]pyrimidin-4(3H)-one [ka] To methyl 3-amino-5,6-dichloropicolinate (Preparation 286, 1.1 g, 4.97 mmol) in formamide (10 mL) was added AcOH (1 mL) at room temperature, and the reaction was heated to 120° C. for 16 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL×3) and saturated brine (100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified on a silica gel column with DCM:MeOH=20:1 to give the title compound (900 mg, yield: 84.1%) as a brown solid. LCMS m / z = 215 [M+H] + .

[0500] Preparation 288: 7-chloro-6-((4-methoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4(3H)-one [ka] To 6,7-dichloropyrido[3,2-d]pyrimidin-4(3H)-one (Preparation 287, 900 mg, 4.16 mmol) in DMSO (10 mL) was added 1-(4-methoxyphenyl)methanamine (2.85 g, 20.8 mmol), and the resulting mixture was heated at 80° C. for 16 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL×3) and saturated brine (100 mL). The organic layer was dried over NaSO, filtered, and evaporated. The crude product was purified by preparative TLC with DCM:MeOH=20:1 to give the title compound (900 mg, yield: 68.7%) as a brown solid. LCMS m / z = 317 [M+H] + .

[0501] Preparation 289: 4,7-Dichloro-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine [ka] N,N-Diethylaniline (2.95 g, 19.8 mmol) was added to MeCN (15 mL) containing POCl3 (2.17 g, 14.2 mmol) and 7-chloro-6-((4-methoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4(3H)-one (Preparation 288, 900 mg, 2.84 mmol) at room temperature. The resulting mixture was heated at 80 °C for 2 h. The resulting solution was added to ice water, and then 1 M Na2CO3 was added until pH = 8. The solution was extracted with EtOAc and concentrated in vacuo. The residue was purified on a silica gel column with DCM: EtOAc = 3:1 to give the title compound (360 mg, yield: 37.8%) as a yellow solid. LCMS m / z = 335 [M+H] + .

[0502] Preparation 290: 7-chloro-N-(4-methoxybenzyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-amine [ka] A mixture of Pd(dppf)Cl (76.0 mg, 0.104 mmol), KPO (330 mg, 1.56 mmol), 4,7-dichloro-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 289, 350 mg, 1.04 mmol), and 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (295 mg, 1.04 mmol) in dioxane / HO (8 mL / 2 mL) was heated at 80 °C for 16 h under N. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL x 3) and saturated brine (100 mL). The organic layer was dried over NaSO, filtered, and evaporated. The crude product was purified by silica gel column chromatography with DCM:MeOH=20:1 to give the title compound (350 mg, yield: 73.6%) as a yellow solid. LCMS m / z = 457 [M+H] + .

[0503] Preparation 291: 7-chloro-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-amine [ka] A solution of 7-chloro-N-(4-methoxybenzyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 290, 340 mg, 0.744 mmol) in TFA (3 mL) was heated to 60° C. for 2 hours. The mixture was concentrated in vacuo. The crude product was purified by preparative TLC with DCM:MeOH=10:1 to give the title compound (160 mg, yield: 64.0%) as a yellow solid. LCMS m / z = 337 [M+H] + .

[0504] Preparation 292: N-(7-chloro-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl)-3-oxabicyclo[3.1.0]hexane-1-carboxamide [ka] 2,4,6-Trichlorobenzoyl chloride (324 mg, 1.33 mmol) was added to a solution of TEA (224 mg, 2.22 mmol) and 3-oxabicyclo[3.1.0]hexane-1-carboxylic acid (169 mg, 1.33 mmol) in THF (10 mL) at 0 °C. After stirring for 1 h, 7-chloro-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 291, 150 mg, 0.445 mmol) was added, and the mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL x 3) and brine (100 mL). The organic layer was dried over Na SO , filtered, and evaporated to give the crude product. The crude product was purified by preparative TLC using DCM:MeOH = 20:1. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30 * Purification with 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 30% B to 50% B in 8 min) afforded the title compound (34.1 mg, 17.2%) as a white solid. LCMS: m / z = 447 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.03 (s, 1H), 8.94 (s, 1H), 8.64 (s, 1H), 7.52 - 7.45 (m, 2H), 7.31 (q, J = 2.9 Hz, 3H), 4.06 - 3.98 (m, 5H), 3.80 (s, 2H), 2.36 (t, J = 6.5 Hz, 1H), 1.56 (dd, J = 8.3, 4.5 Hz, 1H), 0.99 (t, J = 4.9 Hz, 1H).

[0505] Preparation 293: 6-((4-methoxybenzyl)amino)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-7-ol [ka] To 7-methoxy-N-(4-methoxybenzyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 212, 2 g, 4.41 mmol) in THF (16 mL) was added L-Selectride (1.67 g, 8.82 mmol), and the reaction mixture was stirred at 80 °C for 2 h, then diluted with EtOAc (200 mL) and washed with brine (2 × 10 mL). The organic layer was dried over Na SO and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, 25:1 DCM / MeOH) to give the title compound as a white solid (1.1 g, 55%). LCMS m / z = 439 [M+H] + .

[0506] Preparation 294: 6-((4-methoxybenzyl)amino)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-7-yl trifluoromethanesulfonate [ka] TfO (321 mg, 1.14 mmol) was added to a solution of 6-((4-methoxybenzyl)amino)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-7-ol (Preparation 293, 500 mg, 1.14 mmol), DMAP (137 mg, 0.57 mmol), and pyridine (456 mg, 5.70 mmol) in DCM (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then diluted with EtOAc (100 mL) and washed with brine (2 x 50 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, 15:1 DCM / MeOH) to give the title compound as a white solid (160 mg, 32%). LCMS m / z = 571 [M+H] + .

[0507] Preparation 295: N-(4-Methoxybenzyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-7-(3-morpholinoprop-1-yn-1-yl)pyrido[3,2-d]pyrimidin-6-amine [ka] CuI (10.0 mg, 0.524 mmol) was added to a mixture of TEA (119 mg, 1.04 mmol), 6-((4-methoxybenzyl)amino)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-7-yl trifluoromethanesulfonate (Preparation 294, 150 mg, 0.262 mmol), and 4-(prop-2-yn-1-yl)morpholine (98.3 mg, 0.786 mmol) in DME (5 mL), and the reaction was stirred at 80 °C for 2 h under N. The mixture was diluted with EtOAc (150 mL) and washed with brine (2 x 75 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 15:1 DCM / EtOAc) to give the title compound as an off-white solid (80 mg, 54%). LCMS m / z = 546 [M+H] + .

[0508] Preparation 296: 4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-7-(3-morpholinoprop-1-yn-1-yl)pyrido[3,2-d]pyrimidin-6-amine [ka] TFA (5 mL) was added to N-(4-methoxybenzyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-7-(3-morpholinoprop-1-yn-1-yl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 295, 80 mg, 0.146 mmol) at room temperature. The reaction mixture was stirred at 60° C. for 3 hours, then diluted with EtOAc (100 mL) and washed with brine (2×50 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, 18:1 DCM / MeOH) to give the title compound as a yellow solid (50 mg, 63%). LCMS m / z = 426 [M+H] + .

[0509] Preparation 297: 2-(4-(6-bromo-7-methoxyquinazolin-4-yl)-3-phenyl-1H-pyrazol-1-yl)-N,N-dimethylethan-1-amine [ka] NaH (60%, 66.6 mg, 1.67 mmol) was added to a DMF solution (15 mL) of 6-bromo-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 107, 320 mg, 839 μmol), (2-bromoethyl)dimethylamine hydrobromide (389 mg, 1.67 mmol), and the mixture was stirred at 50° C. for 2 hours. The reaction was quenched with water and evaporated to dryness in vacuo. The residue was purified by preparative TLC (20:1 DCM / MeOH) to give the title compound as a yellow solid (100 mg, 10.5%). LCMS m / z = 452,454 [M+H] + .

[0510] Preparation 298: tert-Butyl 3-carbamoyl-3-(trifluoromethyl)pyrrolidine-1-carboxylate [ka] To a solution of 1-(tert-butoxycarbonyl)-3-(trifluoromethyl)pyrrolidine-3-carboxylic acid (300 mg, 1.05 mmol) in DCM (10 mL) were added EDCI (256 mg, 1.65 mmol) and HOBt (222 mg, 1.65 mmol). The mixture was stirred at room temperature for 2 hours, and then NH3 (35% aqueous solution, 3 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The residue was purified by preparative TLC (15:1 DCM / MeOH) to give the title compound (200 mg, 66%) as a gray solid, which was used without further purification.

[0511] Preparation 299: 6-chloro-4-(1-ethyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidine [ka] A 20 mL pressure tank reactor purged and maintained with an inert atmosphere of nitrogen was charged with 1-ethyl-3-(4-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 44, 400 mg, 1.26 mmol), KCO (324 mg, 2.52 mmol), Pd(dppf)Cl (92 mg, 0.126 mmol), 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine (Preparation 224, 289 mg, 1.26 mmol), dioxane (5 mL), and water (1 mL), and the resulting solution was stirred for 2 h at 80° C. The reaction mixture was applied to a silica gel column and eluted with 20:1 DCM / MeOH to afford the title compound as an off-white solid (200 mg, 41%). LCMS: m / z = 384 [M+H] + .

[0512] Preparation 300: (1S,5S)-3-oxabicyclo[3.1.0]hexane-1-carboxamide [ka] Step 1: Ethyl (1R,5S)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate To a solution of diethyl malonate (228 g, 1.42 mol) in ethanol (1.2 L) was slowly added a solution of 20% sodium ethoxide (463 g, 1.36 mol) in ethanol at 20°C. The mixture was stirred at 20°C for 0.5 hours under nitrogen. To this mixture was then added a solution of (S)-2-(chloromethyl)oxirane (120 g, 1.30 mol) in ethanol (200 mL) at 20°C. The mixture was stirred at 80°C for 16 hours under nitrogen. Upon completion, after cooling to 25°C, the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (1.0 L) and aqueous hydrochloric acid (1.0 M, 1.4 L) and partitioned. The aqueous phase was extracted with ethyl acetate (700 mL x 2). The organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 3:1) to give the title compound (168 g, 76% yield) as a pale yellow oil.

[0513] Step 2: Ethyl (1S,2S)-1,2-bis(hydroxymethyl)cyclopropane-1-carboxylate This reaction was carried out in two parallel batches: To a solution of ethyl (1R,5S)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate (84.0 g, 493 mmol) in ethanol (850 mL) was added sodium borohydride (14.9 g, 395 mmol) in small portions at 0–5°C. The mixture was stirred at 20°C for 2 h. Upon completion, the reaction was quenched with aqueous hydrochloric acid (0.2 M, 100 mL) at 0°C, and the mixture was stirred at 20°C for 0.5 h. The mixture from the two batches was combined and concentrated in vacuo. The residue was diluted with brine (200 mL) and extracted with dichloromethane / isopropanol = 3:1 (100 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (136 g, 79% yield) as a pale yellow oil.

[0514] Step 3: Ethyl (1S,5S)-3-oxabicyclo[3.1.0]hexane-1-carboxylate This reaction was carried out in two parallel batches: p-toluenesulfonyl chloride (138 g, 723 mmol) was slowly added to a solution of ethyl (1S,2S)-1,2-bis(hydroxymethyl)cyclopropane-1-carboxylate (63.0 g, 361 mmol), triethylamine (110 g, 1.09 mol), and N,N-dimethylpyridin-4-amine (8.84 g, 72.3 mmol) in dichloromethane (1.2 L) at 0-5 °C. The mixture was stirred under nitrogen at 20 °C for 16 h. Upon completion, the mixture from the two batches was combined. The mixture was washed with aqueous hydrochloric acid (2.0 M, 1.2 L). The aqueous phase was extracted with dichloromethane (1.0 L). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to give the title compound (130 g, crude) as a pale yellow oil.

[0515] Step 4: (1S,5S)-3-Oxabicyclo[3.1.0]hexane-1-carboxylic acid To a solution of ethyl (1S,5S)-3-oxabicyclo[3.1.0]hexane-1-carboxylate (130 g, crude) in tetrahydrofuran (1.2 L) and methanol (200 mL) was added a solution of lithium hydroxide hydrate (70.0 g, 1.67 mol) in water (400 mL) at 20 °C. The mixture was stirred at 20 °C for 3 h. Upon completion, the mixture was diluted with water (2.5 L) and extracted with tert-butyl methyl ether (1.0 L × 3). The aqueous phase was acidified with solid potassium hydrogen sulfate (700 g, 5.14 mol), and the mixture was stirred for 0.5 h. Ethyl acetate (1.5 L) was added to the mixture, and the mixture was filtered and partitioned. The aqueous phase was extracted with ethyl acetate (1....

Claims

1. Formula (A): 【Chemistry 1】 The compound, or a pharmaceutically acceptable salt thereof [in the formula, X is CR ｘ or N, R ｘ is H or F, L １ This is a bond, NH, -NHC(O)- ＊ , -NHC(O)O- ＊ , O, or -OC(O)- ＊ (Here, - ＊ R １ (This represents the point where the points connect.) L ２ is either a bond or O, R １ is H, or Halo, deuterium, OR ａ , NR ａ R ｂ , C ３ -C ６ C is appropriately substituted with 1 to 4 groups independently selected from cycloalkyl, 4-12 membered heterocyclyl, and 5-10 membered heteroaryl groups. １ -C ４ Alkyl (the heterocyclyl and heteroaryl are, respectively, halo, deuterium, and C) １ -C ４ (Substituted as appropriate with 1 to 4 groups independently selected from alkyl groups), or C ３ -C ８ Cycloalkyl, phenyl, 4-12 member heterocyclyl, or 5-12 member heteroaryl (R １ The cycloalkyl, phenyl, heterocyclyl, and heteroaryl represented by R are each R １１ (It is appropriately substituted with 1 to 4 groups independently selected from the above.) Each R １１ is halo, deuterium, OR ａ , C(O)R ａ , C(O)NR ａ R ｂ , NR ａ C(O)OR ａ , NR ａ R ｂ , S(O) ２ R ａ , C １ -C ４ Alkyl, C ３ -C ６ Cycloalkyl, phenyl, 4-12 member heterocyclyl, and 5-12 member heteroaryl (R １１ The alkyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl represented by each are deuterium, halo, and C, respectively. １ -C ４ Alkyl, OR ａ , and NR ａ R ｂ (Substituted as appropriate with 1 to 4 groups selected from) Independently selected from, or two R groups bonded to the same carbon atom １１ These two elements come together to form the O shape. R ２ teeth, H, C １ -C ４ Alkyl, C ３ -C ８ Cycloalkyl, C ２ -C ４ Alkenil, or C ２ -C ４ Alkinyl (these are respectively Halo, Deuterium, OR) ａ , NR ａ R ｂ , as well as halo, deuterium, and C １ -C ４ (R) 4-12 member heterocyclils, which are appropriately substituted with 1-4 groups independently selected from alkyl groups, or 4-12 member heterocyclils or 5-12 member heteroaryls (R) ２ The heterocyclyl and heteroaryl represented by each of these terms are deuterium, C １ -C ４ Alkyl, C(O)R ａ , as well as halo, deuterium, and C １ -C ４ It is appropriately substituted with 1 to 4 groups selected from alkyl groups, and is appropriately substituted with 1 to 4 groups selected from 4 to 12-membered heterocyclines. R ３ It is bonded to any nitrogen atom in the pyrazole ring, and is H, deuterium, C １ -C ４ Alkyl, C ３ -C ６ Cycloalkyl and 4-6 membered heterocyclyl (R ３ The alkyl, cycloalkyl, and heterocyclyl represented by each are halo, deuterium, OR ａ , NR ａ R ｂ , and C ３ -C ６ Selected from (substituted as appropriate with 1 to 4 groups independently selected from cycloalkyl groups), Each R ４ is halo, deuterium, and OR ａ Selected independently from, R ５ H, deuterium, halo, and halo, deuterium, OR ａ , NR ａ R ｂ , C ３ -C ６ C is appropriately substituted with 1 to 4 groups independently selected from cycloalkyl, 4-12 membered heterocyclyl, and 5-10 membered heteroaryl groups. １ -C ４ Alkyl (the heterocyclyl and heteroaryl are, respectively, halo, deuterium, and C) １ -C ４ Selected from (substituted as appropriate with 1 to 4 groups independently selected from alkyl groups), Each R ａ is independently selected from H, deuterium, C １ -C ４ -alkyl, C １ -C ４ -haloalkyl, C ３ -C ６ -cycloalkyl, and 4- to 6-membered heterocyclyl, Each R ｂ is independently selected from H, deuterium, and C １ -C ４ alkyl, n is 0, 1, 2, 3, 4, or 5.

2. A compound according to claim 1, wherein formula (B) or (C): 【Chemistry 2】 The aforementioned compound, or a pharmaceutically acceptable salt thereof, (i) If L1 and L2 are both bonds, then R1 is H and R2 is not H. or (ii) R2 is a C1-C4 alkyl, C3-C8 cycloalkyl, C2-C4 alkenyl, or C2-C4 alkynyl (each of which is appropriately substituted with halo, deuterium, OR a, NR a R b, and 1 to 4 groups independently selected from a 4-12 membered heterocyclyl which is appropriately substituted with 1 to 4 groups independently selected from halo, deuterium, and C1-C4 alkyl), or a 4-12 membered heterocyclyl or a 5-12 membered heteroaryl (the heterocyclyl and heteroaryl represented by R2 are each deuterium, C1-C4 alkyl, C(O)R a, and halo, deuterium, and C1-C4 It is appropriately substituted with 1 to 4 groups selected from alkyl groups, and is appropriately substituted with 1 to 4 groups selected from 4 to 12-membered heterocyclines. or (iii) R 5 is H, F, or methyl. A compound, or a pharmaceutically acceptable salt thereof.

3. Equation (I): 【Transformation 3】 Compounds of or pharmaceutically acceptable salts thereof [wherein, X is CR ｘ or N, R ｘ is H or F, L １ This is a bond, NH, -NHC(O)- ＊ , -NHC(O)O- ＊ , O, or -OC(O)- ＊ (Here, - ＊ R １ (This represents the point where the points connect.) L ２ is a bond or O, R １ is H, or Halo, deuterium, OR ａ , NR ａ R ｂ , C ３ -C ６ C is appropriately substituted with 1 to 4 groups independently selected from cycloalkyl, 4-12 membered heterocyclyl, and 5-10 membered heteroaryl groups. １ -C ４ Alkyl (the heterocyclyl and heteroaryl are, respectively, halo, deuterium, and C) １ -C ４ (Substituted as appropriate with 1 to 4 groups independently selected from alkyl groups), or C ３ -C ８ Cycloalkyl, phenyl, 4-12 member heterocyclyl, or 5-12 member heteroaryl (R １ The cycloalkyl, phenyl, heterocyclyl, and heteroaryl represented by R are each R １１ (It is appropriately substituted with 1 to 4 groups independently selected from the above.) Each R １１ is halo, deuterium, OR ａ , C(O)R ａ , C(O)NR ａ R ｂ , NR ａ C(O)OR ａ , NR ａ R ｂ , S(O) ２ R ａ , C １ -C ４ Alkyl, C ３ -C ６ Cycloalkyl, phenyl, 4-12 member heterocyclyl, and 5-12 member heteroaryl (R １１ The alkyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl represented by each are deuterium, halo, and C, respectively. １ -C ４ Alkyl, OR ａ , and NR ａ R ｂ (Substituted as appropriate with 1 to 4 groups selected from) Independently selected from, or two R groups bonded to the same carbon atom １１ These two elements come together to form the O shape. R ２ teeth, C １ -C ４ Alkyl, C ３ -C ８ Cycloalkyl, C ２ -C ４ Alkenil, or C ２ -C ４ Alkinyl (these are respectively Halo, Deuterium, OR) ａ , NR ａ R ｂ , as well as halo, deuterium, and C １ -C ４ (R) 4-12 member heterocyclils, which are appropriately substituted with 1-4 groups independently selected from alkyl groups, or 4-12 member heterocyclils or 5-12 member heteroaryls (R) ２ The heterocyclyl and heteroaryl represented by each of these terms are deuterium, C １ -C ４ Alkyl, C(O)R ａ , as well as halo, deuterium, and C １ -C ４ It is appropriately substituted with 1 to 4 groups selected from alkyl groups, and is appropriately substituted with 1 to 4 groups selected from 4 to 12-membered heterocyclines. R ３ H, deuterium, C １ -C ４ Alkyl, C ３ -C ６ Cycloalkyl, or 4-6 membered heterocyclyl (R ３ The alkyl, cycloalkyl, and heterocyclyl represented by each are halo, deuterium, OR ａ , NR ａ R ｂ , and C ３ -C ６ (It is appropriately substituted with 1 to 4 groups independently selected from cycloalkyl groups.) Each R ４ is halo, deuterium, and OR ａ Selected independently from, Each R ａ H, deuterium, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C ３ -C ６ Independently selected from cycloalkyl and 4-6 membered heterocyclyl groups, Each R ｂ These are H, deuterium, and C １ -C ４ Selected independently from alkyl, n is 0, 1, 2, 3, 4, or 5.

4. (i) The following structural formula: 【Chemistry 4-1】 【Chemistry 4-2】 A compound, or a pharmaceutically acceptable salt thereof, represented by one of the following: or (ii) The following structural formula: 【Chemistry 5-1】 【Chemistry 5-2】 It is represented by one of the following: A compound, or a pharmaceutically acceptable salt thereof, The compound according to claim 3.

5. The compound according to claim 1, (i) R １ is H, or Hello, OR ａ , NR ａ R ｂ , C ３－ C ５ C is appropriately substituted with one or two groups independently selected from cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl groups. １ -C ３ Alkyl (the heterocyclyl and heteroaryl are, respectively, halo and -CH ３ (Substituted as appropriate with one or two groups independently selected from, or C ３ -C ８ Cycloalkyl, phenyl, 4-9 member heterocyclyl, or 5-10 member heteroaryl (R １ The cycloalkyl, phenyl, heterocyclyl, and heteroaryl groups represented by are each R １１ (It is appropriately substituted with 1 to 3 groups independently selected from the above.) Each R ａ These are independently H or -CH ３ And each R ｂ ha-CH ３ And, or (ii) R1 is H, or R1 is selected from -CH3, -CH2CH3, -CH2CH3CH3, and -CH(CH3)2 (each of which is appropriately substituted with one to three groups selected from F, -OH, -OCH3, -N(CH3)2, cyclopropyl, morpholinyl, oxadiazolyl, oxetanyl, oxazolyl, pyridinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, and triazolyl, and each of which is appropriately substituted with F, -CH3, or -CH2CH3), or R1 is azabicyclo[3.1.0]hexanil, azetidinil, 1H-benzo[d]imidazolyl, bicyclo[1.1.1]pentanil, kubanil, cyclobutyl, cyclopropyl, dihydroisoquinolinyl, dihydropyrrolyl, dihydro-2H-benzo[b][1,4]oxazinyl, dioxepanil, hexahydro-1H-pyrrolidinyl, imidazolidinyl, indazolyl, isoindolinyl, isothiazolyl, morpholinyl, octahydropyrrolyl Selected from [1,2-a]pyradinyl, oxabicyclo[3.1.0]hexanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, oxabicyclo[3.3]heptanyl, 7-oxa-4-azaspiro[2.5]octanyl, oxetanyl, phenyl, piperidinyl, pyrazolyl, pyridadinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolopyridinyl, tetrahydrofuranyl, tetrahydropyranyl, and thiazolyl (each of which is appropriately substituted with 1 to 3 groups independently selected from R 11), or (iii) R 1 is H, -CH 3 , -CH 2 (R 11 ), -CH(R 11 ) 2 , -CH 2 CH 3 , -CH(R 11 )-CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 2 -R 11 , -CH 2 CH 2 CH 2 -R 11 , -CH(CH 3 )CH 2 -R 11 , 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 Selected from, A compound, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, (i) Each R １１ Hello, OR ａ , C(O)R ａ , C(O)NR ａ R ｂ , NR ａ C(O)OR ａ , NR ａ R ｂ , C １ -C ４ Alkyl, C ３ -C ６ Cycloalkyl, 4-12 member heterocyclyl, and 5-12 member heteroaryl (R １１ The alkyl, cycloalkyl, heterocyclyl, and heteroaryl represented by each are deuterium, halo, OR ａ , and NR ａ R ｂ (Substituted as appropriate with 1 to 3 groups selected from) Independently selected from, or two R groups bonded to the same carbon atom １１ These two elements come together to form the O shape. Each R ａ H, C １ -C ４ Alkyl, C ３ -C ６ Independently selected from cycloalkyl and 4-6 membered heterocyclyl groups, Each R ｂ H and C １ -C ４ Selected independently from alkyl, or (ii) Each R 11 is independently selected from halo, OR a, C(O)R a, C(O)NR a R b, NR a C(O)OR a, NR a R b, C1-C3 alkyl, morpholinyl, oxazolyl, oxadiazolyl, oxetanyl, pyridinyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl, and thiazolyl (each of the alkyl, morpholinyl, oxazolyl, oxadiazolyl, oxetanyl, pyridinyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl, and thiazolyl represented by R 11 is appropriately substituted with 1 to 3 groups selected from deuterium, halo, OR a, and NR a R b), or two R 11s bonded to the same carbon atom form a single O molecule. Each R a is H, -CH3, -CH2CH3, -C(CH3)3, 【Transformation 7】 Selected independently from, Each R b is independently H or -CH3. or (iii) Each R 11 is Cl, F, -OH, -OCH 3 , -C(O)CH 2 CH 3 , -N(CH 3 ) 2 , -NHC(O)OC(CH 3 ) 3 , -CH 3 , -CD 3 , -CHF 2 , -CF 3 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 -N(CH 3 ) 2 , -CH 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 -N(CH 3 ) 2 , -CH(CH 3 ) 2 , -C(CH 3 ) 2 -OH, 【Transformation 8】 Either they are independently selected, or two R11 atoms bonded to the same carbon atom unite to form =O. A compound, or a pharmaceutically acceptable salt thereof.

7. L ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is O.

8. The compound according to claim 1, (i) R ２ C １ -C ４ Alkyl, C ３ -C ８ Cycloalkyl, C ２ -C ４ Alkenil, or C ２ -C ４ Alkinyl (these are respectively Halo, OR ａ , NR ａ R ｂ , and appropriately substituted with 1 to 3 groups independently selected from 4 to 12-membered heterocyclines), or 4 to 12-membered heterocyclines or 5 to 12-membered heteroaryls (R ２ The heterocyclyl and heteroaryl represented by are each C １ -C ４ Alkyl, C(O)R ａ , as well as Halo and C １ -C ４ (It is appropriately substituted with 1 to 4 groups selected from a 4 to 12-membered heterocycline, which is appropriately substituted with 1 to 3 groups selected from alkyl groups.) Each R ａ H and C １ -C ４ Selected independently from alkyl, Each R ｂ H and C １ -C ４ Selected independently from alkyl, or (ii) R2 is a C1-C3 alkyl, C3-C5 cycloalkyl, or C3-C4 alkynyl (each of which is appropriately substituted with one or two groups independently selected from halo, OR a, NR a R b, and 4- to 6-membered heterocyclines), or a 5- to 7-membered heterocycline or a 5- to 6-membered heteroaryl (the heterocycline and heteroaryl in the group represented by R2 are each appropriately substituted with one or two groups appropriately selected from C1-C2 alkyl, C(O)R a, and 6-membered heterocyclines appropriately substituted with C1-C2 alkyl), Each Ra is independently selected from H and -CH3, Each R b is -CH3. or (iii) R 2 is -CH 3, -CH 2 CH 3, -CH(CH 3) 2, cyclopropyl, or 【Chemistry 9】 (These are each appropriately substituted with F, -OCH3, -N(CH3)2, morpholinyl, or oxetanyl) or R2 is diazaspiro[3.3]heptanyl, pyrazolyl, pyrimidinyl, or tetrahydrofuranyl (each of which is appropriately substituted with a C1-C2 alkyl, C(O)C1-C4 alkyl, or piperidinyl which is appropriately substituted with -CH3). or (iv) R 2 is -CH 3, -CHF 2, -CH 2 CH 3, -CH 2 CH 2 -OCH 3, -CH 2 CH 2 -N(CH 3) 2, -CH(CH 3) 2, cyclopropyl, 【Chemistry 10】 is, or R2 is, 【Chemistry 11】 (These are respectively -CH3, C(O)CH3, or 【Chemistry 12】 (This is replaced as appropriate.) A compound, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, (i) R ３ H, C １ -C ４ Alkyl, C ３ -C ６ Cycloalkyl, or 4-6 membered heterocyclyl (R ３ The alkyl, cycloalkyl, and heterocyclyl represented by each are halo, deuterium, OR ａ , NR ａ R ｂ , and C ３－ C ６ (It is appropriately substituted with one to three groups independently selected from cycloalkyl groups.) Each R ａ H or C １ -C ４ It is alkyl, Each R ｂ H or C １ -C ４ It is alkyl. or (ii) R3 is a C1-C3 alkyl group which is appropriately substituted with one to three groups independently selected from H, cyclopropyl, oxetanyl, tetrahydropianyl, or halo, deuterium, OH, N(CH3)2, and cyclopropyl. or (iii) R 3 is H, -CH 3 , -CHF 2 , -CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 -OH, -CH 2 CH 2 -N(CH 3 ) 2 , -CH 2 CH 3 CH 3 , -CH(CH 3 ) 2 , 【Chemistry 13】 Selected from, A compound, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, Each R ４ is a halo or OR ａ And, Each R ａ H and C １ -C ４ Selected independently from alkyl, n is 0, 1, 2, or 3, or, as appropriate, n is 0, or n is 1 or 2, and each R 4 is independently selected from F and OH. A compound, or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, (i) The following structural formula: 【Chemistry 14】 It is represented by one of the following: or (ii) The following structural formula: 【Chemistry 15】 It is represented by one of the following: A compound, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 11, R １ teeth, C is appropriately substituted with 5-10 member heteroaryls. １ -C ４ Alkyl (the aforementioned 5-10 member heteroaryl is C １ -C ２ (Substituted with alkyl as appropriate), or C ３ -C ８ Cycloalkyl, 4-12 member heterocyclyl, or 5-12 member heteroaryl (R １ The cycloalkyl, heterocyclyl, and heteroaryl represented by R are each R １１ (It is appropriately substituted with 1 to 3 groups independently selected from the above.) Each R １１ Hello, NR ａ R ｂ , C ３ -C ６ C is appropriately substituted with cycloalkyl and 1 to 3 halos. １ -C ４ Selected independently from alkyl groups, each R ａ H and C １ -C ４ Selected independently from alkyl, R ２ and R ３ Each is independently C １ -C ４ It is alkyl, R ４ is a halo, and n is 0, 1, or 2. or (ii) R 1 is, A C1-C2 alkyl group appropriately substituted with a 5-membered heteroaryl group (the 5-membered heteroaryl group is appropriately substituted with a C1-C2 alkyl group), or C3-C5 cycloalkyl, 5-7 membered heterocyclyl, or 5-6 membered heteroaryl (each of the cycloalkyl, heterocyclyl, and heteroaryl represented by R1 is appropriately substituted with one or two groups independently selected from R11), Each R11 is independently selected from halo, N(CH3)2, C3-C5 cycloalkyl, and C1-C2 alkyl which is appropriately substituted with 1 to 3 halos. R2 and R3 are each independently C1-C2 alkyl groups. R 4 is a halo, n is 0, 1, or 2. or (iii) R 1 is -CH 2 CH 3 substituted with oxadiazolyl which is appropriately substituted with -CH 3, or R1 is selected from azabicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cyclopropyl, 3-oxabicyclo[3.1.0]hexanyl, piperidinyl, pyrazolyl, and pyridinyl (each of which is appropriately substituted with one or two groups independently selected from R11), Each R 11 is F, -N(CH3)2, -CH3, -CF3, 【Chemistry 16】 Selected independently from, or (iv) R 1 is, 【Chemistry 17】 Selected from, each R 11 is, F, -N(CH 3 ) 2 , -CH 3 , -CF 3 , [Chemistry 18] Selected independently from, A compound, or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 12, (i) R ２ C １ -C ４ It is alkyl, R ３ C １ -C ４ It is alkyl, Each R ４ It is independently a halo, n is 0, 1, or 2. or (ii) R2 is -CH3 or -CH2CH3, R3 is -CH3, R 4 is F, n is either 0 or 1. A compound, or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 3, (i) Formula (III): 【Chemistry 19】 Represented by, or (ii) Equation (III-1) or (III-2): 【Chemistry 20】 Represented by, A compound, or a pharmaceutically acceptable salt thereof. 【Request Item 15】 【Chemistry 21】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by [the specified formula].

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

17. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for use in the treatment of cancer in a patient, wherein (i) the cancer is lung cancer, colon cancer, urothelial carcinoma, breast cancer, prostate cancer, brain cancer (glioma), ovarian cancer, gastric cancer, pancreatic cancer, head and neck cancer, bladder cancer, or mesothelioma, or (ii) the cancer is non-small cell lung cancer, or (iii) the cancer in the subject requiring it is metastatic, a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

18. (i) the cancer is characterized by an epidermal growth factor receptor (EGFR) L858R mutation, or (ii) the cancer is characterized by an epidermal growth factor receptor (EGFR) exon 19 deletion, or (iii) the cancer is characterized by an epidermal growth factor receptor (EGFR) C797S mutation or an epidermal growth factor receptor (EGFR) T790M mutation, the compound according to claim 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

19. A compound according to claim 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, further comprising administering an effective amount of afatinib or osimertinib to the subject requiring the same.

20. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for use in inhibiting epidermal growth factor receptor (EGFR).

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