EGFR inhibitors

Abstract

The present disclosure provides a compound represented by Structural Formula (A) or (I): or a pharmaceutically acceptable salt thereof, which is useful in the treatment of cancer. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 327,631, filed on April 5, 2022. The entire contents of the above-referenced applications are incorporated herein by reference. Background Art

[0003] EGFR (epidermal growth factor receptor) is a member of the erbB receptor family, which includes transmembrane protein tyrosine kinase receptors. By binding to its ligand (such as epidermal growth factor (EGF)), EGFR can form homodimers on the cell membrane or form heterodimers with other receptors in the family (such as erbB2, erbB3 or erbB4). The formation of these dimers can cause the phosphorylation of key tyrosine residues in EGFR cells, thereby activating multiple downstream signaling pathways in the cells. These intracellular signaling pathways play an important role in cell proliferation, survival and anti-apoptosis. Disturbances in the EGFR signal transduction pathway (including increased expression of ligands and receptors, EGFR gene amplification and changes such as mutations, deletions, etc.) can promote the malignant transformation of cells and play an important role in tumor cell proliferation, invasion, metastasis and angiogenesis. For example, changes such as mutations and deletions in the EGFR gene have been found in non-small cell lung cancer (NSCLC) tumors. The two most frequent EGFR alterations found 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 alterations are known as sensitizing mutations, leading to ligand-independent EGFR activation, and are known as primary or activating mutations in EGFR-mutant NSCLC (EGFR M+). Clinical experience shows an objective response rate (ORR) of approximately 60%-85% in patients with EGFR M+ NSCLC treated with the EGFR tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, afatinib, and osimertinib as first-line (1L) therapy (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. 2016, Vol. 17, 577; N. Engl. J. Med. 2017 Nov 18, Doi: 10.1056 / NEJMoa1713137; Lancet Oncol. 2016, Vol. 17, 577; N. Engl. J. Med. 2016, ... Oncol. 2011, Vol. 12, 735), thereby demonstrating that the survival and proliferation of EGFR-mutant NSCLC tumors are dependent on oncogenic EGFR activity, establishing del19 and L858R mutant EGFR as oncogenic drivers of the disease, and thus validating drug targets and biomarkers for the treatment of NSCLC.

[0004] Osimertinib is a covalent third (3rd) generation EGFR TKI, which is now an approved first-line (1L) standard of care (SOC) for the treatment of NSCLC with del19 and L858R mutations. Progression-free survival (PFS) is 18.9 months (JC Soria et al., NEJM, January 2018; 378 (2): 113-125), which shows a transformative result for patients compared to first-generation TKIs. However, after an average of 10-12 months of treatment, drug resistance is observed in almost all NSCLC patients (Lancet Oncol. February 2010; 11 (2): 121-8.; Lancet Oncol. May 2016; 17 (5): 577-89; Lancet Oncol. August 2011; 12 (8): 735-42). Other third-generation TKIs are currently used in the frontline setting (e.g., lazertinib) and rely on the same covalent mechanism of binding to EGFR. The most prominent mechanism of on-target resistance is attributed to the secondary EGFR mutation C797X (where "X" can be "S," "G," "N," "Y," "T," or "D"), which occurs in 7% to 22% of patients who progress on third-generation EGFR inhibitors used as frontline therapy (Blakely, 2012; Kobayashi, 2005). This secondary C797S mutation reduces the drug's affinity for the target, thereby conferring resistance and leading to tumor recurrence or disease progression. The resulting "double-mutated" tumors, harboring both the sensitizing mutations del19 or L858R and the resistance mutation C797X (e.g., C797S), are no longer sensitive to second- and third-generation TKIs. There are no approved treatments for patients with this double mutation. First-generation TKIs (gefitinib and erlotinib) are active against C797X (e.g., C797S), but they are poorly tolerated due to activity associated with wild-type EGFR inhibition and do not control encephalopathy due to their low ability to cross the blood-brain barrier (BBB).

[0005] There is an unmet need for selective therapeutics that treat doubly mutated tumors, are brain penetrant, and treat encephalopathy with reduced toxicities (diarrhea, rash) associated with wild-type EGFR inhibition. Summary of the Invention

[0006] The applicant has discovered novel compounds that are effective inhibitors of certain mutant forms of EGFR (see Synthesis Examples 1-454 and 458-500). Specifically, it has been confirmed that the compounds of the present disclosure can effectively inhibit certain mutant forms of EGFR. The compounds of the present disclosure (also referred to herein as "disclosed compounds") or pharmaceutically acceptable salts thereof can effectively inhibit EGFR with one or more changes, including L858R or exon 19 deletion mutations and C797X (e.g., C797S) mutations (hereinafter "EGFR with LRCS mutations" or "double mutant EGFR") (see Biological Example 1), and can be used to treat a variety of cancers, such as lung cancer (see Biological Example 2). Importantly, the disclosed compounds are selective EGFR inhibitors, that is, the disclosed compounds are inactive or have low activity against wild-type EGFR and kinome. Advantages associated with this selectivity may include promoting effective administration and reducing EGFR-mediated on-target toxicity. Some disclosed compounds exhibit good brain and blood-brain barrier penetration (e.g., PGP efflux ratio is less than 5). Therefore, it is expected that the compounds of the present disclosure or their pharmaceutically acceptable salts can be effective in treating metastatic cancers, including brain metastases, including leptomeningeal disease and other systemic metastases. Some of the disclosed compounds also have the advantage of high microsomal stability. The compounds of the present disclosure may also have favorable toxicity profiles related to other non-kinase targets.

[0007] In one aspect, the present disclosure provides a compound represented by the following structural formula (A) or (I):

[0008]

[0009] or a pharmaceutically acceptable salt thereof, the definitions of each variable are provided below.

[0010] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and one or more compounds disclosed herein or pharmaceutically acceptable salts thereof ("the pharmaceutical composition of the present disclosure").

[0011] The present disclosure provides a method for treating a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula (A) or Formula (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 metastases from non-small cell lung cancer.

[0012] 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.

[0013] The treatment methods disclosed herein also include administering to a subject an effective amount of an EGFR inhibitor (eg, afatinib and / or osimertinib) and a MET inhibitor in combination with an effective amount of a compound of the present disclosure.

[0014] The present disclosure also provides a method of 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 Formula (I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0015] The present disclosure also provides the use of an effective amount of a compound of the present disclosure (e.g., a compound of Formula (A) or Formula (I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for preparing a medicament for treating cancer.

[0016] In another aspect, provided herein is a compound of Formula (A) or Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for use in treating cancer. DETAILED DESCRIPTION

[0017] definition

[0018] The term "halo" as used herein means halogen and includes chlorine, fluorine, bromine and iodine.

[0019] The term "alkyl," used alone or as part of a larger moiety (e.g., "alkoxy," etc.), means a saturated aliphatic straight or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 6 carbon atoms, i.e., a (C1-C6)alkyl group. As used herein, "(C1-C6)alkyl" means a group having 1 to 6 carbon atoms in a straight or branched chain arrangement. Examples include methyl, ethyl, n-propyl, isopropyl, and the like.

[0020] The term "haloalkyl" or "C 1-4 "Haloalkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a halogen atom. 1-4 The haloalkyl group may be a monohalogenated-C 1-4 Alkyl, dihalogenated-C1-4 Alkyl or polyhalogenated-C 1-4 Alkyl, including perhalogenated-C 1-4 Alkyl. Monohalogenated-C 1-4 The alkyl group may have one iodine, bromine, chlorine or fluorine within the alkyl group. 1-4 Alkyl and polyhalogenated-C 1-4 An alkyl group may have two or more of the same halogen atoms or a combination of different halogen groups within the alkyl group. 1-4 The alkyl group contains 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 groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. 1-4 Alkyl refers to a C 1-4 alkyl.

[0021] The term "alkoxy" means an alkyl group attached via an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0022] The term "cycloalkyl" refers to a monocyclic or bicyclic or polycyclic saturated hydrocarbon ring system. Cycloalkyl can include fused and / or bridged rings and / or spirocycles. 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, etc. Cycloalkyl also includes spirocycles (e.g., spirobicycles in which two rings share a 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 3-12 carbon atoms. For example, C 3- C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless otherwise specified, "cycloalkyl" groups have 3 to 6 carbon atoms.

[0023] The term "heterocyclyl" or "heterocycle" refers to a group of a 4- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxides and sulfones ("4-12 membered heterocyclyl"). In some embodiments, the heterocyclyl is a 4- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 (usually 1 to 2) ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("4-8 membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom when valence permits. The heterocyclyl may be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a bicyclic system ("bicyclic heterocyclyl") or a tricyclic system ("tricyclic heterocyclyl")). Polycyclic systems include fused, bridged, or spirocyclic systems. When the heterocyclic group is a polycyclic ring system, the ring system includes at least one non-aromatic ring. Exemplary monocyclic heterocyclic groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidin-2-one group, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxetanyl, thiepanyl, tetrahydropyridinyl, etc. The heterocyclic group polycyclic ring system can include heteroatoms in one or more rings in the polycyclic ring system, including polycyclic ring systems in which non-aromatic rings are fused to phenyl or heteroaryl rings. 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]hexyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-6-azaspiro[3.3]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, tetrahydropyrazolo[1,5-a]pyridinyl, and the like. Substituents may be present on one or more rings in a polycyclic system.

[0024] "Heteroaryl" refers to a group of a 4 to 12-membered aromatic ring system having annular carbon atoms and 1 to 4 annular heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, heteroaryl is a 5-membered or 6-membered heteroaryl group having annular carbon atoms and 1 to 4 annular heteroatoms (typically 1 to 2). Representative heteroaryl groups include ring systems in which each ring contains heteroatoms and is aromatic, such as imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrolyl, furyl, thienyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.

[0025] A bridged bicyclic ring system has two non-aromatic rings containing 5-12 ring atoms (heterocyclyl or cycloalkyl) and sharing three or more ring atoms, wherein 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; examples include bicyclo[1.1.1]pentyl, 3-oxabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.2.1]octyl, 6-oxa-2-azabicyclo[3.2.1]octyl, 6-oxa-3-azabicyclo[3.2.1]octyl, and 8-oxa-3-azabicyclo[3.2.1]octyl.

[0026] A fused bicyclic ring system has two rings containing 6-12 ring atoms and sharing two adjacent ring atoms. When the fused bicyclic ring system is a heterocyclic group, at least one ring 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.

[0027] Spirobicyclic ring systems have two non-aromatic rings (heterocyclyl or cycloalkyl) containing 7-12 ring atoms and sharing one ring atom. Examples of spirobicyclic ring systems include 1-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl, and 1,4-dioxa-9-azaspiro[5.5]undec-9-yl.

[0028] Compounds of the present disclosure

[0029] Disclosed herein are embodiments of compounds having the general structure of Formula (A) or Formula (I). The compounds are selective inhibitors of L858R, Ex19del, L858RC797S, and Ex19DelC797S EGFR. Compared to other EGFR inhibitors that irreversibly bind to EGFR (such as osimertinib), the compounds of the present disclosure are non-covalent inhibitors.

[0030] In a first embodiment, the present disclosure provides a compound represented by the following structural formula (A):

[0031]

[0032] or a pharmaceutically acceptable salt thereof, wherein

[0033] X is CR x or N;

[0034] R x is H or F;

[0035] L1 is a bond, NH, -NHC(O)-*, -NHC(O)O-*, O, or -OC(O)-*; where -* indicates attachment to R 1 point;

[0036] L 2 is a key or O;

[0037] R 1 is H; or

[0038] C1-C4 alkyl optionally substituted by 1 to 4 groups independently selected from the group consisting of halo, deuterium, OR a NR a R b , C3-C6 cycloalkyl, 4 to 12 membered heterocyclyl, and 5 to 10 membered heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium, and C1-C4 alkyl; or

[0039] C3-C8 cycloalkyl, phenyl, 4 to 12-membered heterocyclyl or 5 to 12-membered heteroaryl, wherein R 1 The cycloalkyl, phenyl, heterocyclyl and heteroaryl groups represented by 11 The group substitution;

[0040] Each R 11 Independently selected from halogen, 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)2R a , C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, wherein R 11 The alkyl, cycloalkyl, phenyl, heterocyclyl and heteroaryl groups represented by each of the above groups are optionally substituted by 1 to 4 groups selected from deuterium, halogen, C1-C4 alkyl, OR a and NR a R b or two R 11 Together they form =O;

[0041] R 2 yes:

[0042] H, C1-C4 alkyl, C3-C8 cycloalkyl, C2-C4 alkenyl or C2-C4 alkynyl, each of which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halo, deuterium, ORa NR a R b and 4 to 12 membered heterocyclyl optionally substituted by 1 to 4 groups independently selected from halo, deuterium and C1-C4 alkyl; or

[0043] 4 to 12-membered heterocyclic or 5 to 12-membered heteroaryl, wherein R 2 The heterocyclic and heteroaryl groups represented by the present invention are each optionally substituted by 1 to 4 groups selected from the group consisting of deuterium, C1-C4 alkyl, C(O)R a and a 4- to 12-membered heterocyclyl group optionally substituted by 1 to 4 groups selected from halo, deuterium and C1-C4 alkyl;

[0044] R 3 is connected 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 heterocyclic groups, wherein R 3 The alkyl, cycloalkyl and heterocyclic groups represented by a NR a R b and C3-C6 cycloalkyl groups;

[0045] Each R 4 Independently selected from halo, deuterium and OR a ;

[0046] R 5 is selected from H, deuterium, halo, and C1-C4 alkyl optionally substituted by 1 to 4 groups independently selected from halo, deuterium, OR a NR a R b , C3-C6 cycloalkyl, 4 to 12 membered heterocyclyl, and 5 to 10 membered heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium, and C1-C4 alkyl;

[0047] Each R a independently selected from H, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocyclyl;

[0048] Each R b are independently selected from H, deuterium, and C1-C4 alkyl; and

[0049] n is 0, 1, 2, 3, 4 or 5.

[0050] In a second embodiment, the compound according to formula (A) is represented by a formula selected from (B) and (C):

[0051]

[0052] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first embodiment.

[0053] In a third embodiment, the present disclosure provides a compound according to formula (A), (B) or (C), or a pharmaceutically acceptable salt thereof, wherein when L 1 and L 2 When each is a bond, R 1 It's H, R 2 is not H, and wherein the remaining variables are as defined in the first embodiment.

[0054] In a fourth embodiment, the present disclosure provides a compound according to 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 optionally substituted with 1 to 4 groups independently selected from the group consisting of halo, deuterium, OR a NR a R b and 4 to 12 membered heterocyclyl optionally substituted by 1 to 4 groups independently selected from halo, deuterium and C1-C4 alkyl; or 4 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl, wherein R 2 The heterocyclic and heteroaryl groups represented by the present invention are each optionally substituted by 1 to 4 groups selected from the group consisting of deuterium, C1-C4 alkyl, C(O)R a and 4- to 12-membered heterocyclyl optionally substituted with 1 to 4 groups selected from halo, deuterium, and C1-C4 alkyl, and wherein the remaining variables are as defined in the first or third embodiment.

[0055] In a fifth embodiment, the present disclosure provides a compound according to formula (A), (B) or (C), or a pharmaceutically acceptable salt thereof, wherein R 5 is H, F or methyl, and wherein the remaining variables are as defined in the first, third or fourth embodiment.

[0056] In a sixth embodiment, the present disclosure provides a compound represented by the following structural formula (I):

[0057]

[0058] or a pharmaceutically acceptable salt thereof, wherein

[0059] X is CR x or N;

[0060] R x is H or F;

[0061] L 1is a bond, NH, -NHC(O)-*, -NHC(O)O-*, O, or -OC(O)-*; where -* indicates attachment to R 1 point;

[0062] L 2 is a key or O;

[0063] R 1 is H; or

[0064] C1-C4 alkyl optionally substituted by 1 to 4 groups independently selected from the group consisting of halo, deuterium, OR a NR a R b , C3-C6 cycloalkyl, 4 to 12 membered heterocyclyl, and 5 to 10 membered heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium, and C1-C4 alkyl; or

[0065] C3-C8 cycloalkyl, phenyl, 4 to 12-membered heterocyclyl or 5 to 12-membered heteroaryl, wherein R 1 The cycloalkyl, phenyl, heterocyclyl and heteroaryl groups represented by 11 The group substitution;

[0066] Each R 11 Independently selected from halogen, 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)2R a , C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, wherein R 11 The alkyl, cycloalkyl, phenyl, heterocyclyl and heteroaryl groups represented by each of the above groups are optionally substituted by 1 to 4 groups selected from deuterium, halogen, C1-C4 alkyl, OR a and NR a R b or two R 11 Together they form =O;

[0067] R 2 yes:

[0068] C1-C4 alkyl, C3-C8 cycloalkyl, C2-C4 alkenyl or C2-C4 alkynyl, each of which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halo, deuterium, OR a NRa R b and 4 to 12 membered heterocyclyl optionally substituted by 1 to 4 groups independently selected from halo, deuterium and C1-C4 alkyl; or

[0069] 4 to 12-membered heterocyclic or 5 to 12-membered heteroaryl, wherein R 2 The heterocyclic and heteroaryl groups represented by the present invention are each optionally substituted by 1 to 4 groups selected from the group consisting of deuterium, C1-C4 alkyl, C(O)R a and a 4- to 12-membered heterocyclyl group optionally substituted by 1 to 4 groups selected from halo, deuterium and C1-C4 alkyl;

[0070] R 3 is H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic group, wherein R 3 The alkyl, cycloalkyl and heterocyclic groups represented by a NR a R b and C3-C6 cycloalkyl groups;

[0071] Each R 4 Independently selected from halo, deuterium and OR a ;

[0072] Each R a independently selected from H, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocyclyl;

[0073] Each R b are independently selected from H, deuterium, and C1-C4 alkyl; and

[0074] 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.

[0075] In a seventh embodiment, the compound according to formula (I) is represented by one of the following formulae: (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):

[0076]

[0077]

[0078] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first, third, fourth or sixth embodiment.

[0079] In an eighth embodiment, the compound of formula (I) is represented by one of the following structural formulas: (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):

[0080]

[0081]

[0082] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first, third, fourth or sixth embodiment.

[0083] In a ninth embodiment, the present disclosure provides a compound according to the following 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 wherein the remaining variables are as defined in the first, third, fourth, fifth or sixth embodiment.

[0084] In a tenth embodiment, the present disclosure provides a compound according to the following 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 C1-C3 alkyl optionally substituted by 1 to 2 groups independently selected from the group consisting of halo, OR a NR a R b 、C 3-C5 cycloalkyl, 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with 1 to 2 groups independently selected from halo and -CH3; or C3-C8 cycloalkyl, phenyl, 4 to 9 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein R 1 The cycloalkyl, phenyl, heterocyclic and heteroaryl groups in the group represented by are each optionally substituted by 1 to 3 groups independently selected from R 11 and each R a are independently H or -CH3; and each R b is -CH3, and wherein the remaining variables are as defined in the first, third, fourth, fifth, sixth or ninth embodiment.

[0085] In an eleventh embodiment, the present disclosure provides a compound according to the following 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 1 R is selected from -CH3, -CH2CH3, -CH2CH3CH3 and -CH(CH3)2, each of which is optionally substituted with 1-3 groups selected from F, -OH, -OCH3, -N(CH3)2, cyclopropyl, morpholinyl, oxadiazolyl, oxetanyl, oxazolyl, pyridinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl and triazolyl, wherein each of the pyridinyl, thiadiazolyl, thiazolyl and triazolyl is optionally substituted with F, -CH3 or -CH2CH3; or R 1selected from azabicyclo[3.1.0]hexyl, azetidinyl, 1H-benzo[d]imidazolyl, bicyclo[1.1.1]pentyl, cubanyl, cyclobutyl, cyclopropyl, dihydroisoquinolinyl, dihydropyrrolyl, dihydro-2H-benzo[b][1,4]oxazinyl, dioxepanyl, hexahydro-1H-pyrrolazinyl, imidazolidinyl, indazolyl, isoindolinyl, isothiazolyl, morpholinyl, octahydropyrrolo[1,2- a] pyrazinyl, oxabicyclo[3.1.0]hexyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, oxabicyclo[3.3]heptyl, 7-oxa-4-azaspiro[2.5]octyl, oxetanyl, phenyl, piperidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolopyridinyl, tetrahydrofuranyl, tetrahydropyranyl and thiazolyl, each of which is optionally substituted by 1 to 3 independently selected R 11 and wherein the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth or tenth embodiment.

[0086] In a twelfth embodiment, the present disclosure provides a compound according to the following 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 Selected from 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 、

[0087]

[0088] and wherein the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth or eleventh embodiment.

[0089] In a thirteenth embodiment, the present disclosure provides a compound according to the following 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 independently selected from halogen, OR a 、C(O)R a 、C(O)NR a R b NR a C(O)OR a NR a R b , C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 12-membered heterocyclyl and 5- to 12-membered heteroaryl, wherein R 11 The alkyl, cycloalkyl, heterocyclyl and heteroaryl groups represented by a and NR a R b or two R 11 Together form =O; each R a is independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl and 4 to 6 membered heterocyclyl; and each R b is independently selected from H and C1-C4 alkyl, and wherein the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh or twelfth embodiment.

[0090] In a fourteenth embodiment, the present disclosure provides a compound according to the following 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 independently selected from halogen, ORa 、C(O)R a 、C(O)NR a R b NR a C(O)OR a NR a R b 、C 1- C3 alkyl, morpholinyl, oxazolyl, oxadiazolyl, oxetanyl, pyridyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl and thiazolyl, wherein R 11 The alkyl, morpholinyl, oxazolyl, oxadiazolyl, oxetanyl, pyridyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl and thiazolyl groups represented by each are optionally substituted by 1 to 3 groups selected from deuterium, halogen, OR a and NR a R b or two R 11 Together form =O; each R a independently selected from H, -CH3, -CH2CH3, -C(CH3)3, And each R b is independently H or -CH3, and wherein the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth or thirteenth embodiment.

[0091] In a fifteenth embodiment, the present disclosure provides a compound according to the following 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 Independently selected from Cl, F, -OH, -OCH3, -C(O)CH2CH3, -N(CH3)2, -NHC(O)OC(CH3)3, -CH3, -CD3, -CHF2, -CF3, -CH2OH, -CH2OCH3, -CH2-N(CH3)2, -CH2CH3, -CH2CF3, -CH2CH2-N(CH3)2, -CH(CH3)2, -C(CH3)2-OH, or two R attached to the same carbon atom 11Together they form =0, and wherein the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth or fourteenth embodiment.

[0092] In a sixteenth embodiment, the present disclosure provides a compound according to the following 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 0, and wherein the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment.

[0093] In a seventeenth embodiment, the present disclosure provides a compound according to the following 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 by 1 to 3 groups independently selected from halo, OR a NR a R b and 4 to 12 membered heterocyclic groups, or 4 to 12 membered heterocyclic groups or 5 to 12 membered heteroaryl groups, wherein R 2 The heterocyclic and heteroaryl groups represented by the present invention are each optionally substituted by 1 to 4 groups selected from the group consisting of C1-C4 alkyl, C(O)R a and a 4- to 12-membered heterocyclic group optionally substituted by 1 to 3 groups selected from halogen and C1-C4 alkyl; each R a are independently selected from H and C1-C4 alkyl; and each R bis independently selected from H and C1-C4 alkyl, and wherein the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth or sixteenth embodiment.

[0094] In an eighteenth embodiment, the present disclosure provides a compound according to the following 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 optionally substituted by 1 to 2 independently selected halogen, OR a NR a R b and 4 to 6 membered heterocyclic groups, or 5 to 7 membered heterocyclic groups or 5 to 6 membered heteroaryl groups, wherein R 2 The heterocyclic group and heteroaryl group in the group represented by are each optionally substituted by 1 to 2 groups selected from the following groups: C1-C2 alkyl, C(O)R a and a 6-membered heterocyclic group optionally substituted by a C1-C2 alkyl group; each R a are independently selected from H and -CH3; and each R b is -CH3, and wherein the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth or seventeenth embodiment.

[0095] In a nineteenth embodiment, the present disclosure provides a compound according to the following 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 R2 is -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl or each of which is optionally substituted with F, -OCH3, -N(CH3)2, morpholinyl or oxetanyl; or R 2 is diazaspiro[3.3]heptyl, pyrazolyl, pyrimidinyl, or tetrahydrofuranyl, each of which is optionally substituted with C1-C2 alkyl, C(O)C1-C4 alkyl, or piperidinyl optionally substituted with -CH3, and wherein the remaining variables are as defined in the first, third, fourth, fifth, sixth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment.

[0096] In a twentieth embodiment, the present disclosure provides a compound according to the following 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, -CHF2, -CH2CH3, -CH2CH2-OCH3, -CH2CH2-N(CH3)2, -CH(CH3)2, cyclopropyl, or R 2 yes Each of which is optionally replaced by -CH3, C(O)CH3 or and wherein 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.

[0097] In a twenty-first embodiment, the present disclosure provides a compound according to the following 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 heterocyclic group, wherein R 3 The alkyl, cycloalkyl and heterocyclic groups represented by a NR a R b and C 3- C6 cycloalkyl group substituted; each R a are independently H or C1-C4 alkyl; and each R b is independently H or C1-C4 alkyl, and wherein 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.

[0098] In a twenty-second embodiment, the present disclosure provides a compound according to the following 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 wherein 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, or twenty-first embodiment.

[0099] In a twenty-third embodiment, the present disclosure provides a compound according to the following 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 Selected from H, -CH3, -CHF2, -CD3, -CH2CH3, -CH2CHF2, -CH2CF3, -CH2CH2-OH, -CH2CH2-N(CH3)2, -CH2CH3CH3, -CH(CH3)2, and wherein 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.

[0100] In a twenty-fourth embodiment, the present disclosure provides a compound according to the following 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 a halogen or OR a ; Each R a is independently selected from H and C1-C4 alkyl; and n is 0, 1, 2, or 3, and wherein 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, or twenty-third embodiment.

[0101] In a twenty-fifth embodiment, the present disclosure provides compounds according to the following formulas: (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-9 a), (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 wherein 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.

[0102] In a twenty-sixth embodiment, the present disclosure provides a compound according to the following 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 is independently selected from F and OH, and wherein 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.

[0103] In a twenty-seventh embodiment, the compound of formula (I) is represented by one of structural formulas (II-3c) or (II-3b):

[0104]

[0105] 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.

[0106] In a twenty-eighth embodiment, the compound of formula (I) is represented by one of structural formulas (II-7a) or (II-7b):

[0107]

[0108] 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.

[0109] In the 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- to 10-membered heteroaryl, wherein said 5- to 10-membered heteroaryl is optionally substituted with C1-C2 alkyl, or C3-C8 cycloalkyl, 4- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl, wherein R 1 The cycloalkyl, heterocyclyl and heteroaryl groups represented by 11 substituted by a group; each R 11 independently selected from halo, NR a R b , C3-C6 cycloalkyl and C1-C4 alkyl optionally substituted by 1 to 3 halogen groups, and each R a R is independently selected from H and C1-C4 alkyl; 2 and R 3 are each independently C1-C4 alkyl; and R 4 is halo, wherein n is 0, 1, or 2, and wherein 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, or twenty-sixth embodiment.

[0110] In a thirtieth embodiment, the present disclosure provides a compound according to 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 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with C1-C2 alkyl, or C3-C5 cycloalkyl, 5-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein R 1 The cycloalkyl, heterocyclyl and heteroaryl groups represented by 11 substituted by a group; each R 11 R is independently selected from halo, N(CH3)2, C3-C5 cycloalkyl and C1-C2 alkyl optionally substituted with 1 to 3 halo groups; 2 and R 3 are each independently C1-C2 alkyl; R 4 is halo; and n is 0, 1 or 2, and wherein 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 or twenty-ninth embodiment.

[0111] 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 by oxadiazolyl, said oxadiazolyl being optionally substituted by -CH3; or R 1 selected from azabicyclo[3.1.0]hexyl, bicyclo[1.1.1]pentyl, cyclopropyl, 3-oxabicyclo[3.1.0]hexyl, piperidinyl, pyrazolyl and pyridinyl, each of which is optionally substituted by 1 to 2 groups independently selected from R 11 The group substituted, each R 11 Independently selected from F, -N(CH3)2, -CH3, -CF3, and wherein 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.

[0112] 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 1Selected from And each R 11 Independently selected from F, -N(CH3)2, -CH3, -CF3, and wherein 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.

[0113] In a thirty-third embodiment, the present disclosure provides a compound according to formula (II-3c), (II-3b), (II-7a) or (II-7b), or a pharmaceutically acceptable salt thereof, wherein R 2 is a C1-C4 alkyl group; R 3 is a C1-C4 alkyl group; each R 4 and n is 0, 1 or 2, and wherein 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, thirty-first or thirty-second embodiment.

[0114] 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; R 3 is -CH3; R 4 is F; and n is 0 or 1, and wherein 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, thirty-first, thirty-second or thirty-third embodiment.

[0115] In a thirty-fifth embodiment, the compound of formula (I) is represented by the following structural formula (III):

[0116]

[0117] or a pharmaceutically acceptable salt thereof, and 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.

[0118] In a thirty-sixth embodiment, the compound of formula (I) is represented by one of the following structural formulas (III-1) or (III-2):

[0119]

[0120] or a pharmaceutically acceptable salt thereof, and 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.

[0121] 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 wherein 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.

[0122] In a thirty-eighth 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.

[0123] Table 1

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196] In one embodiment, the present disclosure excludes the compounds of Examples 455-457 and 458A in Table 3 and pharmaceutically acceptable salts thereof.

[0197] In some embodiments, the present disclosure provides a compound according to the following 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-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, wherein one or more hydrogens are replaced by deuterium.

[0198] 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 excessive toxicity, irritation, or allergic response, and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0199] Pharmaceutically acceptable salts of the compounds disclosed herein are included in the present teachings. Compounds having basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. 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). The present teaching compounds having acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic 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).

[0200] Compounds with one or more chiral centers can exist in multiple stereoisomeric forms, i.e., each chiral center can have the R or S configuration, or can be a mixture of the two. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers with two or more chiral centers that are not identical and are not mirror images of each other.

[0201] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is indicated by its chemical name (e.g., where the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., where the configuration is indicated by a "wedge-shaped" bond), the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. In this case, stereoisomeric purity 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.

[0202] When a disclosed compound with a chiral center is depicted by a structure without showing the configuration at the chiral center, the structure is intended to encompass compounds having the S configuration at the chiral center, compounds having the R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center. When a disclosed compound with a chiral center is depicted by its chemical name without using "S" or "R" to indicate the configuration at the chiral center, the name is intended to encompass compounds having the S configuration at the chiral center, compounds having the R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center.

[0203] When two stereoisomers are depicted by their chemical names or structures and the names or structures are linked by "or," one or the other of the two stereoisomers is intended, but not both.

[0204] 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 and diastereomeric mixtures of the compounds disclosed herein.

[0205] Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically pure or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0206] "First eluting compound" or "Peak 1" in the experimental section refers to the expected reaction product compound obtained from chromatographic separation / purification that elutes earlier than the second expected reaction product compound from the same previous reaction. The second expected product compound is referred to as the "second eluting compound" or "Peak 2."

[0207] In the compounds of the present disclosure, any position specifically designated as "D" or "deuterium" is understood to have 50%, 80%, 90%, 95%, 98% or 99% deuterium enrichment. "Deuterium enrichment" is a mole % 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," the position has hydrogen at its natural abundance. When a position is not specified as having hydrogen or deuterium, the position has hydrogen at its natural abundance. A specific alternative embodiment relates to compounds of the present disclosure having at least 5%, 10%, 25%, 50%, 80%, 90%, 95%, 98% or 99% deuterium enrichment at one or more positions not specifically designated as "D" or "deuterium."

[0208] As used herein, many moieties (e.g., alkyl, alkoxy, cycloalkyl, or heterocyclyl) are referred to as being "substituted" or "optionally substituted." When a moiety is modified by one of these terms, unless otherwise noted, it indicates that any portion of the moiety known to those skilled in the art for substitution may be substituted, including one or more substituents. If more than one substituent is present, each substituent may be independently selected. Such substitution patterns are well known in the art and / or taught by this disclosure. An optional substituent may be any substituent suitable for attachment to a moiety.

[0209] The compounds disclosed herein are selective EGFR inhibitors. As used herein, the term "selective EGFR inhibitor" refers to compounds that selectively inhibit certain mutant EGFR kinases compared to wild-type EGFR and kinase bodies. In other words, selective EGFR inhibitors have no activity or low activity against wild-type EGFR and kinase bodies. 50 values, which show that selective EGFR inhibitors have more potent inhibitory activity against certain mutant EGFR kinases (i.e., IC values) than their inhibitory activity against wild-type EGFR and many other kinases. 50 Values ​​are subnanomolar concentrations). Potency can be measured using known biochemical assays.

[0210] Some compounds disclosed herein have the advantage of good brain penetration. A combination of various known methods or such methods can be used to assess the ability of a particular compound to penetrate the BBB and penetrate into the brain. An in vitro method commonly used to predict the in vivo brain penetration of a compound is the P-gp efflux ratio. P-glycoprotein (P-gp) is expressed at the blood-brain barrier (BBB) ​​and limits its substrate penetration into the central nervous system (CNS). Compounds found to be good P-gp substrates in vitro (i.e., having a high efflux ratio) are predicted to have poor in vivo brain penetration. To measure the P-gp efflux ratio, the apparent top-to-bottom permeability (Papp[AB]) and apparent bottom-to-top permeability (Papp[BA]) of the compound were measured using Madin-Darby canine kidney cells (MDCK-MDR1 cells) that overexpress P-gp. The P-gp efflux ratio is a measure of the Papp[BA] / Papp[AB] ratio. In some embodiments, the 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.

[0211] Some compounds of the present disclosure have the advantage of good metabolic stability. One indicator of good metabolic stability is high microsomal stability. Liver metabolism is the main elimination pathway for small molecule drugs. The clearance of compounds by liver metabolism can be assessed in vitro using human liver microsomes (HLM) or human hepatocytes. The compound is incubated with HLM plus appropriate cofactors or human hepatocytes and compound consumption is measured to determine the in vitro intrinsic clearance (Clint). Clint is proportionally expanded to the systemic clearance (CL), and the liver extraction rate (ER) is determined by dividing the CL by the standard human liver blood flow. Compounds with low liver extraction rates are considered to have good metabolic stability. In some embodiments, compounds of the present disclosure have a calculated ER of <0.3, <0.4, <0.5, <0.6.

[0212] Pharmaceutical composition

[0213] The pharmaceutical compositions of the present disclosure (also referred to herein as "disclosed pharmaceutical compositions") comprise one or more pharmaceutically acceptable carriers or diluents and a compound of the present disclosure (e.g., a compound of Formula (A) or Formula (I)) or a pharmaceutically acceptable salt thereof.

[0214] "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to substances that aid in the formulation of an active agent and / or the administration of an active agent to a subject and / or absorption by a subject, and that can be incorporated into the pharmaceutical compositions of the present disclosure without producing significant adverse toxicological effects on the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, physiological saline solution, lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates (e.g., lactose, amylose, or starch), hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidine, and colorants, among others. Such preparations can be sterilized and, if necessary, mixed with auxiliary agents that do not deleteriously react with the compounds provided herein or interfere with the activity of the compounds, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, and / or aromatic substances, etc. Those of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds or their pharmaceutically acceptable salts.

[0215] The pharmaceutical composition of the present disclosure optionally includes one or more pharmaceutically acceptable carriers and / or diluents, 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 complete list of suitable excipients can be found in Handbook of Pharmaceutical Excipients (5th edition, Pharmaceutical Press (2005)). Those skilled in the art will know how to prepare preparations suitable for various types of routes of administration. Conventional procedures and ingredients for selecting and preparing suitable preparations are described in, for example, Remington's Pharmaceutical Sciences (2003, 20th edition) and The United States Pharmacopeia: The National Formulary (USP 24NF19), disclosed in 1999. Carriers, diluents and / or excipients are "acceptable" in the sense that they are compatible with the other ingredients of the pharmaceutical composition and are harmless to their recipients.

[0216] Treatment

[0217] The present disclosure provides a method for inhibiting certain mutant forms of epidermal growth factor receptor (EGFR) in a subject in need thereof, the method 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 having an LRCS mutation (exon 19 deletion (del19) or exon 21 (L858R) substitution mutation, and a C797X (e.g., C797S) mutation). A subject who "needs to inhibit EGFR" is a subject suffering from a disease for which a beneficial therapeutic effect can be achieved by inhibiting at least one mutant EGFR, the beneficial therapeutic effect being, for example, slowing disease progression, alleviating one or more symptoms associated with the disease, or extending the lifespan of the subject according to the disease.

[0218] In some embodiments, the present disclosure provides a method for treating a disease / disorder / or cancer associated with or regulated by mutant EGFR, wherein inhibiting mutant EGFR has therapeutic benefit, including but not limited to treating cancer in a subject in need thereof. The method comprises administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0219] In another embodiment, the present disclosure provides a method for treating a subject with cancer, the method comprising administering an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein to the subject. Cancers to be treated according to the disclosed method 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 metastasis (particularly brain metastasis) of all cancers listed. Generally, cancer is characterized by one or more EGFR mutations as described herein. In a specific embodiment, cancer has progressed during or after EGFR tyrosine kinase inhibitor (TKI) therapy. In a specific embodiment, the disease has progressed during or after first-line 3rd generation TKI (e.g., osimertinib). In a specific embodiment, cancer has not been previously treated.

[0220] 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.

[0221] In another embodiment, the disease / disorder / or cancer associated with or modulated by mutant EGFR is characterized by an EGFR genotype selected from genotypes 1-36 according to the table below (del18 = exon 18 deletion, in particular, e.g., delE709_T710 insD; and del19 = exon 19 deletions, specifically, e.g., delE746_A750 (most common), delE746_S752insV, del747_A750insP, delL747_P753insS, and delS752_I759; ex20ins - exon 20 insertions, specifically, e.g., D761-E762insX, A763-Y764insX, Y764-V765insX, V765-M766insX, A767-S768insX, S768-D769insX, V769-D770insX, N771-P772insX, P772-H773insX, H773-V774insX, and V774-C775insX):

[0222] EGFR genotype

[0223]

[0224]

[0225] In another embodiment, the disease / disorder / or cancer (eg, NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR del19.

[0226] In another embodiment, the disease / disorder / or cancer (eg, NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del 19 C797S.

[0227] In another embodiment, the disease / disorder / 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 C797X (C797G or C797N or C797Y or C797T or C797D).

[0228] In another embodiment, the disease / disorder / 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 L792X (L792F, L792H, or L792Y).

[0229] In another embodiment, the disease / disorder / or cancer (eg, NSCLC) treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del 19 G796R (G796S).

[0230] In another embodiment, the disease / disorder / or cancer (eg, NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 L792R (L792V or L792P).

[0231] In another embodiment, the disease / disorder / or cancer (eg, 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).

[0232] In another embodiment, the disease / disorder / or cancer (eg, 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.

[0233] In another embodiment, the disease / disorder / or cancer (eg, 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.

[0234] In another embodiment, the disease / disorder / or cancer (e.g., NSCLC) treated with the disclosed compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein is characterized by an EGFR comprising EGFR L858R C797X (797G or C797N or C797Y or C797T or C797D).

[0235] In another embodiment, the disease / disorder / or cancer (e.g., NSCLC) treated with the disclosed compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein is characterized by an EGFR comprising EGFR L858R L792X (L792F, L792H, or L792Y).

[0236] In another embodiment, the disease / disorder / or cancer (eg, 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).

[0237] In another embodiment, the disease / disorder / 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).

[0238] In another embodiment, the disease / disorder / 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).

[0239] In another embodiment, the disease / disorder / or cancer (eg, NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by an EGFR comprising EGFR del18.

[0240] In another embodiment, the disease / disorder / 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 G719X (G719A, G719S, G719C, G719R, G719D, or G719V).

[0241] In another embodiment, the disease / disorder / 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 E709X (E709K, E709H, or E709A).

[0242] In another embodiment, the disease / disorder / 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 E709X (E709K, E709H, or E709A) (G719A, G719S, G719C, G719D, G719R, or G719V).

[0243] In another embodiment, the disease / disorder / 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 G719X (G719A, G719S, G719C, G719D, G719R, or G719V) S768I.

[0244] In another embodiment, the disease / disorder / or cancer (eg, NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR S768I.

[0245] In another embodiment, the disease / disorder / or cancer (eg, NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR ex20ins.

[0246] In another embodiment, the disease / disorder / or cancer (eg, NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR ex20ins L718Q.

[0247] In another embodiment, the disease / disorder / or cancer (eg, NSCLC) treated with a disclosed compound, pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR ex20ins C797S.

[0248] In another embodiment, the disease / disorder / or cancer (eg, 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.

[0249] In another embodiment, the disease / disorder / 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.

[0250] In another embodiment, the disease / disorder / 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.

[0251] In another embodiment, the disease / disorder / 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.

[0252] In another embodiment, the disease / disorder / 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.

[0253] In another embodiment, the disease / disorder / 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 and afatinib.

[0254] In another embodiment, the disease / disorder / 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 and dacomitinib.

[0255] In another embodiment, the disease / disorder / 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.

[0256] In another embodiment, the disease / disorder / 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 avantamab and lazertinib.

[0257] In another embodiment, the disease / disorder / 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 aumolertinib (formerly almonertinib).

[0258] In another embodiment, the disease / disorder / 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.

[0259] In another embodiment, the disease / disorder / 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.

[0260] In another embodiment, the disease / disorder / 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.

[0261] Another embodiment is the treatment of a subject with metastatic NSCLC whose tumor carries an activating exon 19 deletion or L858R EGFR mutation, G719X (A, S, C, D, R, V), S768I, and L861Q, and a resistance mutation disclosed herein, as detected by an approved molecular test.

[0262] Another embodiment is a disclosed compound for use in combination with a 2nd or 3rd generation TKI indicated for the treatment of a subject with metastatic NSCLC whose tumor carries a C797X mutation as detected by an approved test and whose disease has progressed on or after 1 or 2 prior EGFR TKI therapies.

[0263] Another embodiment is a disclosed compound for use in treating a subject with metastatic NSCLC whose disease has progressed on or after any EGFR TKI with on-target EGFR resistance. In a specific embodiment, the disclosed compound is used in combination with a 2nd or 3rd generation TKI suitable for treating a subject with metastatic NSCLC.

[0264] Another embodiment is a disclosed compound for use in treating a subject with metastatic EGFR C797X mutation-positive NSCLC, as detected by an approved molecular test, whose disease has progressed on or after first-line or second-line osimertinib. In a specific embodiment, the disclosed compound is used in combination with a second-generation or third-generation TKI indicated for the treatment of a subject with metastatic NSCLC.

[0265] In a specific embodiment, the deletions, mutations, and insertions disclosed herein are detected by an FDA-approved test.

[0266] One of ordinary skill in the art can readily determine whether a subject has certain EGFR alterations in a cell, cancer, gene, or gene product, e.g., whether a subject has one or more mutations or deletions described herein, using detection methods selected from, for example, those known in the art: hybridization-based methods, amplification-based methods, microarray analysis, flow cytometric analysis, DNA sequencing, next generation sequencing (NGS), primer extension, PCR, in situ hybridization, fluorescence in situ hybridization, dot blot, and Southern blot.

[0267] 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 can be collected from subjects. The sample is processed, nucleic acids are isolated using techniques known in the art, and then the nucleic acids are sequenced using methods known in the art. The sequence is then mapped to individual exons, and the measure of transcriptional expression (e.g., RPKM, or per kilobase read per million reads mapped) is quantified. Raw sequence and exon array data can be obtained from sources such as TCGA, ICGC, and NCBI gene expression collections (Gene Expression Omnibus, GEO). For a given sample, individual exon coordinates are annotated with gene identifier information, and exons belonging to the kinase domain are marked. The exon levels of all tumor samples are then z-score normalized.

[0268] Compounds of the present disclosure, 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 later responded poorly or did not respond at all. In some embodiments, the subject has become refractory to one or more first-generation EGFR inhibitors (e.g., erlotinib, gefitinib, icotinib, or lapatinib). In some embodiments, the subject has become refractory to treatment with one or more second-generation EGFR inhibitors (e.g., 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 (e.g., osimertinib, neratinib, 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.

[0269] combination

[0270] The compounds of the present disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein may be used in combination with one or more other pharmacologically active substances. For example, the present disclosure includes methods of treating a condition / disease / or cancer comprising administering to a subject in need thereof a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition 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), amolertinib (formerly almonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilitertinib, icotinib, JND-3229, lazertinib, nazartinib (EGFR), or a combination thereof. 816), avitinib, PCC-0208027, rezivertinib (BPI-7711), TQB3804, zorifertinib (AZ-3759) or DZD9008; EGFR antibodies, such as cetuximab, panitumumab, necitumumab, HLX07, JMT101; or bispecific EGFR and MET antibodies (such as avantumab (JNJ-61186372, JNJ-372)). For the treatment of cancer (such as NSCLC), the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein in combination with a first-line therapy (such as a first-generation, second-generation 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.

[0271] In one aspect, the compounds of the present disclosure, their pharmaceutically acceptable salts, or pharmaceutical compositions disclosed herein may be administered in combination with compounds disclosed in International Application Publication No. WO 2021 / 133809, their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same.

[0272] In one embodiment, the compounds of the present disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein may be administered in combination with the compounds provided below:

[0273] (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,

[0274] (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,

[0275] 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,

[0276] 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,

[0277] 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,

[0278] 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,

[0279] (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,

[0280] (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,

[0281] 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,

[0282] (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,

[0283] (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,

[0284] (3S,4S)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropylisoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol,

[0285] (3R,4R)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropylisoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol,

[0286] A pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0287] Alternatively, the compounds of the present disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein can be administered in combination with other anticancer agents that are not EGFR inhibitors, for example, in combination with: 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); anti-angiogenic agents, such as bevacizumab, nintedanib; apoptosis inducers, such as Bcl-2 inhibitors, such as venetoclax, obatoclax, navitoclax, palcitoclax (APG-1252), and Mcl-1 inhibitors, such as AZD-5991, AMG-176, S-64315 mTOR inhibitors, such as rapamycin, temsirolimus, everolimus, and ridoforolimus; RET inhibitors, such as pralsetinib and selpercatinib, and PI3K inhibitors dactolisib (BEZ235), pictilisib (GDC-0941), LY294002, and 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., oncoprex).

[0288] A "subject" is a human being in need of treatment.

[0289] Method of administration and dosage form

[0290] The precise amount of compound administered to provide an "effective amount" to a subject will depend on the mode of administration, the type and severity of the cancer, and the characteristics of the subject, such as general health, age, sex, weight, and tolerance to the drug. One skilled in the art will be able to determine an appropriate dose based on these and other factors. When administered in combination with other therapeutic agents, such as anticancer agents, an "effective amount" of any other therapeutic agent will depend on the type of drug used. Suitable doses of approved therapeutic agents are known and can be adjusted by one skilled in the art based on the subject's condition, the type of illness being treated, and the amount of the compound of Formula (A) or Formula (I) used, by following, for example, the dosages reported in the literature and recommended in Physician's Desk Reference (57th edition, 2003).

[0291] "Treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect can be a therapeutic effect, which includes partially or substantially achieving one or more of the following results: partially or substantially reducing the extent of the disease, disorder, or cancer; improving or ameliorating clinical symptoms or indicators associated with the disease, disorder, or cancer; delaying, inhibiting, or reducing the likelihood of progression of the disease, disorder, or cancer; or reducing the likelihood of recurrence of the disease, disorder, or cancer.

[0292] The term "effective amount" means an amount that produces a beneficial or desired result (including a clinical result, such as inhibition, suppression or alleviation of the symptoms of the subject's treated disorder as compared to a control) when administered to a subject. For example, a therapeutically effective amount can be administered in a unit dosage form (e.g., 0.1 mg to about 50 g / day, or 1 mg to about 5 grams / day; and in another alternative, 10 mg to 1 gram / day).

[0293] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a composition to a desired site of biological action. These methods include, but are not limited to, intraarticular (in 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 are found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0294] In addition, the compounds of the present invention, its pharmaceutically acceptable salt or pharmaceutical composition of the present invention can be co-administered with other therapeutic agents. As used herein, the terms "co-administered", "administered in combination with ... " and grammatical equivalents thereof are intended to encompass administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agent is 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 invention, its pharmaceutically acceptable salt or pharmaceutical composition of the present invention will be co-administered with other agents. These terms encompass administration of two or more agents to a subject, so that two agents and / or their metabolites are present in the subject simultaneously. It includes administration with a separate composition simultaneously, administration at different times with a separate composition and / or administration with a composition in which two agents are present. Therefore, in some embodiments, the compounds as herein described and other agents are administered with a single composition. In some embodiments, the compounds as herein described and other agents are mixed in the composition.

[0295] The specific mode of administration and dosage regimen will be selected by the attending clinician based on the specific circumstances of the case (e.g., the subject, the disease, the disease state involved, the specific treatment). Treatment may involve daily or multiple days or less than daily (e.g., weekly or monthly, etc.) dosing over a period of several days to several months or even years. However, considering the dosage of approved compositions for treating diseases using the disclosed EGFR inhibitors as a guide, one of ordinary skill in the art will immediately recognize appropriate and / or equivalent dosages.

[0296] As will be appreciated 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 according to the selected route of administration. The compounds of this teaching can be administered, for example, orally, parenterally, buccally, sublingually, nasally, rectally, by patch, pump, or transdermal administration, and the pharmaceutical composition can be formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical administration modes. Parenteral administration can be performed by continuous infusion over a selected time period.

[0297] The pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. In one embodiment, the composition is formulated according to conventional 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.

[0298] Typically, for oral therapeutic administration, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0299] Typically, for parenteral administration, solutions of the disclosed compounds or pharmaceutically acceptable salts thereof are prepared in water suitably mixed with a surfactant (e.g., hydroxypropylcellulose). Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, and in oils. Under ordinary storage and use conditions, these formulations contain a preservative to prevent microbial growth.

[0300] Generally, for injectable use, sterile aqueous solutions or dispersions of the disclosed compounds and sterile powders of the disclosed compounds for the extemporaneous preparation of sterile injectable solutions or dispersions are appropriate.

[0301] The compounds of the present disclosure can be prepared according to the following general synthetic methods.

[0302] General synthetic scheme

[0303] According to the first method, a compound of formula (I) (A) (wherein L 1is a bond) can be prepared from compounds of Formula (II), Formula (III) and Formula (IV) as illustrated by Scheme 1A.

[0304]

[0305]

[0306] LG is a suitable leaving group, usually halide or triflate, and preferably Cl or Br or triflate. The compound of formula (I) (A) can be prepared from a compound of formula (II) and R 1 MgBr, prepared by Fe-catalyzed cross-coupling reaction of process step (a) with a Grignard reagent in the presence of NMP, such as et al., Angew. Chem. Int. Ed. 2018, 57, 6496. Preferred conditions include reacting a compound of formula (II) with R in THF between 0°C and room temperature. 1 Reaction of MgBr, Fe(III) acetylacetone, and NMP.

[0307] Alternatively, the compound of formula (I) (A) can be prepared from the compound of formula (II) and R 1 Sn(alkyl)3, prepared by a palladium-catalyzed cross-coupling reaction (Stille reaction) of method step (b) with a suitable alkyl or aryl stannane. Typical cross-coupling reaction conditions include a palladium catalyst containing a suitable phosphine ligand, in the presence of an inorganic base, in a suitable aqueous solvent, at a temperature between room temperature and the reflux temperature of the reaction. Preferred conditions include reacting a compound of formula (II) with R in the presence of a suitable catalyst (e.g., Pd(PPh3)2Cl2, Pd(PPh3)4), optionally in the presence of an additive, typically LiCl, in a suitable solvent (e.g., dioxane), at elevated temperature (e.g., 90°C-100°C). 1 SnBu3 reaction.

[0308] Alternatively, the compound of formula (I) (A) can be prepared from the compound of formula (II) and R 1 BPin or R 1 B(OH)2, prepared by a palladium-catalyzed cross-coupling reaction (e.g., Suzuki reaction) according to step (c) of the method. Typical cross-coupling reaction conditions include reacting a compound of formula (II) with R in the presence of an inorganic base in a suitable aqueous solvent at a temperature between room temperature and the reflux temperature of the reaction. 1 BPin or R 1B (OH) 2 and a palladium catalyst containing a suitable phosphine ligand. Preferred conditions include reacting a compound of formula (II) with R in the presence of Xphos Pd G3, Pd (dppf) Cl2, Pd2 (dppf) 3 Pd (PPh3) 4, cataCXium A Pd G3 or PdCl2 (Amphos) 2 and a suitable base (e.g., K3PO4, KHCO3, K2CO3 or Cs2CO3) in a suitable solvent (e.g., aqueous dioxane, DME or DMSO) at temperatures between 70°C and 100°C. 1 BPin or R 1 B(OH)2 reaction.

[0309] Alternatively, a compound of formula (I) (A) (wherein R 1 is C1-C4 alkyl or C3-C6 cycloalkyl substituted by OH) can be obtained from the compound of formula (II) and R 1 C(O)R a or R 1 C(O), prepared by process step (d). Preferred conditions include reacting a compound of formula (II) with R in the presence of a strong base (e.g. n-BuLi) in a suitable solvent (e.g. THF) at low temperature (e.g. -78°C). 1 C(O)R a or R 1 C(O) reaction.

[0310] The compound of formula (III) (wherein R 1 is an alkyl, cycloalkyl or heterocyclic group, and R 1 ' is its unsaturated precursor) can be obtained from the compound of formula (II) and R 1 'H, prepared by a palladium-catalyzed cross-coupling reaction (e.g., Heck reaction) in step (e) of the method. Preferred conditions include reacting a compound of formula (II) with R in the presence of a suitable palladium catalyst (e.g., Pd(dppf)Cl2 or Pd(PPh3)4), in the presence of a suitable base (e.g., K2CO3 or K3PO4), in a suitable solvent (e.g., aqueous dioxane or THF), at elevated temperature (e.g., 80°C). 1 'H reaction.

[0311] Compounds of formula (I) (A) can be prepared from compounds of formula (III) by reduction in process step (f). Preferred conditions include reacting a compound of formula (III) with a suitable reducing agent (e.g. NaCNBH 3 ) in the presence of AcOH in a suitable alcoholic solvent (e.g. MeOH) at room temperature.

[0312] Or, where R 1 is a heteroaryl group, the compound of formula (I) (A) can be prepared from the compound of formula (II) and R 1H was prepared by the method as described previously, step (e).

[0313] The compound of formula (IV) can be prepared from the compound of formula (II) and R 1 (BPin)2 is prepared by the method described previously above, step (c). 1 is a cycloalkyl substituted with OH) can be prepared from a compound of formula (IV) by oxidation reaction in process step (g). Typical conditions include reacting a compound of formula (IV) with a suitable oxidizing agent (e.g., NaBO3) in a suitable solvent (e.g., aqueous THF) at about room temperature.

[0314] According to the second method, the compound of formula (I) (A) (wherein L 1 is a bond) can be prepared from compounds of Formula (II), Formula (V), Formula (VI) and Formula (VII) as illustrated by Scheme 1B.

[0315]

[0316] Compounds of formula (V) can be prepared from compounds of formula (II) and (C1-C4alkyl)OC(CH)Sn(alkyl)3 by palladium-catalyzed cross-coupling of process step (b) with an appropriate alkylstannane (Stille reaction as previously described in Scheme 1A).

[0317] Compounds of formula (VI) can be prepared from compounds of formula (V) by oxidation reaction in process step (h). Typical conditions include reacting compounds of formula (V) with KMnO4, NaIO4 in a suitable solvent (e.g., aqueous DCM) at room temperature.

[0318] Compounds of formula (I) (A) can be prepared from compounds of formula (VI) by reduction of the ester according to process step (i). Typical conditions include reacting the compound of formula (VI) with DIBAL-H in a suitable solvent (e.g. THF) at low temperature (e.g. -30°C).

[0319] Compounds of formula (VII) may be prepared from compounds of formula (V) by process step (j). Typical conditions include reaction of a compound of formula (V) with TFA in DCM at room temperature.

[0320] Compounds of formula (I) (A) can be prepared from compounds of formula (VII) by reduction of the ketone in process step (k). Typical conditions include reacting the compound of formula (VII) with a suitable reducing agent (e.g. NaBH4) in a suitable solvent (e.g. MeOH).

[0321] According to the third method, the compound of formula (I) (B) (wherein L 1(O) can be prepared from compounds of formula (VIII) as illustrated by Scheme 1C.

[0322]

[0323] Compounds of formula (I) (B) can be prepared from compounds of formula (VIII) by the Mitsunobu reaction of process step (1). Typical conditions include the reaction of an alcohol of formula (VIII) with R in the presence of PPh3 and a suitable azodicarboxylate (e.g., DEAD, DIAD, or DBAD) in a suitable solvent (e.g., THF) at temperatures between -10°C and room temperature. 1 OH reaction.

[0324] Alternatively, the compound of formula (I)(B) can be prepared from a compound of formula (VIII) and R 1 OH is prepared by the alkylation reaction of process step (m). Typical conditions include reacting a compound of formula (VIII) with R in the presence of an inorganic base (e.g., NaH, KOtBu, KOH, or K2CO3) in a suitable solvent (e.g., DMF or THF) at a temperature between room temperature and elevated temperature (e.g., 80°C). 1 OH reaction.

[0325] According to the fourth method, the compound of formula (I) (B) (wherein L 1 (O) can be prepared from compounds of formula (II) as illustrated by Scheme ID.

[0326]

[0327] The compound of formula (I) (B) can be prepared from the compound of formula (II) and R 1 OH was prepared by alkylation as previously described in Scheme 1C above.

[0328] According to the fifth method, the compound of formula (I)(C) (wherein L 1 (OC(O)) can be prepared from compounds of formula (VIII) and formula (IX) as illustrated by Scheme IE.

[0329]

[0330] Compounds of formula (IX) can be prepared from compounds of formula (VIII) by phosgenation in process step (o). Typical conditions include reacting a compound of formula (VIII) with phosgene or triphosgene in the presence of a suitable organic base (e.g., DIPEA) in a suitable solvent (e.g., THF) at low to room temperature.

[0331] The compound of formula (I)(C) can be prepared from the compound of formula (IX) and R 1H is prepared according to process step (p). Typical conditions include reacting 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 H reaction.

[0332] Alternatively, the compound of formula (I)(C) can be prepared from a compound of formula (VIII) and R 1 COCl, prepared by process step (n). Typical conditions include reacting a compound of formula (VIII) with R in the presence of a suitable inorganic or organic base (e.g. K2CO3 or TEA or pyridine) in a suitable solvent (e.g. DMF, THF, MeCN or DCM) at room temperature and elevated temperature (e.g. 80°C). 1 COCl reaction.

[0333] According to the sixth method, the compound of formula (I) (D) (wherein L 1 is NH, or L 1 is a key and R 1 is an N-linked heterocycle) can be prepared from compounds of formula (II) as illustrated by Scheme IF.

[0334]

[0335] The compound of formula (I) (D) can be prepared from the compound of formula (II) and R 1 NH2 is prepared according to method 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 NH2 reaction. Preferred conditions include the presence of BrettPhos Pd G3, Rockphos Pd, XantphosPd G3, RuPhos Pd, E-Phos Pd G4, PEPPSIPd-Ipent-O-picoline or BINAP Pd G2 or a combination of Xphos or Xphos Pd G3 and Pd2(dba)3 in the presence of a suitable base (e.g., Cs2CO 3、 In the presence of K2CO3, K3PO4, KOAc or NaOtBu), in a suitable solvent (such as toluene, dioxane or MeCN), at 80°C and 120°C, the compound of formula (II) and R 1 NH2 reaction.

[0336] Alternatively, the compound of formula (I)(D) can be prepared from a compound of formula (II) and R 1NH2 is prepared by amination according to method step (z). Preferred conditions include reacting a compound of formula (II) with R in the presence of an organic or inorganic base, optionally in a suitable solvent (e.g. DMSO), at elevated temperature (e.g. 100°C). 1 NH2 reaction.

[0337] According to the seventh method, the compound of formula (I) (E) (wherein L 1 (NHC(O)) can be prepared from compounds of formula (X) as illustrated by Scheme 1G.

[0338]

[0339] The compound of formula (I) (E) can be prepared from the compound of formula (X) and R 1 H is prepared according to process step (r). Typical conditions include reaction of a compound of formula (XX) with a suitable "carbonylating agent" (e.g. 4-nitrophenyl chloroformate, 2,4,6-trichlorobenzoyl chloride or CDI) in the presence of a suitable organic base (e.g. pyridine or TEA), optionally in a suitable solvent (e.g. DCM) at between -78°C and 60°C, followed by reaction with R optionally in the presence of an organic base (e.g. TEA), in a suitable solvent (e.g. DCM) at between room temperature and about 80°C. 1 H reaction.

[0340] Alternatively, the compound of formula (I)(E) may be prepared from a compound of formula (X) and R 1 C(O)Cl is prepared according to the method step (n) as previously described in Scheme 1E above. Alternatively, a compound of formula (I)(E) can be prepared from a compound of formula (X) and R in the presence of a suitable coupling agent and an organic base, optionally in a suitable polar aprotic solvent. 1 CO2H is prepared according to the amide bond formation reaction of method step (s). Preferred conditions include the addition of a coupling agent (preferably In the presence of a combination of CDI or HATU) and 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 a temperature between room temperature and the reflux temperature of the reaction, an amine of formula (X) and R 1 CO2H reaction.

[0341] Alternatively, the compound of formula (I)(E) may be prepared from a compound of formula (X) and R 1 C(O)imidazole is prepared according to process step (t). Preferred conditions include reacting a compound of formula (X) with R in the presence of a strong base (e.g. NaH) in a suitable solvent (e.g. THF) at low temperature (usually 0°C). 1 C(O)imidazole reaction.

[0342] According to an eighth method, compounds of formula (I)(E) can be prepared from compounds of formula (II) as illustrated by Scheme 1H.

[0343]

[0344] The compound of formula (I) (E) can be prepared from the compound of formula (II) and R 1 CONH2 was prepared according to the method described previously in Scheme 1F, step (q).

[0345] Alternatively, the compound of formula (I) (E) can be prepared from a compound of formula (II) and R 1 CONH2 is prepared according to the Ullmann-type copper-mediated coupling reaction of method step (u). Preferred conditions include reacting a compound of formula (II) with R in the presence of CuI, a suitable ligand (e.g., N1, N2-dimethylethane-1,2-diamine or L-proline), a suitable inorganic base (e.g., K2CO3 or K3PO4), in dioxane or DMSO at a temperature between 90°C and 120°C. 1 CONH2 reaction.

[0346] According to the ninth method, the compound of formula (I) (F) (wherein L 1 (NHC(O)O) can be prepared from compounds of formula (X) as illustrated by Scheme II.

[0347]

[0348] The compound of formula (I) (F) can be prepared from the compound of formula (X) and R 1 OC(O)Cl was prepared according to the method step (n) as previously described in Scheme IE above.

[0349] According to the tenth method, the compound of formula (I) (G) (wherein L 2 (O) can be prepared from compounds of formula (XI) as illustrated by Scheme 2A.

[0350]

[0351] LG is as defined previously.

[0352] The compound of formula (I) (G) can be prepared from the compound of formula (XI) and R 2 OH is prepared according to the Buchwald-Hartwig cross-coupling reaction of process step (v). Typical conditions include reacting 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. 2OH reaction. Preferred conditions include reacting a compound of formula (XI) with R in the presence of BrettPhos Pd G3, Rockphos Pd, Xantphos Pd G3 or t-BuXphos and Pd2(dba)3 and a suitable base (e.g., Cs2CO3) in a suitable solvent (e.g., toluene, DMSO or aqueous dioxane) at about 95°C. 2 OH reaction.

[0353] According to the eleventh method, the compound of formula (I) (G) (wherein L 2 (O) can be prepared from compounds of formula (XII) as illustrated by Scheme 2B.

[0354]

[0355] The compound of formula (I) (G) can be prepared from the compound of formula (XII) and R 2 OH was prepared according to the method described previously in Scheme 1C, step (1) Mitsunobu reaction.

[0356] Alternatively, the compound of formula (I)(G) can be prepared from a compound of formula (XII) and R 2 OH is prepared by alkylation reaction as previously described in Scheme 1C above, step (m).

[0357] According to the twelfth method, the compound of formula (I) (H) (wherein L 2 is a bond) can be prepared from compounds of formula (XI) as illustrated by Scheme 2C.

[0358]

[0359] The compound of formula (I) (H) can be prepared from the compound of formula (XI) and R 2 MgBr was prepared by the method step (a) as previously described in Scheme 1A above.

[0360] Alternatively, the compound of formula (I)(H) may be prepared from a compound of formula (XI) and R 2 SnBu3 was prepared by the method step (b) as previously described in Scheme 1A above.

[0361] Alternatively, the compound of formula (I)(H) may be prepared from a compound of formula (XI) and R 2 BPin was prepared by the method as previously described in Scheme 1A above, step (c).

[0362] Alternatively, the compound of formula (I)(H) may be prepared from a compound of formula (XI) and R 2 C(O)R a Prepared by the method as previously described above in Scheme 1A, step (d).

[0363] Alternatively, the compound of formula (I)(H) may be prepared from a compound of formula (XI) and R 2 'H was prepared by the method steps (e) and (f) as previously described in Scheme 1A above.

[0364] Or, where R 2 is a C2-C4 alkynyl group, the compound of formula (I) (H) can be prepared from a compound of formula (XI) and R 2 H is prepared according to the palladium-catalyzed cross-coupling reaction (Sonagashira-type reaction) of process step (w). Typical conditions include reacting a compound of formula (XI) with R in the presence of a suitable Cu(I) salt (e.g., CuI), a suitable palladium catalyst (e.g., Pd(PPh3)4), an organic base (e.g., TEA), in DMF at elevated temperature (e.g., 100°C). 2 H reaction.

[0365] Or, where R 2 is an N-linked heterocyclic ring, the compound of formula (I) (H) can be prepared from the compound of formula (XI) and R 2 H. Prepared according to the method step (q) Buchwald reaction as previously described in Scheme 1F above.

[0366] According to a thirteenth method, compounds of formula (I) can be prepared from compounds of formula (XIII) and formula (XIV), as illustrated by Scheme 3.

[0367]

[0368] Hal is a halogen, preferably Cl or Br.

[0369] Compounds of formula (I) can be prepared from compounds of formula (XIII) and formula (XIV) according to the method step (c) Suzuki type cross coupling reaction as previously described above in Scheme 1A.

[0370] According to a fourteenth method, compounds of formula (II) can be prepared from compounds of formula (XV), formula (XVI) and formula (XIV), as illustrated by Scheme 4.

[0371]

[0372] Compounds of formula (XVI) can be prepared from compounds of formula (XV) by halogenation in process step (x) using a suitable halogenating agent. Typical conditions include reacting a compound of formula (XV) with a suitable halogenating agent (e.g., POCl or CCl or POBr) in the presence of PPh, optionally in the presence of an organic base (e.g., DIPEA or N,N-diethylaniline), optionally in a suitable solvent (e.g., DCE or MeCN) at elevated temperature (e.g., 70° C. to 100° C.).

[0373] Compounds of formula (II) can be prepared from compounds of formula (XVI) and formula (XIV) by Suzuki-type cross-coupling reaction as previously described in Scheme 1A above, step (c).

[0374] According to a fifteenth method, compounds of formula (VIII) can be prepared from compounds of formula (II), formula (XIV) and formula (XVII), as illustrated by Scheme 5.

[0375]

[0376] Compounds of formula (VIII) can be prepared from compounds of formula (II) by a Buchwald-type cross-coupling reaction as previously described in Scheme 2A above, step (v).

[0377] Compounds of formula (VIII) can be prepared from compounds of formula (XVII) and formula (XIV) by a Suzuki-type cross-coupling reaction as previously described in Scheme 1A above, step (c).

[0378] According to a sixteenth method, compounds of formula (XI) can be prepared from compounds of formula (XVIII) and formula (XIX), as illustrated by Scheme 6.

[0379]

[0380] Compounds of formula (XIX) can be prepared from compounds of formula (XVIII) by halogenation as described previously in Scheme 4, step (x).

[0381] Compounds of formula (XI) can be prepared from compounds of formula (XIX) and formula (XIV) according to step (c) of the process as previously described in Scheme 1A.

[0382] According to the eighteenth method, compounds of formula (XII) can be prepared from compounds of formula (XX) and formula (XIV), as illustrated by Scheme 7.

[0383]

[0384] Compounds of formula (XII) can be prepared from compounds of formula (XX) and formula (XIV) according to step (c) of the process as previously described in Scheme 1A.

[0385] According to the nineteenth method, compounds of formula (X) can be prepared from compounds of formula (XIV), formula (XXI) and formula (XXII), as illustrated by Scheme 8.

[0386]

[0387] Compounds of formula (XXII) can be prepared from compounds of formula (XXI) and formula (XIV) by Suzuki cross-coupling reaction as previously described in Scheme 1A, step (c).

[0388] Compounds of formula (X) can be prepared from compounds of formula (XXII) by reduction of the nitro group in process step (y). Typical conditions include reacting compounds of formula (XXII) with iron in the presence of a weak acid in a suitable alcoholic solvent (e.g. aqueous EtOH) at elevated temperature (e.g. 80°C).

[0389] According to the twentieth method, compounds of formula (XIII) can be prepared from compounds of formula (XVII) and formula (XXIII), as illustrated by Scheme 9.

[0390]

[0391] The compound of formula (XIII) can be prepared from the compound of formula (XVII) and R 1 OH was prepared according to the method described previously in Scheme 1C, step (1) Mitsunobu reaction.

[0392] Alternatively, compounds of formula (XIII) can be prepared from compounds of formula (XXIII) by halogenation as described previously in Scheme 4, step (x).

[0393] Compounds of formula (XIV), formula (XV), formula (XVII), formula (XVIII), formula (XX), formula (XXI) and formula (XXIII) are commercially available or can be prepared by methods analogous to methods known in the literature or as described in the experimental section below.

[0394] Compounds of Formula (I) (I), (II), (VIII), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), and (XXII) may 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 such transformations include, but are not limited to, reductive amination of an N atom, alkylation or acetylation of a heteroatom (e.g., N or O), Chan-Lam coupling of NH-containing compounds, or reduction of esters to alcohols.

[0395] Those skilled in the art will appreciate that it may be necessary to use a suitable protecting group strategy to prepare compounds of formula (I). Typical protecting groups may include carbamates and preferably Boc for protecting amines, TBS or benzyl for protecting primary alcohols, benzyl, methyl or TBDMS for protecting phenolic OH, THP or groups for protecting pyrazole N atoms.

[0396] It will further be appreciated that it may be necessary or desirable to perform the transformations in an order different from that depicted in the schemes, or to modify one or more transformations, in order to provide the desired compounds of the present invention.

[0397] The following examples are intended to be illustrative and are not intended to limit the scope of the present disclosure in any way.

[0398] example

[0399] Preparation of exemplary compounds

[0400] definition

[0401] ℃ degrees Celsius

[0402] CC silica gel column chromatography

[0403] CAN, MeCN, acetonitrile

[0404] AcOH acetic acid

[0405] DCM dichloromethane

[0406] DIEA Diisopropylethylamine

[0407] DMF dimethylformamide

[0408] DMF-DMA N,N-dimethylformamide dimethyl acetal

[0409] DMSO dimethyl sulfoxide

[0410] EA Ethyl acetate

[0411] EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide

[0412] EtOAc

[0413] H, h, hr hours

[0414] HOBt 1-Hydroxybenzotriazole

[0415] HPLC high-performance liquid chromatography

[0416] IC 50 50% inhibitory concentration

[0417] i-PrOH isopropyl alcohol

[0418] IPA Isopropyl alcohol

[0419] min

[0420] MTBE methyl tert-butyl ether

[0421] MeOH methanol

[0422] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0423] Pd(dppf)Cl2.DCM [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane

[0424] PE petroleum ether

[0425] rt room temperature

[0426] TEA triethylamine

[0427] TFA trifluoroacetic acid

[0428] THF Tetrahydrofuran

[0429] RT retention time

[0430] Preparative HPLC Preparative high performance liquid chromatography

[0431] Preparative TLC Preparative thin layer chromatography

[0432] TLC thin layer chromatography

[0433] MsCl methanesulfonyl chloride

[0434] Bpin Boric acid pinacol ester

[0435] BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)

[0436] Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium

[0437] XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0438] The method for preparing the compounds of the present invention can be implemented in a suitable solvent that can be easily selected by a person skilled in the art of organic synthesis. At the temperature when the reaction is carried out (e.g., a temperature in the range of the solvent freezing point to the solvent boiling point), the suitable solvent may not react with the starting material (reactant), intermediate or product. A given reaction can be implemented in a solvent or a mixture of more than one solvent. Depending on the specific reaction steps, a solvent suitable for the specific reaction steps can be selected by those skilled in the art.

[0439] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. Those skilled in the art can easily determine the need for protection and deprotection and the selection of appropriate protecting groups. The chemistry of protecting groups can be found in, for example, Wuts and Greene, Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons: New Jersey, (2014), which is incorporated herein by reference in its entirety.

[0440] The reaction can be monitored by any suitable method known in the art. For example, the reaction can be monitored by spectroscopy (e.g., nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry (MS)) or by chromatographic methods (e.g., high performance liquid chromatography (HPLC) or thin layer chromatography (TLC)) to monitor product formation. Analytical instruments and methods for compound characterization:

[0441] LC-MS Liquid chromatography-mass spectrometry (LC-MS) data (analyzing sample purity and identity) were obtained using:

[0442] An Agilent 1260 LC system using an Agilent 6120 mass spectrometer with ES-API ionization, equipped with an Agilent Poroshel 120 (EC-C18, 2.7 μm particle size, 3.0 x 50 mm size) reverse phase column, was operated at 22.4 degrees Celsius. The mobile phase consisted of a mixture of water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid. A constant gradient from 95% aqueous / 5% organic to 5% aqueous / 95% organic mobile phase over a 4-minute period was used. The flow rate was constant at 1 mL / min; or

[0443] A Shimadzu LCMS system was used, using a Shimadzu LCMS mass spectrometer utilizing ESI ionization, equipped with an Agilent (Poroshel HPH-C18 2.7 μm particle size, 3.0 x 50 mm size) reverse phase column at 22.4 degrees Celsius. The mobile phase consisted of a mixture of water and acetonitrile containing 5 mM NH4HCO3 (or 0.05% TFA) as the solvent. A constant gradient from 90% aqueous / 10% organic to 5% aqueous / 95% organic mobile phase was used over a 2-minute period. The flow rate was constant at 1.5 mL / min.

[0444] Preparative LC-MS Preparative HPLC was performed on a Shimadzu Discovery equipped with a Luna 5u C18(2)100A, AXIA packed, 250x21.2mm reverse phase column. The analysis was performed at 22.4°C on a preparative system. The mobile phase consisted of a mixture of water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid. A constant gradient from 95% aqueous / 5% organic to 5% aqueous / 95% organic mobile phase over 25 minutes was used. The flow rate was maintained at 20 mL / min.

[0445] Manufacturer: Yantai Xinnuo Chemicals Co., Particle size: 10-40 μm, pH = 6.2-7, Thickness: 1 mm, Adhesive: CMC, Specifications: 200*200 mm

[0446] Silica gel chromatography Silica gel chromatography was performed at Teledyne Isco Rf device or Isolera Four device or Implemented on the Isolera Prime device.

[0447] Proton NMR : 1 H NMR spectra were obtained using the following:

[0448] Varian 400 MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.5 seconds, delay 1 second; 16 to 64 scans). For characterization, all protons are reported as parts per million (ppm) relative to residual DMSO (2.50 ppm) in DMSO-d6 solvent; or

[0449] Avance 400 MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.99 sec, delay 1 sec; 4 to 64 scans) or Avance 300 MHz Unity Inova 300 MHz NMR instrument (acquisition time = 5.45 sec, delay 1 sec; 4 to 64 scans).

[0450] Preparative LC-MS Preparative HPLC was performed on a Waters preparative system equipped with an XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; the mobile phase consisted of a solvent mixture of an aqueous solvent (water (10 mmol / L NH4HCO3 + 0.05% NH3.H2O)) and an organic solvent (acetonitrile). A constant gradient from 95% aqueous / 5% organic to 5% aqueous / 95% organic mobile phase was used. The flow rate was constant and typically 60 mL / min.

[0451] Reactions carried out in the microwave were performed in a Biotage Initiator microwave apparatus.

[0452] One of ordinary skill in the art will recognize that gradients, column lengths, and flow rates can be modified and that some conditions may be more suitable for compound characterization than others, depending on the chemical being analyzed.

[0453] Preparation of intermediates

[0454] Preparation 1: 1-Ethyl-3-phenyl-1H-pyrazole

[0455]

[0456] Cs2CO3 (441 g, 1.35 mol) is added to a solution of 3-phenyl-1H-pyrazole (65 g, 451 mmol) in DMF (250 mL), and the mixture is warmed to 45-60 ° C. Iodoethane (141 g, 902 mL) is added dropwise and the reactants are stirred at 45-60 ° C overnight. The cooled mixture is diluted with water (2.5 L) and extracted with EtOAc (700 mL x 3). The combined organic extracts are washed with brine (1 L x 3), dried over Na2SO4, filtered, and the filtrate is evaporated under reduced pressure to give the title compound (80.8 g). LCMS m / z=173.1[M+H] + .

[0457] Preparation 2: 1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazole

[0458]

[0459] At 45 ° C, 1,1-difluoro-2-iodoethane (223g, 1.17mol) was added dropwise to a solution of 3-phenyl-1H-pyrazole (84.0g, 582mmol) and Cs2CO3 (569g, 1.75mol) in DMF (900mL), and the mixture was stirred at 45 ° C for 12h. The reaction mixture was diluted with H2O (1.50L) ​​and extracted with EtOAc (1.50L x 3). The combined organic layer was washed with brine (2.00L x 2), dried over (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE: EtOAc = 20: 1 to 3: 1) to obtain the title compound (137g, crude) as a light yellow oil. LCMS m / z = 209.2 [M + H] + .

[0460] Preparation 3: 1-ethyl-3-(4-fluorophenyl)-1H-pyrazole

[0461]

[0462] NaH (295 mg, 12.3 mmol) was added to 3-(4-fluorophenyl)-1H-pyrazole (2 g, 12.3 mmol) in DMF (20 mL) and the solution was stirred for 30 min. Iodoethane (1.91 g, 12.3 mmol) was added and the resulting solution was stirred at room temperature for 1 h. The reaction was quenched with water (5 mL) and the resulting solution was extracted with DCM (3x10 mL). The combined organic extracts were evaporated under reduced pressure to give the title compound (1.5 g, 64.3% yield) as a light yellow solid. LCMS m / z=191[M+H] + .

[0463] Preparation 4: 1-ethyl-3-(2-fluorophenyl)-1H-pyrazole

[0464]

[0465] At 0 ° C, NaH (590 mg, 24.6 mmol) was slowly added to 3- (2-fluorophenyl) -1H-pyrazole (2 g, 12.3 mmol) in DMF (10 mL), and the mixture was stirred for 30 min, then iodoethane (3.83 g, 24.6 mmol) was added to the mixture at 0 ° C and the mixture was stirred at 60 ° C for 16 h. The solution was diluted with water (500 mL) and extracted with EtOAc (3x200 mL). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography (10: 1PE / EtOAc) to give the title compound (2 g, 85%) as a yellow oil. LCMS: m / z = 191 [M + H] + .

[0466] Preparation 5: 1-(Oxetan-3-yl)-3-phenyl-1H-pyrazole

[0467]

[0468] 3-iodooxetane (794 μ L, 9.02 mmol) is 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 reactant is stirred at room temperature for 24 h. NaOtBu (242 mg) and 3-iodooxetane (0.26 mL) are added and the reactant is stirred for another 24 h. The reactant is diluted with water, each layer is separated and the aqueous phase is extracted with EtOAc (2 x 10 mL). The combined organic layer is washed with water (3 x 5 mL), dried over anhydrous Na2SO4, filtered and the solvent is removed under reduced pressure. The crude product is purified by ISCO CombiFlash (0-30% EtOAc in hexane) to obtain the title compound (870 mg, 62.6% yield) as a light yellow oil. 1H NMR (500MHz, CDCl3) δ7.84(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).

[0469] Preparation 6: 3-(2-Fluorophenyl)-1-methyl-1H-pyrazole

[0470]

[0471] 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) under N2, followed by 1-bromo-2-fluorobenzene (1.183 mL, 10.81 mmol) and stirred at 90°C for 1 h. The reaction mixture was diluted with water and EtOAc, the organic layer separated, washed with saturated brine, dried over anhydrous NaSO, and concentrated in vacuo. The crude product was purified by ISCO Combiflash (0-60% EtOAc in hexanes) to give the title compound (637 mg, 50% yield) as an orange oil.

[0472] Preparation 7: 3-(2,6-difluorophenyl)-1-methyl-1H-pyrazole

[0473]

[0474] The title compound (1.05 g, 56% yield) was obtained as a yellow oil following the procedure described in Preparation 6 from 2-bromo-1,3-difluorobenzene and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

[0475] Preparation 8: 3-(4-Fluorophenyl)-1-methyl-1H-pyrazole

[0476]

[0477] A mixture of Pd(dppf)Cl2 (465 mg, 0.571 mmol), K2CO3 (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 H2O (6 mL) and dioxane (24 mL) was stirred at 80 ° C under N2 for 2 h. The reaction mixture was diluted with DCM (100 mL) and washed with H2O (2 x 50 mL), dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (20:1 DCM / MeOH) to give the title compound (800 mg, 80%) as an off-white solid. LCMS: m / z=177 [M+H] + .

[0478] Preparation 9: 3-(2,4-difluorophenyl)-1-methyl-1H-pyrazole

[0479]

[0480] The title compound (990 mg) was obtained as a yellow oil from 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1-bromo-2,4-difluorobenzene following the procedure described in Preparation 8. LCMS m / z = 195 [M+H] + .

[0481] Preparation 10: 1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-1H-pyrazole

[0482]

[0483] A mixture of Pd(dppf)Cl2 (1.39 g, 1.91 mmol), K2CO3 (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 / H2O (120 mL / 30 mL) was stirred at 80 ° C under N2 for 2 h. The reaction mixture was extracted with EtOAc (3 x 150 mL) and the combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (2:1 PE / EtOAc) to give the title compound (3.5 g, 70%) as a white solid. LCMS: m / z=259 [M+H] + .

[0484] Preparation 11: 3-(2,6-difluorophenyl)-1-methyl-1H-pyrazole

[0485]

[0486] 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)Cl2 (2.01 g, 3.10 mmol) and K3PO4 (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 (3 g, 50%) as a white solid. LCMS m / z=195[M+H] + .

[0487] Preparation 12: 4-Bromo-1-ethyl-3-phenyl-1H-pyrazole

[0488]

[0489] NBS (87.2g, 490mmol) is added to a solution of 1-ethyl-3-phenyl-1H-pyrazole (preparation 1,80.8g, 466mmol) in MeCN (850mL), and the reactant is stirred at room temperature for 1h. The mixture is concentrated in a vacuum, and residue is dissolved in EtOAc (100mL) and washed with NaHCO the aqueous solution (700mL). The aqueous solution is extracted with EtOAc (200mL x 3), the organic phase merged is washed with salt water (250mL x 5), through Na sO dried, filtered and concentrated in a vacuum. By silica gel column chromatography (PE / EtOAc 20 / 1 to 10 / 1) purification of residue, 115g brown oil is obtained. The oil was further purified by SFC using a DAICEL CHIRALCEL OJ (250 mm*50 mm, 10 μm) column and IPA (0.05% DEA) as the mobile phase to afford 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).

[0490] Preparation 13: 4-Bromo-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole

[0491]

[0492] A mixture of 1-ethyl-3-(4-fluorophenyl)-1H-pyrazole (Preparation 3, 2 g, 10.5 mmol) and NBS (1.86 g, 10.5 mmol) in MeCN (5.00 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography using DCM / MeOH (20 / 1) to give the title compound (1.5 g, 53%) as a light yellow solid. LCMS m / z = 269 [M+H] + .

[0493] Preparation 14: 4-Bromo-1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazole

[0494]

[0495] 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 2 , 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] + .

[0496] Preparation 15: 4-Bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazole

[0497]

[0498] At room temperature, NBS (968 mg, 5.44 mmol) was added to 3-(4-fluorophenyl)-1-methyl-1H-pyrazole (preparation 8,800 mg, 4.54 mmol) in DMF (15 mL), and the resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (100 mL) and washed with brine (2 x 50 mL). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography (25:1 DCM / MeOH) to give the title compound (720 mg, 90%) as a yellow solid. LCMS: m / z=255[M+H] + .

[0499] Preparation 16: 5-Bromo-2-methyl-4-phenylthiazole

[0500]

[0501] The title compound (1.3 g, 90%) was prepared as a white solid from 2-methyl-4-phenylthiazole using a method similar to that described for Preparation 15. LCMS: m / z = 254 [M+H] + .

[0502] Preparation 17: 4-Bromo-3-(2-fluorophenyl)-1-methyl-1H-pyrazole

[0503]

[0504] NBS (643 mg, 3.62 mmol) was added portionwise to a solution of 3-(2-fluorophenyl)-1-methyl-1H-pyrazole (preparation 6, 637 mg, 3.62 mmol) in DMF (9 mL) over 10 min, and the reactants were stirred at room temperature for 3 h. The reaction was quenched with water, extracted with EtOAc, and 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 in hexane) to give the title compound (428 mg, 46% yield) as a light brown oil. LCMS m / z=255[M+H] + .

[0505] Preparation 18 to 22

[0506] The compounds in the following table were prepared following a procedure similar to that described in Preparation 17 from the appropriate pyrazole.

[0507]

[0508]

[0509] Preparation 23: 3-(4-bromo-1-methyl-1H-pyrazol-3-yl)phenol

[0510]

[0511] 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 x 100 mL), and the combined organics were dried (Na2SO4) and evaporated to dryness. The residue was purified by silica gel chromatography (33% EtOAc / PE) to give the title compound (2.6 g, 76%) as a white solid. LCMS: m / z = 253 [M+H] + .

[0512] Preparation 24: 4-Bromo-3-(2-fluorophenyl)-1H-pyrazole

[0513]

[0514] 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 h. The resulting solution was concentrated in vacuo. The residue was purified by preparative TLC (30:1 DCM / MeOH) to give the title compound (1.2 g, 93%) as a light yellow liquid. LCMS m / z = 241 [M+H] + .

[0515] Preparation 25: 4-Bromo-3-(3-chlorophenyl)-1H-pyrazole

[0516]

[0517] The title compound (1.36 g, 95%) was obtained as an off-white solid from 3-(3-chlorophenyl)-1H-pyrazole following a procedure similar to that described in Preparation 24. LCMS m / z = 257, 259 [M+H] + .

[0518] Preparation 26: 4-Bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

[0519]

[0520] 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 p-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 (SiO2, 25% EtOAc / PE) to give the title compound (480 mg, 70%) as an off-white solid. LCMS m / z = 307,309 [M + H] + .

[0521] Preparation 27: 4-Bromo-3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

[0522]

[0523] The title compound (750 mg, 47% yield) was obtained as a colorless liquid from 4-bromo-3-(2-fluorophenyl)-1H-pyrazole following a procedure similar to that described for Preparation 26. LCMS m / z = 325 [M+H] + .

[0524] Preparation 28: 4-Bromo-3-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

[0525]

[0526] The title compound (900 mg, 68% yield) was obtained as an off-white solid from 4-bromo-3-(3-chlorophenyl)-1H-pyrazole (Preparation 25) and dihydropyran following a procedure similar to that described in Preparation 26. LCMS m / z = 341, 343 [M+H] + .

[0527] Preparation 29: 4-Bromo-3-(2,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

[0528]

[0529] The title compound (570 mg, 67% yield) was obtained as a colorless liquid from 4-bromo-3-(2,5-difluorophenyl)-1H-pyrazole (Preparation 21) using a procedure similar to that described in Preparation 26. LCMS m / z = 343, 345 [M+H] + .

[0530] Preparation 30: 4-Bromo-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole

[0531]

[0532] 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 gel 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).

[0533] Preparation 31: 4-Bromo-3-(3-((tert-butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-pyrazole

[0534]

[0535] At 0 ° C, 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), and the reaction mixture was stirred at room temperature for 2 h. The resulting solution was extracted with EtOAc (3 x 100 mL), and the combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (50% DCM / PE) to give the title compound (3 g, 80%) as a white solid. LCMS: m / z=367 [M+H] + .

[0536] Preparation 32: 4-Bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazole

[0537]

[0538] 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 h. 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 (3.2 g, 85%) as a yellow liquid. LCMS: m / z = 383 [M + H] + .

[0539] Preparation 33: 1-ethyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole

[0540]

[0541] A solution of 4-bromo-1-ethyl-3-phenyl-1H-pyrazole (preparation 12,40g, 159mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (59.3g, 319mmol) in THF (400mL) was cooled to -78°C, and n-BuLi (127mL, 2.5M) was added dropwise. The reactant was stirred at -60°C for 1h, then warmed to room temperature and stirred for another 30min. At 0°C, the mixture was poured into a saturated NH4Cl (water) solution (500mL) and the solution was extracted with EtOAc (500mL x 3). The combined organic extracts were washed with brine (500mL), 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] + .

[0542] Preparation 34: 3-(2,6-difluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane alkyl-2-yl)-1H-pyrazole

[0543]

[0544] The title compound (364 mg, 49%) was obtained as a white solid from 4-bromo-3-(2,6-difluorophenyl)-1-methyl-1H-pyrazole (Preparation 19) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane following a procedure similar to that described in Preparation 33. 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).

[0545] Preparation 35: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-3-phenyl-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0546]

[0547] 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 (500 mg, 13%) as a yellow solid. LCMS: m / z = 429 [M + H] + .

[0548] Preparation 36: 2-Methyl-4-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene azole

[0549]

[0550] At -78 ° C, 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), and the resulting mixture was stirred under N2 for 1 h. At -78 ° C, 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (878 mg, 4.72 mmol) was added to this, and the reaction mixture was warmed to room temperature and stirred at 25 ° C for 2 h. The resulting solution was extracted with EtOAc (3 x 100 mL), and the combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography (25:1 DCM / MeOH) to give the title compound (400 mg, 28%) as an off-white solid. LCMS: m / z=254[M+H] + .

[0551] Preparation 37: 3-(2-Fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-aminobenzoyl)-1H-pyrazole

[0552]

[0553] 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)2 (469 mg, 1.846 mmol) and PdCl2(dppf)DCM (68.5 mg, 0.084 mmol) in dioxane (1.86 mL) was purged with N2 and stirred at 100°C for 3 h. The mixture was washed with EtOAc. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column (0-30% EtOAc in hexanes) to give the title compound as a white sticky solid (220 mg, 43% yield). 1H NMR (500 MHz, CDCl 3 ) 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).

[0554] Preparation 38: 1-(Oxetan-3-yl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) Pentan-2-yl)-1H-pyrazole

[0555]

[0556] The title compound (281 mg, 40% yield) was obtained as a white solid from 4-bromo-1-(oxetan-3-yl)-3-phenyl-1H-pyrazole (Preparation 22) following the procedure described in Preparation 37. 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).

[0557] Preparation 39: 3-(3-((tert-Butyldimethylsilyl)oxy)phenyl)-1-methyl-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0558]

[0559] 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. under N2 for 2 h. The reaction mixture was extracted with EtOAc (3×100 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 (500 mg, 17%) as a white solid. LCMS: m / z=415 [M+H] + .

[0560] Preparation 40: 1-ethyl-3-(2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-aminobenzoyl)-1H-pyrazole

[0561]

[0562] Pd (dppf) Cl2 (544 mg, 0.743 mmol) and KOAc (1.45 g, 14.8 mmol) were added to a 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) in DMSO, and the mixture was stirred at 80 ° C overnight. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3x200 mL). The combined extracts were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography (10: 1PE / EtOAc) to give the title compound (2.1 g, 89%) as an oil. LCMS: m / z = 317 [M + H] + .

[0563] Preparation 41: 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) alkyl-2-yl)-1H-pyrazole

[0564]

[0565] A mixture of 4-bromo-1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazole (preparation 14,160g, 557mmol), (BPin)2(283g, 1.11mol), Pd(dppf)Cl2.DCM(45.5g, 55.7mmol) and KOAc(164g, 1.67mol) in DMSO(1.80L) was degassed and purged with N2(x 3), and the mixture was stirred at 90°C under N2 for 4h. The reaction mixture was filtered, then diluted with HO(3.60L) and extracted with EtOAc(2.0L x 3). The combined organic layer was washed with brine (3.0L x 2), dried over (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 further purified by preparative HPLC (column: Phenomenex luna c18 250 mm*100 mm*10 um; mobile phase: [water (0.225% FA)-MeCN]; B%: 50%-70%, 25 min) to give the title compound as a light yellow solid (60.0 g, 31.4% yield). LCMS m / z = 335.2 [M+H] + .

[0566] Preparation 42: 3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) Heterocyclopentan-2-yl)-1H-pyrazole

[0567]

[0568] 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)2 (726 mg, 2.86 mmol), K3PO4 (607 mg, 2.86 mmol) and Pd(dppf)Cl2.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 (SiO2, 10% MeOH / DCM) to give the title compound (400 mg, 79%) as a light yellow solid. LCMS m / z=355[M+H] + .

[0569] Preparation 43: 3-(4-Fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-aminobenzoyl)-1H-pyrazole

[0570]

[0571] 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 H2O (4 mL) and DMSO (16 mL) was stirred at 100 ° C under N2 for 2 h. The mixture was diluted with EtOAc (150 mL), washed with brine (2x75 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 (600 mg, 83%) as a light yellow solid. LCMS: m / z=303[M+H] + .

[0572] Preparation 44: 1-ethyl-3-(4-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-aminobenzoyl)-1H-pyrazole

[0573]

[0574] The title compound (1 g, 56.8% yield) was obtained as an off-white solid from 4-bromo-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole (Preparation 13) following the procedure described in Preparation 43. LCMS m / z = 317 [M+H] + .

[0575] Preparation 45: 3-(2,4-difluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) alkyl-2-yl)-1H-pyrazole

[0576]

[0577] The title compound (900 mg) was obtained as an off-white solid from 3-(2,4-difluorophenyl)-1-methyl-1H-pyrazole (Preparation 18) following a procedure similar to that described in Preparation 43. LCMS m / z = 321 [M+H] + .

[0578] Preparation 46: 3-(2-Fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dihydro- Oxaborol-2-yl)-1H-pyrazole

[0579]

[0580] The title compound (650 mg, 76% yield) was obtained as a colorless liquid from 4-bromo-3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 27) following a procedure similar to that described in Preparation 43. LCMS m / z = 373 [M+H] + .

[0581] Preparation 47: 3-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dihydro- Oxaborol-2-yl)-1H-pyrazole

[0582]

[0583] The title compound (380 mg, 84%) was obtained as a yellow solid from 4-bromo-3-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 28) following a procedure similar to that described in Preparation 43. LCMS m / z = 389 [M+H] + .

[0584] 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

[0585]

[0586] A mixture of 4-bromo-3-(2,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 29, 300 mg, 0.874 mmol), B(Pin)2 (441 mg 1.74 mmol), Pd(PPh3)4 (20.1 mg, 0.0174 mmol), and NaOAc (142 mg, 1.74 mmol) in DMSO (3 mL) was stirred at 100°C for 16 h. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative TLC (4:1 PE / EtOAc) to give the title compound (130 mg, 38%) as a light yellow oil. LCMS m / z = 391 [M+H] + .

[0587] Preparation 49: 1,4-dioxepan-6-ol

[0588]

[0589] To a mixture of 1,4-dioxepane-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 min. The resulting solution was diluted with water (30 mL), extracted with EtOAc (2x20 mL) and the organic layers were combined. The resulting organic solution was washed with salt water (20 mL), dried over anhydrous NaSO and concentrated under vacuum to give the title compound (150 mg, 85% yield) as a white solid.

[0590] Preparation 50: 1-(5-methylthiazol-4-yl)ethan-1-ol

[0591]

[0592] Methylmagnesium bromide (3M in Et2O, 2mL) was added to 5-methyl-1,3-thiazole-4-carbaldehyde (250mg, 1.96mmol) in THF (5mL) at 0°C, and the reaction mixture was stirred at room temperature for 2h. The reaction was quenched by adding 1M HCl (5mL) and the mixture was extracted with EtOAc (3x50mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give the title compound (250mg, 89% yield) as a clear liquid. LCMS: m / z=144[M+H] + .

[0593] Preparation 51: 1-(5-methyl-1,3,4-thiadiazol-2-yl)ethan-1-ol

[0594]

[0595] The title compound was prepared from 5-methyl-1,3,4-thiadiazole-2-carbaldehyde following the procedure described in Preparation 50. LCMS m / z = 145 [M+H] + .

[0596] Preparation 52: 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4] Oxazin-3(4H)-one

[0597]

[0598] A mixture of 8-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-one (300 mg, 1.31 mmol), (BPin)2 (497 mg, 1.96 mmol), Pd(dppf)Cl2 (96.0 mg, 1.96 mmol) and KOAc (192 mg, 1.96 mmol) in DMSO (15 mL) was stirred at 80 ° C under N2 for 3 h. The solution was diluted with H2O (500 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative TLC using PE:EtOAc=2:1 to give the title compound (120 mg) as a brown solid. LCMS: m / z=276[M+H] + .

[0599] Preparation 53: (S)-2,4-Dimethylpiperazine-1-carbonyl chloride

[0600]

[0601] To a solution of triphosgene (59 mg, 0.20 mmol) in DCM (1 mL) was added pyridine (0.142 mL, 1.75 mmol) at 0°C under N2, followed by (S)-1,3-dimethylpiperazine (0.067 mL, 0.5 mmol). The reaction mixture was slowly warmed to room temperature and stirred overnight. The solvent was removed under reduced pressure to give the title compound.

[0602] Preparation 54 to 58

[0603] The compounds in the table below were obtained from the appropriate amines and phosgene following the procedures described above in the preparations.

[0604]

[0605]

[0606] Preparation 59: (S)-4-Ethyl-2-methylpiperazine-1-carbonyl chloride

[0607]

[0608] At 0 DEG C, triphosgene (115mg, 0.389mmol) is added in batches to pyridine (184mg, 2.33mmol) and (3S)-1-ethyl-3-methylpiperazine (100mg, 0.779mmol) in DCM (10mL), and the reactant is stirred at room temperature for 2h. The mixture is diluted with DCM (50mL) and washed with saline (20mL x2), over NaSOThe organic layer is dried and concentrated under vacuum. PE:EtOAc=2:1 is used to purify residue by preparative TLC to obtain title compound (100mg) as a white solid.

[0609] Preparation 60: Tetrahydro-1H-pyrrolizine-7a(5H)-carboxamide

[0610]

[0611] Methyl hexahydro-1H-pyrrolazine-7a-carboxylate (200 mg, 1.18 mmol) was added to methanolic ammonia, and the mixture was stirred at 80°C for 16 h. 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 (150 mg, 82%) as a white solid. LCMS: m / z = 155 [M+H] + .

[0612] Preparation 61: Ethyl 1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-carboxylate

[0613]

[0614] 1H-pyrazole-4-carboxylic acid ethyl ester (300mg, 2.14mmol), (2-bromoethyl) dimethylamine (976mg, 6.42mmol) and Cs2CO3 (2.09g, 6.42mmol) were added to DMF, and the reactants were stirred at 60°C for 5h. The solution was diluted with water (500mL) and then extracted with EtOAc (3x200mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column using DCM:MeOH=10:1 to give the title compound (200mg) as a yellow oil. LCMS m / z=212[M+H] + .

[0615] Preparation 62: 1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-carboxamide

[0616]

[0617] 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 h. 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] + .

[0618] Preparation 63: tert-Butyl (3-carbamoylbicyclo[1.1.1]pentan-1-yl)carbamate

[0619]

[0620] A mixture of ethyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (2 g, 8.28 mmol) in NH OH was stirred at 60° C. for 16 h. The solution was evaporated to dryness to give tert-butyl (3-carbamoylbicyclo[1.1.1]pentan-1-yl)carbamate (1.5 g) as a white solid, which was used without further purification.

[0621] Preparation 64: 3-Oxabicyclo[3.1.0]hexane-1-carboxamide

[0622]

[0623] To a solution of 3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acid (200 mg, 1.56 mmol) in DCM (10 mL) was added EDCI (450 mg, 2.34 mmol) and HOBt (316 mg, 4.00 mmol), and the solution was stirred at room temperature for 2 h. 35% NH3 aqueous solution (3 mL) was added, and the reactants were stirred at room temperature for 1 h and then concentrated to dryness. The residue was purified by preparative TLC (5% MeOH in DCM) to give the title compound (140 mg, yield = 70%) as a white solid. LCMS: m / z = 128 [M+H] + .

[0624] Preparation 65: tert-Butyl 1-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0625]

[0626] 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% NH3 aqueous solution (3 mL) was added, and the reaction was stirred at 25 ° C for 1 h, then concentrated to dryness. The residue was purified on preparative TLC using DCM:MeOH=15:1 to give the title compound (160 mg, yield: 80.4%) as a white solid. LCMS m / z=171[M+H] + .

[0627] Preparation 66: 2-Methyltetrahydrofuran-2-carboxamide

[0628]

[0629] The title compound (150 mg, 76% yield) was obtained as a white solid from 2-methyltetrahydrofuran-2-carboxylic acid following a procedure similar to that described in Preparation 65. LCMS: m / z = 130 [M+H] + .

[0630] Preparation 67: (R)-2-Methyltetrahydrofuran-2-carboxamide

[0631]

[0632] The title compound (70 mg, 71%) was prepared as a white solid from (R)-2-methyltetrahydrofuran-2-carboxylic acid using a method similar to that described for Preparation 65. LCMS: m / z = 130 [M+H] + .

[0633] Preparation 68: 1-(Trifluoromethyl)cyclopropane-1-carboxamide

[0634]

[0635] 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 batches. The solution was stirred at room temperature for 2 h, and then 35% NH3 aqueous solution (5 mL) was added. The reactants were stirred at room temperature for 1 h and then concentrated to dryness. The residue was purified on a silica gel column using 5% MeOH in DCM to give the title compound as a white solid (9.1 g, yield: 91%). LCMS: m / z=154[M+H] + .

[0636] Preparation 69 to 75

[0637] The compounds in the following table were prepared following similar procedures as described in Preparation 68 from the appropriate carboxylic acids.

[0638]

[0639]

[0640] Preparation 76: 1-(Trifluoromethyl)-1H-pyrazole-4-carboxamide

[0641]

[0642] By 1- (trifluoromethyl) pyrazole -4- carboxylic acid (200mg, 1.11mmol), HOBT (225mg, 1.67mmol), EDCI (319mg, 1.67mmol) and NH4OH (77.8mg, 2.22mmol) in DCM (5mL) is stirred at room temperature for 3h. The reaction is quenched by adding water and the resulting solution is extracted with DCM (3x10 mL). The combined organic matter is evaporated to dryness in a vacuum and passed through column chromatography (SiO2, 20: 1DCM / MeOH) purification of residue to obtain the title compound (150mg, 75%) as an off-white solid.

[0643] Preparation 77: 1-Isopropyl-3-methyl-1H-pyrazole-4-carboxamide

[0644]

[0645] The title compound (90 mg) was obtained as a white solid from 1-isopropyl-3-methylpyrazole-4-carboxylic acid following the procedure described in Preparation 76. LCMS: m / z = 168 [M+H] + .

[0646] Preparation 78: 2-(Trifluoromethyl)pyrrolidine-2-carboxamide

[0647]

[0648] 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 h. 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 (140 mg, 42%) as a colorless oil. LCMS: m / z=183[M+H]+ .

[0649] Preparations 79 and 80: 1-(Bromodifluoromethyl)-1H-pyrazole-3-carboxylic acid methyl ester and 1-(Bromodifluoromethyl)-1H-pyrazole- 5-Methyl formate

[0650]

[0651] At 0 ° C, NaH (1.42 g, 59.2 mmol) was added to a mixture of 1H-pyrazole-3-formic acid methyl ester (3 g, 23.7 mmol) in DMF (45 mL), and the reaction mixture was stirred at 0 ° C for 15 min. Dibromodifluoromethane (14.9 g, 71.1 mmol) was added and the reactant was stirred at 25 ° C for 16 h. The reaction mixture was added to ice water and extracted with EtOAc. The combined organic matter was evaporated to dryness in a vacuum and the residue was purified by column chromatography (14% EtOAc / PE) to obtain the title compound.

[0652] Peak 1, Preparation 79; 1-(bromodifluoromethyl)-1H-pyrazole-3-carboxylic acid methyl ester (colorless oil, 3 g, 50%). LCMS: m / z = 255 [M+H] + ; 1 H NMR (300MHz, DMSO-d6) δ: 8.61 (dt, 1H), 7.06 (d, 1H), 3.87 (s, 4H).

[0653] Peak 2, Preparation 80; 1-(bromodifluoromethyl)-1H-pyrazole-5-carboxylic acid methyl ester (colorless oil, 400 mg, 7%). LCMS: m / z = 255 [M+H] + ; 1 H NMR (300MHz, DMSO-d6) δ8.02(d,1H),7.26(dt,1H),3.89(s,3H).

[0654] Preparation 81: methyl 1-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0655]

[0656] At -78 ° C under N2 atmosphere, to a mixture of 1- (bromodifluoromethyl) -1H- pyrazole -5- carboxylic acid methyl ester (preparation 80,400mg, 1.56mmol) in DCM (20mL) was added AgBF4 (912mg, 4.68mmol), and the reactant was stirred at room temperature overnight. The resulting solution was diluted with water (40mL) and extracted with DCM (2x 50mL). The combined organic matter was washed with brine (30mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography (10% EtOAc / PE) to obtain the title compound (300mg, 99%) as a yellow oil. LCMS: m / z = 195 [M + H] + .

[0657] Preparation 82: 1-(Trifluoromethyl)-1H-pyrazole-5-carboxylic acid

[0658]

[0659] To a solution of methyl 1-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Preparation 81, 300 mg, 1.54 mmol) in THF / H 2 O 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 (150 mg, 54%) as a white solid, which was used without further purification.

[0660] Preparation 83: 1-(Bromodifluoromethyl)-3-methyl-1H-pyrazole-4-carboxylic acid methyl ester and 1-(Bromodifluoromethyl)-5-methyl Methyl 1H-pyrazole-4-carboxylate

[0661]

[0662] NaH (567 mg, 14.2 mmol) was added to methyl 3-methyl-1H-pyrazole-4-carboxylate (2 g, 14.2 mmol) in DMF (10 mL) at 0°C and then stirred at 0°C for 30 min. CF2Br2 (4.43 g, 21.3 mmol) was then added and the resulting mixture was stirred at room temperature for 16 h. The mixture was evaporated to dryness in vacuo and the residue was purified by preparative TLC (2:1 PE / EtOAc) to give a mixture of the title compounds as a light yellow solid (1.9 g, 50%). LCMS: m / z = 269 [M+H] + .

[0663] Preparation 84: 3-Methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid methyl ester and 5-methyl-1-(trifluoromethyl)- 1H-pyrazole-4-carboxylic acid methyl ester

[0664]

[0665] At -78 ° C under N2, AgBF4 (2.88 g, 14.8 mmol) was added to a mixture of 1- (bromodifluoromethyl) -3- methyl -1H- pyrazole -4- carboxylic acid methyl ester and 1- (bromodifluoromethyl) -5- methyl -1H- pyrazole -4- carboxylic acid methyl ester (preparation 83, 2 g, 7.43 mmol) in DCM (30 mL), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (50% EtOAc / PE) to give a mixture of the title compound as an off-white oil (540 mg). LCMS: m / z = 209 [M + H] + .

[0666] Preparation 85: 3-Methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid and 5-methyl-1-(trifluoromethyl)-1H-pyrazole oxazole-4-carboxylic acid

[0667]

[0668] At room temperature, LiOH (343 mg, 14.3 mmol) was added to a mixture of 3-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid methyl ester and 5-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid methyl ester (preparation 84, 500 mg, 2.40 mmol) in THF / H2O (15 mL / 5 mL), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and the pH was 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 (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography (20:1 DCM / MeOH) to give the title compound (430 mg, 92%) as a white solid. LCMS: m / z=195[M+H] + .

[0669] Preparation 86: 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol

[0670]

[0671] 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)Cl2 (1.38 g, 1.89 mmol) and K3PO4 (4.0 g, 18.9 mmol) in dioxane and H2O was stirred at 100 ° C under N2 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 Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound (2.20 g, 69.8%) as a yellow solid. LCMS m / z=333[M+H] + .

[0672] Preparation 87: 6-Bromo-7-fluoroquinazolin-4(3H)-one

[0673]

[0674] 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, the residue was diluted with water and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and the filtrate was evaporated under reduced pressure to give the title compound as an off-white solid (2 g, yield = 96%). LCMS m / z = 243,245 [M+H] + .

[0675] Preparation 88: 6-Bromo-7-ethoxyquinazolin-4(3H)-one

[0676]

[0677] 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 h. 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 as a white solid (2.1 g, yield = 90%). LCMS m / z = 271 [M + H] + .

[0678] Preparation 89: 6-Bromo-4-chloro-7-ethoxyquinazoline

[0679]

[0680] A solution of 6-bromo-7-ethoxyquinazolin-4(3H)-one (Preparation 88, 2.2 g, 8.17 mmol) in POCl3 (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 Na2CO3 (aqueous solution) (30 mL) and the mixture was extracted with DCM. The organic layer was dried over Na2SO4, 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] + .

[0681] Preparation 90: 6-Bromo-7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline

[0682]

[0683] 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), K 3 PO 4 (331 mg, 1.56 mmol), and Pd(PPh 3 ) 4 (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 (225 mg, 53%) as a yellow solid. LCMS: m / z = 409, 411 [M+H] + .

[0684] Preparation 91: 6-Bromo-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline

[0685]

[0686] The title compound (1.0 g, 49%) was obtained as a white solid from 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 following a procedure similar to that described in Preparation 90. LCMS m / z = 397 [M+H] + .

[0687] Preparation 92: 6-Bromo-4-(3-(2,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazoline

[0688]

[0689] The title compound (160 mg, 88%) was prepared as an off-white solid 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) using a method similar to that described for Preparation 90. LCMS: m / z = 397 [M+H] + .

[0690] Preparation 93: 6-Bromo-7-ethoxy-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazoline

[0691]

[0692] The title compound (180 mg, 61% yield) was obtained as an off-white solid from 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) following a procedure similar to that described in Preparation 90. LCMS m / z = 423, 425 [M+H] + .

[0693] Preparation 94: 6-Bromo-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline

[0694]

[0695] The title compound (200 mg, 57% yield) was obtained as a yellow solid from 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) following the procedure described in Preparation 90. LCMS m / z = 409, 411 [M+H] + .

[0696] Preparation 95: 6-Bromo-7-ethoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinone Oxazoline

[0697]

[0698] The title compound (560 mg, 56% yield) was obtained as a yellow solid from 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) following a procedure similar to that described in Preparation 90. LCMS m / z = 479, 481 [M+H] + .

[0699] Preparation 96: 6-Bromo-4-(3-(2,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazoline

[0700]

[0701] Pd(PPh3)4(95.2mg, 0.124mmol) and K3PO4(394mg, 1.86mmol) are added to 3-(2,4-difluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (preparation 45,400mg, 1.24mmol) and 6-bromo-4-chloro-7-methoxyquinazoline (404mg, 1.48mmol) in H2O (4mL) and dioxane (16mL), and the reaction mixture is stirred at 80 DEG C under N2 for 2h.The mixture is diluted with DCM (100mL), washed with brine (50mL x2), dried over Na2SO4, and concentrated under vacuum using the organic layer. The residue is purified by silica gel column using DCM:MeOH=20:1 to obtain the title compound (400mg) as a white solid. LCMS m / z=431[M+H] + .

[0702] Preparation 97: 6-Bromo-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazoline

[0703]

[0704] A mixture of Pd(dppf)Cl2 (465 mg, 0.571 mmol), K3PO4 (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 H2O (6 mL) and dioxane (24 mL) was stirred at 80 ° C under N2 for 2 h. 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 (205 mg, 51%) as an off-white solid. LCMS: m / z=413[M+H] + .

[0705] Preparation 98: 6-Bromo-4-(1-ethyl-3-(2-fluorophenyl)-1H-pyrazol-4-yl)-7-methoxyquinazoline

[0706]

[0707] Pd(dppf)Cl2 (133 mg, 1.82 mmol) and K2CO3 (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 x 20 mL), dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by preparative TLC (30:1 DCM / MeOH) to give the title compound (290 mg, 37%) as a yellow solid. LCMS: m / z = 427 [M+H] + .

[0708] Preparation 99: 6-Bromo-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-ol

[0709]

[0710] 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 h. The mixture was diluted with DCM (100 mL), washed with brine (2 x 50 mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by preparative TLC (25:1 DCM / MeOH) to give the title compound (200 mg, 52%) as a yellow solid. LCMS: m / z = 395 [M+H] + .

[0711] Preparation 100: 6-Bromo-7-(difluoromethoxy)-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazoline

[0712]

[0713] At room temperature, sodium 2-chloro-2,2-difluoroacetate (76.9 mg, 0.505 mmol) was added to a mixture of K2CO3 (69.6 mg, 0.505 mmol), 6-bromo-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-ol (prepared in 99, 200 mg, 0.505 mmol) in DMF (10 mL) and H2O (1 mL), and the resulting mixture was heated to 100 ° C and maintained for 16 h. The mixture was diluted with EtOAc (100 mL) and washed with brine (2 x 50 mL). The combined organics 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 (120 mg, 53%) as a white solid. LCMS: m / z=395[M+H] + .

[0714] Preparation 101: 6-Bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-ol

[0715]

[0716] 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 BBr (10.40 g, 41.51 mmol) was stirred at 80 ° C for 6 h. The mixture was added dropwise to H2O (30 mL) at 0 ° C, the pH was adjusted to pH 8-9 with Na2CO3 and the mixture was extracted with DCM (20 mLx3). The combined organic layers were dried over Na2SO4, 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.

[0717] Preparation 102: 6-Bromo-7-isopropoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline

[0718]

[0719] To a solution of 6-bromo-4-(1-methyl-3-phenyl-1H-pyrazole-4-yl)quinazoline-7-ol (preparation 101,45mg, 0.118mmol) and 2-iodopropane (30.1mg, 0.177mmol) in DMF (3mL) was added KCO (32.63mg, 0.236mmol), and the reactant was stirred at 80°C for 2h. The reaction mixture was diluted with HO (5mL) and extracted with EtOAc (3mLx3). The combined organic layer was washed with brine (5mL x 2), dried over NaSO, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (0 to 100% EtOAc in PE) to give the title compound (27mg, 54%) as a white solid.

[0720] Preparation 103: 7-Isopropoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol

[0721]

[0722] 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 H2O (0.25 mL) was added Pd2(dba)3 (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 under N2 for 2 h. 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.

[0723] Preparation 104: (2-((6-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-yl)oxy)ethyl tert-Butyl)carbamate

[0724]

[0725] 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 Cs2CO3 (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 (3x50 ml). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo and the residue was purified by preparative TLC (10:1 DCM / MeOH) to give the title compound (180 mg, 87%) as a light yellow solid. LCMS: m / z=523[M+H] + .

[0726] Preparation 105: 2-((6-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-yl)oxy)-N,N- Dimethylethan-1-amine

[0727]

[0728] Part 1. TFA was added 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, and the mixture was stirred at room temperature for 4 h. 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.

[0729] 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 1, 150 mg, 0.354 mmol) in DCM, followed by the addition of Na(OAc)3BH (224 mg, 1.06 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched by NH4Cl 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 give the title compound (70 mg, 41%) as a white solid. LCMS: m / z = 454 [M+H] + .

[0730] Preparation 106: 6-Bromo-4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrrolidone oxazol-4-yl)-7-methoxyquinazoline

[0731]

[0732] 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 H2O (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 (240 mg, 52%) as a yellow solid. LCMS: m / z = 541 [M+H] + .

[0733] Preparation 107: 6-Bromo-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)quinazoline

[0734]

[0735] 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 h. 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] + .

[0736] Preparation 108: 6-Bromo-7-methoxy-4-(3-phenyl-1-propyl-1H-pyrazol-4-yl)quinazoline

[0737]

[0738] 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 h. 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 (120 mg, 38%) as a yellow solid. LCMS: m / z=425 [M+H] + .

[0739] Preparation 109: 7-Ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol

[0740]

[0741] 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 Cs2CO3 (598 mg, 1.83 mmol) in H2O (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 (2x50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (15:1 DCM / MeOH) to give the title compound (350 mg, 83%) as a yellow solid. LCMS m / z=347[M+H] + .

[0742] Preparation 110: 7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinazoline- 6-ol

[0743]

[0744] 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)2Cl2 (109 mg, 0.150 mmol), and K3PO4 (1.27 g, 6.0 mmol) in dioxane (9 mL) and H2O (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 (400 mg, 66%) as a light brown syrup. LCMS m / z = 403 [M+H] + .

[0745] Preparation 111: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-ol

[0746]

[0747] 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 / H2O was stirred at 80 ° C for 16 h. The resulting solution was extracted with EtOAc (3x20 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 (2.4 g, 44%) as a yellow solid. LCMSm / z=383[M+H] + .

[0748] Preparation 112: 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-ol

[0749]

[0750] To a mixture of 4-chloro-7-methoxyquinazolin-6-ol (70 mg, 0.332 mmol), K2CO3 (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(PPh3)4 (38.4 mg, 0.033 mmol) and the reaction was stirred at 100°C under N2 for 5 h. The mixture was filtered, eluting with DCM / MeOH and concentrated in vacuo.The residue was purified by Combiflash Isco, 12g gold column, 0-20% MeOH in DCM to give the title compound as a yellow viscous oil (92.4 mg, 63.5% yield).

[0751] Preparation 113: 4-(3-(2,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-ol

[0752]

[0753] The title compound (40.6 mg, 46.4% yield) was obtained as an off-white solid following the procedure described in Preparation 112 from 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).

[0754] Preparation 114: 7-methoxy-4-(1-(oxetan-3-yl)-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol

[0755]

[0756] The title compound (89.6 mg, 36% yield) was obtained as a light yellow solid from 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 following the procedure described in Preparation 112.

[0757] Preparation 115: 7-methoxy-4-(3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)quinazoline-6-yl alcohol

[0758]

[0759] To a mixture of 4-bromo-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (Preparation 30, 250 mg, 0.819 mmol), (BPin)2 (250 mg, 0.983 mmol), KOAc (241 mg, 2.458 mmol) and PdCl2(dppf)-DCM (100 mg, 0.123 mmol) in dioxane (4 mL) was sparged with N2 for 5 min, and the reaction was heated at 90°C overnight. The mixture was cooled to room temperature, 4-chloro-7-methoxyquinazolin-6-ol (86 mg, 0.410 mmol), 2M aqueous K2CO3 (1.229 mL, 2.46 mmol) and additional PdCl2(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 allowed to gravitationally elute with EtOAc. The filtrate was concentrated and dried under vacuum. The residue was purified by silica gel column chromatography (DCM to 20% MeOH in DCM) to give the title compound (142 mg, 39.0%). LCMS m / z=401.1 [M+H] + .

[0760] Preparation 116: 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl trifluoromethanesulfonate ester

[0761]

[0762] At -60 ° C, Tf2O (2.11 g, 7.50 mmol) was added dropwise to 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), and the reaction was stirred for 1 h. The solution was extracted with DCM (2x50 mL), and the combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 1:1 DCM / EtOAc) to give the title compound (1.0 g, 72%) as a yellow solid. LCMS m / z=465[M+H] + .

[0763] Preparation 117: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinoline trifluoromethanesulfonate Oxazolin-6-yl ester

[0764]

[0765] TEA (116 mg, 1.15 mmol) was added to an ice-cooled 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). Tf2O was added dropwise and the reactants were stirred for 1 h. The reaction was neutralized with a NaHCO3 aqueous solution, 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 the title compound (250 mg) as a red solid. LCMS m / z = 515 [M+H] + .

[0766] Preparation 118: 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazole trifluoromethanesulfonate 6-Phenylin-6-yl ester

[0767]

[0768] 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. Tf2O (482 mg, 1.71 mmol) was added and the reaction was stirred at -50 ° C for 1 h. The mixture was concentrated under vacuum, the residue was diluted with water (100 mL), the mixture was extracted with EtOAc (2x100 mL) and the organic layers were combined. The organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The product was purified by chromatography using DCM:MeOH (10: 1) to give the title compound (240 mg, 87.5%) as a yellow solid. LCMS m / z=483[M+H] + .

[0769] Preparation 119: (3R,4R)-3-fluoro-4-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazole tert-Butyl (6-(1,2-pyridin-6-yl)oxy)piperidine-1-carboxylate

[0770]

[0771] At -10 ° C, DIAD (484 mg, 2.40 mmol) was added dropwise to 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 (3R, 4S)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (526 mg, 2.40 mmol) in THF, and the resulting mixture was stirred at room temperature for 8 h. The mixture was diluted with EtOAc (100 mL) and washed with brine (50 mL x 2). The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC, eluting with PE:EtOAc=1:1 to give the title compound (250 mg) as a yellow solid. LCMS m / z=534[M+H] + .

[0772] Preparation 120 to 124

[0773] The compounds in the table below were prepared following similar procedures as described in Preparation 119 from the appropriate quinazolin-6-ol and alcohol.

[0774]

[0775]

[0776] Preparation 125: 4-chloro-7-methoxy-6-((tetrahydrofuran-3-yl)oxy)quinazoline

[0777]

[0778] 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 min. DIAD (382 mg, 1.89 mmol) was added and the reactants were stirred at room temperature for 4 h. 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] + .

[0779] Preparation 126: 4-chloro-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline

[0780]

[0781] The title compound (240 mg, 86% yield) was obtained as a colorless oil from 4-chloro-7-methoxyquinazolin-6-ol and tetrahydro-2H-pyran-4-ol following the procedure described in Preparation 125. LCMS m / z = 295 [M+H] + .

[0782] Preparation 127: trans-rac-4-chloro-6-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-7-methyl Oxyquinazoline

[0783]

[0784] At 0 ° C, 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), and the reaction mixture was stirred at room temperature under N2 for 2 h. The mixture was extracted with EtOAc (3x40 mL), and the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative TLC using DCM:MeOH=25:1 to give the title compound (110 mg, 37%) as a yellow solid. LCMS: m / z=313[M+H] + .

[0785] Preparation 128: 6-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-ol

[0786]

[0787] Pd(dppf)Cl2 (173 mg, 0.237 mmol) and K2CO3 (489 mg, 3.55 mmol) were added to 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 / H2O (4 / 1 V / V). The reaction was stirred at 80 ° C. under N2 overnight. The resulting solution was extracted with EtOAc (3x50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by preparative TLC (25:1 DCM / MeOH) to give the title compound (209 mg, 27%) as a yellow solid. LCMS m / z=333[M+H] + .

[0788] Preparation 129: 4-Chloro-7-ethoxy-6-methoxyquinazoline

[0789]

[0790] At 0 ° C, DIAD (1.15 g, 5.68 mmol) was added dropwise to PPh3 (1.86 g, 7.10 mmol), 4-chloro-6-methoxyquinazolin-7-ol (300 mg, 1.42 mmol) and EtOH (327 mg, 7.10 mmol) in THF (15 mL), and the reaction was stirred at room temperature for 2 h. The resulting solution was extracted with EtOAc (3x50 mL), and the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative TLC using DCM:MeOH=25:1 to give the title compound (200 mg, 59%) as a yellow solid. LCMS m / z=239[M+H] + .

[0791] Preparation 130: 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline

[0792]

[0793] The title compound (500 mg, 56% yield) was obtained as a yellow solid from 4-chloro-6-methoxyquinazolin-7-ol and 2-methoxyethan-1-ol following the procedure described in Preparation 129. LCMS m / z = 269 [M+H] + .

[0794] Preparation 131: 6-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-7-ol

[0795]

[0796] Under N2, 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (565 mg, 1.99 mmol), K2CO3 (458 mg, 3.32 mmol) and Pd(dppf)Cl2 (121 mg, 0.166 mmol) were added to a solution of 4-chloro-6-methoxyquinazolin-7-ol (350 mg, 1.66 mmol) in dioxane / H2O (4 / 1 V / V), and the reactants were 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 x 20 mL), the organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. 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] + .

[0797] Preparation 132: 4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline-6,7-diol

[0798]

[0799] At 0 ° C, to a solution of 6-methoxy-4-(1-methyl-3-phenyl-1H-pyrazole-4-yl)quinazoline-7-ol (preparation 131,140mg, 0.421mmol) in DCE (5mL) was added dropwise BBr (1.06g, 4.21mmol). The mixture was stirred at 25 ° C for 1h, then quenched with H o (10mL) and extracted with DCM (10mL x 2). The aqueous layer was diluted with MeOH (20mL), the mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (150mg, crude) as a yellow solid.

[0800] Preparation 133: 6-(Benzyloxy)-7-bromopyrido[3,2-d]pyrimidin-4-ol

[0801]

[0802] 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 min. 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 min. The reaction was diluted with H2O (8 mL) at 0 ° C, and then 1M HCl was added dropwise until pH = 3. The reaction mixture was filtered and the filter cake was concentrated under reduced pressure to give the title compound as a white solid.

[0803] Preparation 134: 6-(Benzyloxy)-7-methoxypyrido[3,2-d]pyrimidin-4-ol

[0804]

[0805] 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 under N2 for 2 h. The crude product was diluted with H2O (8 mL) at 0 ° C, and then 1M 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 H2O (2 mL) to obtain the title compound as an off-white solid.

[0806] Preparation 135: 6-(Benzyloxy)-4-chloro-7-methoxypyrido[3,2-d]pyrimidine

[0807]

[0808] 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. under N for 2 h. 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.

[0809] Preparation 136: 6-(Benzyloxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3, 2-d]pyrimidine

[0810]

[0811] 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 H O (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. under N for 1 hr. The reaction mixture was concentrated under reduced pressure to obtain 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. 1H-NMR (400 MHz, CDCl3) 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).

[0812] Preparation 137: 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-ol

[0813]

[0814] 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 EtOAc (5.0 mL) was added Pd / C (40.0 mg, 10% purity, 50% in H2O) and the reaction was stirred at 25° C. under H2 (15 psi) 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.

[0815] Preparation 138: (2S)-2,4-dimethylpiperazine-1-carboxylic acid 7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazol-4-yl)quinazolin-6-yl ester

[0816]

[0817] 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 h. The reaction mixture was concentrated to dryness. The residue was purified by silica gel column using 5% MeOH in DCM to give the title compound (100 mg, yield = 74%) as a light yellow solid. LCMS m / z = 543 [M+H] + .

[0818] Preparation 139: (S)-2,4-dimethylpiperazine-1-carboxylic acid 7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)quinazole 6-Phenylin-6-yl ester

[0819]

[0820] To a solution of (2S)-2,4-dimethylpiperazine-1-carboxylic acid 7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinazolin-6-yl ester (Preparation 138, 100 mg, 0.184 mmol) in DCM (5 mL) at 0°C was added TFA (2 mL) and the reaction was stirred at room temperature for 3 h. The mixture was concentrated to dryness, the residue was diluted with DCM and washed with saturated aqueous Na2CO3. The organic layer was separated and dried over Na2SO4, filtered and concentrated to dryness to give the title compound (100 mg, crude) as a light yellow solid. LCMS m / z=459[M+H] + .

[0821] Preparation 140: (2S,5S)-2,5-dimethylpiperazine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-(7-methoxy-4- (1-Methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ester

[0822]

[0823] 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 at 80° C. for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (150 mg, crude) as a yellow solid.

[0824] Preparation 141: (S)-2-Methylpiperazine-1,4-dicarboxylic acid 4-(tert-butyl) ester 1-(7-methoxy-4-(1-methyl-3- phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ester

[0825]

[0826] The title compound (100 mg, crude) was obtained as a yellow solid from 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 following the procedure described in Preparation 140.

[0827] Preparation 142: (2R,3S)-2,3-dimethylpiperazine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-(7-methoxy-4- (1-Methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ester

[0828]

[0829] 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 h 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 chloroformate (500 mg, crude) as a yellow solid, which was used directly in the next step.

[0830] Part 2: To a solution of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl chloroformate (200 mg, 0.507 mmol) and tert-butyl (2R,3S)-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*30 mm*10 um; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 30%-60%, 10 min) to give the title compound (80 mg, 27.6% yield) as a white solid. 1H-NMR(400MHz,CDCl3)δppm 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),4.05-4.0 1(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).

[0831] Preparation 143: (2S,5S)-2,5-dimethylpiperazine-1-carboxylic acid 7-methoxy-4-(1-methyl-3-phenyl-1H-pyridine) oxazol-4-yl)quinazolin-6-yl ester

[0832]

[0833] A mixture of 1-(tert-butyl)-2,5-dimethylpiperazine-1,4-dicarboxylate 4-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ester (Preparation 140, 150 mg, 0.262 mmol) in HCl / EtOAc (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*30 mm*3 um; mobile phase: [water (0.05% NH 3 H 2 O + 10 mM NH 4 HCO 3 )-MeCN]; B%: 20%-45%, 8 min) to give the title compound (66.30 mg, 53.6% yield) as a light yellow solid. 1H-NMR (400MHz, CDCl3) δppm 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=12.4Hz),2.84-2.67(m,2H),1.35(br dd,3H,J=18.0,6.8Hz),1.14-1.13(m,3H).

[0834] Preparation 144: (2S,3R)-2,3-dimethylpiperazine-1-carboxylic acid 7-methoxy-4-(1-methyl-3-phenyl-1H-pyridine) oxazol-4-yl)quinazolin-6-yl ester

[0835]

[0836] The title compound (36.2 mg, 58% yield) was obtained as a yellow solid from 1-(tert-butyl)-(2R,3S)-2,3-dimethylpiperazine-1,4-dicarboxylate 4-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ester (Preparation 142) following a procedure similar to that described in Preparation 143.

[0837] Preparation 145: (S)-2-Methylpiperazine-1-carboxylic acid 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl) Quinazolin-6-yl ester trifluoroacetate

[0838]

[0839] To a mixture of (S)-4-(tert-butyl)2-methylpiperazine-1,4-dicarboxylate 1-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ester (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.

[0840] Preparation 146: Methyl 5-(benzyloxy)-4-bromo-2-nitrobenzoate

[0841]

[0842] At 0 ° C, to a mixture of phenylmethanol (7.76g, 71.8mmol) in THF (200mL) was added NaH (1.72g, 71.8mmol), the solution was stirred at 0 ° C for 15min, then 4-bromo-5-fluoro-2-nitrobenzoic acid methyl ester (10g, 35.9mmol) was added and the reaction mixture was stirred at 25 ° C for 16h. The mixture was added to ice water and extracted with EtOAc. The organic phase was concentrated under vacuum and the residue was purified by column chromatography (50% EtOAc in PE) to give the title compound as a yellow solid (6g, yield: 45.8%). LCMS m / z = 366 [M + H] + .

[0843] Preparation 147: Methyl 2-amino-5-(benzyloxy)-4-bromobenzoate

[0844]

[0845] 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 NaHCO3 and extracted with DCM. The organic phase was dried over Na2SO4, filtered and then concentrated to give the title compound (5 g, 91.4% yield) as a yellow solid. LCMS m / z=336[M+H] + .

[0846] Preparation 148: 2-Amino-5-(benzyloxy)-4-bromobenzoic acid

[0847]

[0848] To a solution of methyl 2-amino-5-(benzyloxy)-4-bromobenzoate (Preparation 147, 5 g, 14.8 mmol) in THF / H2O 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 Na2SO4 and evaporated under reduced pressure to give the title compound (4 g, 84.0%) as a yellow solid. LCMS m / z = 322 [M+H] + .

[0849] Preparation 149: 6-(Benzyloxy)-7-bromoquinazolin-4(3H)-one

[0850]

[0851] To a solution of 2-amino-5-(benzyloxy)-4-bromobenzoic acid (Preparation 148, 4 g, 12.4 mmol) in EtOH (100 mL) was added acetamidine (3.60 g, 62.0 mmol) and the reaction was stirred at 80° C. for 16 h. The solution was concentrated in vacuo, water was added, and the resulting solid was filtered to give the title compound (3.5 g, 85.3%) as a yellow solid. LCMS m / z=322 [M+H] + .

[0852] Preparation 150: 6-(Benzyloxy)-7-bromo-4-chloroquinazoline

[0853]

[0854] 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 phosphorus oxychloride (8.04 g, 52.5 mmol) and the reactants were stirred at 80 ° C for 3 h. The cooled mixture was poured into a sodium bicarbonate solution and extracted with EtOAc. The organic layer was dried (MgSO 4 ), filtered and the solvent was 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] + .

[0855] Preparation 151: 6-(Benzyloxy)-7-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline

[0856]

[0857] By 6- (benzyloxy) -7- bromo -4- chloroquinazoline (preparation 150,699mg, 2mmol), 1- methyl -3- phenyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -1H- pyrazole (625mg, 2.20mmol), Pd (PPh3) 4 (346mg, 0.30mmol) and K3PO4 (805mg, 3.80mmol) in DMSO (20mL) is heated to 80 DEG C and kept for 3h. After cooling to room temperature, the mixture is quenched with 5% NaOH (aqueous solution) (50mL). The mixture is extracted with EtOAc (20mL x 3), the organic layers are combined and concentrated in vacuo. The residue is purified by silica gel column chromatography (DCM / EtOAc = 1: 1 to DCM / MeOH = 15: 1) to obtain the title compound (300mg) as a yellow solid.

[0858] Preparation 152: 7-Bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol

[0859]

[0860] 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 h. After cooling to room temperature, the mixture was evaporated under reduced pressure to give the title compound (190 mg, 83%) as a yellow syrup.

[0861] Preparation 153: (S)-7-Bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-2,4-dimethylpiperazine-1-carboxylic acid Quinazolin-6-yl ester

[0862]

[0863] 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 K2CO3 (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] + .

[0864] Preparation 154: (S)-6-Bromo-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4(3H)-one

[0865]

[0866] 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 reactants were stirred at 80 ° C for 3 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative TLC using DCM:MeOH=25:1 to give the title compound (180 mg, yield: 70%) as a white solid. LCMS: m / z=311, 313 [M+H] + .

[0867] Preparation 155: (S)-6-Bromo-4-chloro-7-((tetrahydrofuran-3-yl)oxy)quinazoline

[0868]

[0869] 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 Na2CO3 (aqueous solution) (30 mL) and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated to dryness to give the title compound (200 mg, crude) as a brown solid. LCMS: m / z=330 [M+H] + .

[0870] Preparation 156: (S)-6-Bromo-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(tetrahydrofuran) (pyran-3-yl)oxy)quinazoline

[0871]

[0872] The title compound (150 mg, 50% yield) was obtained as a yellow solid from (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) following the procedure described in Preparation 90. LCMS: m / z = 501, 503 [M+H] + .

[0873] Preparation 157: 6-Bromo-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline

[0874]

[0875] The title compound (400 mg, 90% yield) was obtained from 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) following a procedure similar to that described in Preparation 90. LCMS: m / z = 445, 447 [M+H] + .

[0876] Preparation 158: 6-Bromo-4-(1-ethyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-7-methoxyquinazoline

[0877]

[0878] The title compound (50 mg, 37% yield) was obtained as a pale yellow solid from 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 following a procedure similar to that described in Preparation 90. LCMS m / z = 427 [M+H] + .

[0879] Preparation 159: 6-Bromo-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-ethoxyquinazoline

[0880]

[0881] Pd(dppf)Cl2 (76.0 mg, 0.104 mmol) and K2CO3 (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 / H2O (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 sequentially with water (100 mL x 3) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by preparative TLC using PE:EtOAc = 1:1 as eluent to afford the title compound (360 mg, 75.4%) as a pale yellow solid. LCMS m / z = 458 [M+H] + .

[0882] Preparation 160: 6-Bromo-7-ethoxy-4-(3-phenyl-1H-pyrazol-4-yl)quinazoline

[0883]

[0884] 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 h. The reaction was concentrated to dryness, the residue was diluted with saturated aqueous Na2CO3 solution 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 light yellow solid. LCMS: m / z = 395, 397 [M+H] + .

[0885] Preparation 161: 6-Bromo-7-ethoxy-4-(1-isopropyl-3-phenyl-1H-pyrazol-4-yl)quinazoline

[0886]

[0887] 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 h. The reaction was quenched with ice water and then concentrated to dryness. The residue was purified by preparative TLC using DCM:MeOH=20:1 to give the title compound (150 mg, yield=68%) as a light yellow solid. LCMS: m / z=437, 439 [M+H] + .

[0888] Preparation 162: 6-Bromo-4-(1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7-ethoxyquinazoline

[0889]

[0890] A mixture of Cu(OAc)2 (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 cooled. 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 Na2CO3 (80 mg, 0.760 mmol) were added and the reaction was stirred at 80 ° C under an O2 atmosphere for 4 h. The mixture was concentrated to dryness and the residue was purified by preparative TLC using DCM:MeOH=25:1 to give the title compound (80 mg, yield: 48%) as a light yellow solid. LCMS: m / z=435, 437 [M+H] + .

[0891] Preparation 163: 6-(1-ethoxyvinyl)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinol Oxazoline

[0892]

[0893] Under N2, to a solution of trifluoromethanesulfonic acid 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazole-4-yl)quinazoline-6-yl ester (preparation 116,1g, 2.15mmol) in dioxane / H2O (20mL / 5mL) was added tributyl (1-ethoxyvinyl) stannane (776mg, 2.15mmol), K2CO3 (593mg, 4.30mmol) and Pd(PPh3)2Cl2 (171mg, 0.21mmol), and the reactant was stirred at 100°C for 4h. The reaction mixture was cooled to room temperature and then diluted with water (25mL). The resulting solution was extracted with EtOAc (2x40 mL) and the organic layers were combined. The resulting mixture was washed with brine (20mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The product was purified by chromatography using PE:EtOAc (1:1) to afford the title compound as a yellow solid (600 mg, 72.2%). LCMS m / z=387 [M+H] + .

[0894] Preparation 164: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6-(1-ethoxyvinyl)- 7-Methoxyquinazoline

[0895]

[0896] The title compound (211 mg, 48%) was obtained as a white solid from 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl trifluoromethanesulfonate (Preparation 117) following the procedure described in Preparation 163. LCMS m / z = 437 [M+H] + .

[0897] Preparation 165: 7-Ethoxy-6-(1-ethoxyvinyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinone Oxazoline

[0898]

[0899] 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-ethoxyvinyl)triethylstannane (270 mg, 0.976 mmol), Pd(PPh3)2Cl2 (30 mg, 0.043 mmol) and Cs2CO3 (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 using DCM:MeOH=15:1 to give the title compound (160 mg, yield: 75.8%) as a pale yellow solid. LCMS: m / z=401[M+H]+ .

[0900] Preparation 166: 7-Ethoxy-6-(1-ethoxyvinyl)-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinone Oxazoline

[0901]

[0902] 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-ethoxyvinyl)stannane (230 mg, 0.637 mmol) and Pd(PPh3)2Cl2 (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 using DCM:MeOH = 20:1 to give the title compound (130 mg, 74%) as a light yellow solid. LCMS: m / z = 415 [M+H] + .

[0903] Preparations 167 to 171

[0904] The compounds in the following table were prepared following a procedure similar to that described in Preparation 166 from the appropriate 6-bromoquinazoline and tributyl(1-ethoxyvinyl)stannane.

[0905]

[0906]

[0907] Preparation 172: 1-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-one

[0908]

[0909] 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 h. The mixture was evaporated under reduced pressure to give the title compound (120 mg, 86.3%) as a yellow solid. LCMS m / z = 359 [M+H] + .

[0910] Preparation 173: 1-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline-6-yl 1-Methyl)ethanone

[0911]

[0912] 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) following the procedure described in Preparation 172. LCMS m / z = 409 [M+H] + .

[0913] Preparation 174: 1-(7-isopropoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethyl-1- ketone

[0914]

[0915] The title compound was obtained as a light 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] + .

[0916] 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

[0917]

[0918] 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 h and then concentrated to dryness. The residue was purified by preparative TLC using DCM:MeOH = 30:1 to give the title compound (90 mg, yield = 86%) as a light yellow solid. LCMS: m / z = 465 [M+H] + .

[0919] Preparation 176: 1-(4-(1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7-ethoxyquinazolin-6-yl)ethyl-1- ketone

[0920]

[0921] The title compound (95 mg, 81% yield) was obtained as an off-white solid from 4-(1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7-ethoxy-6-(1-ethoxyvinyl)quinazoline (Preparation 170) following the procedure described in Preparation 175. LCMS m / z = 399 [M+H] + .

[0922] Preparation 177: 1-(7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-one

[0923]

[0924] 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, yield: 99.1%) as a yellow solid. LCMS m / z=373[M+H] + .

[0925] Preparation 178: 1-(7-ethoxy-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-one

[0926]

[0927] The title compound (100 mg, 82% yield) was obtained as an off-white solid 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] + .

[0928] Preparation 179: 1-(4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl)ethan-1-one

[0929]

[0930] The title compound (140 mg, 68% yield) was obtained as a yellow solid from 6-(1-ethoxyvinyl)-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline (Preparation 167) following the procedure described in Preparation 177. LCMS m / z = 373 [M+H] + .

[0931] Preparation 180: 1-(7-ethoxy-4-(1-isopropyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethyl-1- ketone

[0932]

[0933] 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 and concentrated to dryness and purified on preparative TLC using DCM:MeOH=40:1 to give the title compound (76 mg, yield: 57.3%) as a yellow solid. LCMS: m / z=401[M+H] + .

[0934] Preparation 181: Ethyl 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline-6-carboxylate

[0935]

[0936] 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 NaIO4 (166 mg, 0.776 mmol) in water (2 mL), followed by the addition of KMnO4 (12.2 mg, 0.078 mmol) in portions. The resulting solution was stirred at 25 ° C for 2 h, then extracted with DCM (2 x 20 mL) and the organic layers were combined. The resulting mixture was washed with H2O (2 x 20 mL) and brine (10 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by TLC DCM:MeOH = 10: 1 to give the title compound (100 mg, 66.6%) as a white solid. LCMS m / z = 389 [M + H] + .

[0937] Preparation 182: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline-6-carboxylate Ethyl acetate

[0938]

[0939] Ethyl 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline-6-carboxylate (100 mg, 66.6% yield) was obtained as a white solid from 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6-(1-ethoxyvinyl)-7-methoxyquinazoline (Preparation 164) following a procedure similar to that described in Preparation 181. LCMS m / z = 439 [M+H] + .

[0940] 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

[0941]

[0942] Cs2CO3 (5.11 g, 15.7 mmol) was added to cataCXium A PdG3 (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 / H2O (50 mL / 5 mL), and the reaction was stirred at 100° C. for 16 h. The mixture was diluted with EtOAc (300 mL), washed with brine (100 mL×2), and the organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column eluting with DCM:MeOH=25:1 to give the title compound (2.4 g) as a yellow solid. LCMS: m / z=533 [M+H] + .

[0943] Preparation 184: 6-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2,3-diol tert-Butyl Hydrogen-4H-1,4-oxazine-4-carboxylate

[0944]

[0945] At room temperature, Pd (dppf) Cl 2 (36.9 mg, 0.051 mmol) and K 2 CO 3 (104 mg, 0.757 mmol) were added to 6-bromo-7-methoxy-4- (1-methyl-3-phenyl-1H-pyrazol-4-yl) quinazoline (Preparation 91, 200 mg, 0.505 mmol) and 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester (188 mg, 0.606 mmol) in H 2 O (1 mL) and dioxane (4 mL), and the reaction mixture was heated at 80 ° C. under N 2 for 2 h. The resulting solution was extracted with EtOAc (3 x 50 mL), and the combined organic layers were dried over (Na 2 SO 4) and concentrated under vacuum. The crude product was purified by preparative TLC using DCM:MeOH=25:1 to afford the title compound (150 mg, 59%) as a yellow solid. LCMS: m / z=500 [M+H] + .

[0946] Preparation 185: 6-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-3,4-diol Hydrogen-2H-1,4-oxazine trifluoroacetate

[0947]

[0948] TFA (2 mL) was added 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), and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum to give the title compound as a yellow oil (40 mg, 83%). LCMS: m / z = 400 [M+H] + .

[0949] Preparation 186: 6-(2,5-dihydro-1H-pyrrol-3-yl)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazole- 4-aminoquinazoline trifluoroacetate

[0950]

[0951] 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.

[0952] Preparation 187: Methanesulfonic acid (7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)methanesulfonate ester

[0953]

[0954] Methanesulfonyl chloride (155 mg, 1.25 mmol) was added dropwise to an ice-cooled 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), and the reaction was stirred at room temperature for 1 h. The reaction was extracted with EtOAc (3x50 mL), and the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative TLC using DCM:MeOH=20:1 to give the title compound (200 mg) as a yellow solid. LCMS: m / z=439[M+H] + .

[0955] Preparation 188: (S)-4-(7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-3- tert-Butyl methylpiperazine-1-carboxylate

[0956]

[0957] PEPPSIPd-Ipent-O-picolinidine (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 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×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 using DCM:MeOH=20:1 to give the title compound (220 mg, 85.6%) as a light yellow solid. LCMS m / z=529 [M+H] + .

[0958] Preparation 189: 4-Bromo-7-methoxy-6-nitroquinazoline

[0959]

[0960] At room temperature, phosphorus oxybromide (2.59g, 9.04mmol) is added into 7-methoxyl group -6- nitro -3,4- dihydroquinazoline -4- one (1g, 4.52mmol) in MeCN (10mL), and gained mixture is heated to 90 DEG C and kept for 1h.Reaction mixture is poured into 100g crushed ice and extracted with EtOAc (3x 50mL).Dry (Na2SO4) organic matter merged and evaporated to dryness in a vacuum.By column chromatography (SiO2, 33% EtOAc / PE) purification of residue, obtain light yellow solid title compound (350mg), it is used without further purification.

[0961] Preparation 190: 7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine

[0962]

[0963] 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. under N for 16 h. 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 (300 mg) as a light yellow solid. LCMS: m / z = 362 [M+H] + .

[0964] 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 / H2O (10 mL / 2.5 mL) was heated to 80°C for 1 h. The reaction mixture was filtered through a pad of Celite® 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 (250 mg) as a light yellow solid. LCMS: m / z=332 [M+H] + .

[0965] Preparation 191: (2S,5S)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline-6-yl) tert-Butyl)carbamoyl)-2,5-dimethylpiperazine-1-carboxylate

[0966]

[0967] 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 h at 25° C. The 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 h. 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. 1 H-NMR(400MHz,CDCl3)δppm 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),4.2 8(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).

[0968] Preparation 192: (S)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)amino tert-Butyl (formyl)-3-methylpiperazine-1-carboxylate

[0969]

[0970] The title compound (50 mg, 30% yield) was obtained as a yellow solid from 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 following a procedure similar to that described in Preparation 191.

[0971] Preparation 193: (2R,5S)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline-6-yl) tert-Butyl)carbamoyl)-2,5-dimethylpiperazine-1-carboxylate

[0972]

[0973] The title compound (190 mg, 55% yield) was obtained as a yellow solid from 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 following a procedure similar to that described in Preparation 191.

[0974] Preparation 194: (2S,3R)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline-6-yl) tert-Butyl)carbamoyl)-2,3-dimethylpiperazine-1-carboxylate or (2S,3R)-4-((7-methoxy-4-(1-methyl-3-phenyl)piperazine-1-carboxylate tert-Butyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-2,3-dimethylpiperazine-1-carboxylate

[0975]

[0976] The racemate of the title compound was obtained as a yellow solid from 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 following a procedure similar to that described in Preparation 191. LCMS m / z = 486 [M+H] + The racemate was further purified by the following preparative chiral SFC column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 um); mobile phase: A is CO2 and B is IPA (0.1% NH4OH); gradient: B% = 15% isocratic elution mode; flow rate: 60 g / min, to obtain peak 1 (10.0 mg, 6%) and peak 2 (10.0 mg, 6%), preparation 194, (2S,3R)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-2,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester or (2S,3R)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamoyl)-2,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester. 1 H-NMR(400MHz,CDCl3)δppm 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,1 H),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).

[0977] Preparation 195: (2S,5S)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline-6-yl) 2,5-Dimethylpiperazine-1-carboxamide formate

[0978]

[0979] 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*40 mm*10 um; mobile phase: [water (0.2% FA)-MeCN]; B%: 1%-50%, 8 min) to give the title compound (11.7 mg, 18%) as a pale yellow solid. LCMS m / z = 472 [M+H] + . 1 H-NMR(400MHz,CDCl3)δppm 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).

[0980] Preparation 196: (2R,3S)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline-6-yl) 1-methyl-3-phenyl-1H-pyrazole-4- quinazolin-6-yl)-2,3-dimethylpiperazine-1-carboxamide

[0981]

[0982] 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 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water-(0.05% NH3H2O+10mM NH4HCO3)-MeCN]; B%: 20%-45%, 8 min) to give the title compound (2.60 mg, 30%) as a white solid. LCMS m / z = 472 [M+H] + . 1 H-NMR(400MHz,CDCl3)δppm 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=6.8Hz),1.10(d,3H,J=7.2Hz).

[0983] Preparation 197: (S)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2- Methylpiperazine-1-carboxamide trifluoroacetate

[0984]

[0985] A mixture of (S)-tert-butyl 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 (20 mg, crude) as a yellow oil.

[0986] Preparation 198: (2S,5R)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline-6-yl) 2,5-dimethylpiperazine-1-carboxamide

[0987]

[0988] 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*10um; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 12%-42%, 10 min) to give the title compound (22.1 mg, 13% yield) as a yellow solid. LCMS m / z=472[M+H] + . 1 H-NMR(400MHz,CDCl3)δppm 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).

[0989] Preparation 199: N-(7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl)cyclopropanecarboxamide

[0990]

[0991] Cyclopropanecarbonyl chloride (6.54 g, 62.6 mmol) was added dropwise to 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. The resulting mixture was stirred at room temperature for 1 h. The resulting solid was filtered and washed with EtOAc (20 mL) to give the title compound as a yellow solid (3.9 g, yield: 97%). LCMS m / z = 260 [M+H] + .

[0992] Preparation 200: N-(7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl)propionamide

[0993]

[0994] 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 / H2O (10 mL / 2 mL) and the resulting mixture was heated to 80°C for 2 h. The reaction was filtered and the filtrate was concentrated in vacuo and the residue was purified by preparative TLC (15:1 DCM / MeOH) to give 6-amino-7-methoxyquinazolin-4(3H)-one (300 mg) as a white solid, which was used without further purification.

[0995] 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 h. 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 (180 mg, 40%) as a white solid. LCMS: m / z = 248 [M+H] + .

[0996] Preparation 201: N-(4-chloro-7-methoxyquinazolin-6-yl)cyclopropanecarboxamide

[0997]

[0998] At room temperature, 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). The reaction mixture was heated to 80 ° C and maintained for 2 h, then poured onto ice water. Na2CO3 (1 M) was added to reach pH 8. The resulting solution was extracted with EtOAc and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 5: 1DCM / EtOAc) to give the title compound (400 mg, 75%) as a yellow solid. LCMS m / z = 278 [M + H] + .

[0999] Preparation 202: N-(4-chloro-7-methoxyquinazolin-6-yl)propionamide

[1000]

[1001] POCl3 (167 mg, 1.09 mmol) was added to N-(7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl)propanamide (Preparation 200, 180 mg, 0.727 mmol) in MeCN (5 mL) and heated to 100 ° C for 1 h. The reaction was quenched with H2O (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 (60 mg, 31%) as a light yellow solid. LCMS: m / z = 266 [M+H] + .

[1002] Preparation 203: 4-Chloro-7-methoxy-6-nitroquinazoline

[1003]

[1004] 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 and maintained for 4 h. The reaction mixture was evaporated to dryness in a vacuum and the residue was dissolved in a mixture of DCM (50 mL) and NaHCO aqueous solution (50 mL). The organic layer was dried and evaporated to dryness to give the title compound (7 g, 58%) as a yellow solid, which was used without further purification.

[1005] Preparation 204: 7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-nitroquinazoline

[1006]

[1007] 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), H0 (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 purified by silica gel chromatography ( The residue was purified by HPLC (0-30% EtOAc / PE) to afford the title compound (1 g, 66%) as a yellow solid.

[1008] Preparation 205: 4-(1-ethyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-7-methoxy-6-nitroquinazoline

[1009]

[1010] At 25 ° C, to 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 a mixture of dioxane (8 mL) and H2O (2 mL) was added Pd (dppf) Cl2 (25.7 mg, 0.0352 mmol) and K2CO3 (193 mg, 1.40 mmol), and the mixture was stirred at 80 ° C under N2 for 4 h. 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 (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by preparative TLC (20:1 DCM / MeOH) to give the title compound (120 mg, 43%) as a yellow solid. LCMS: m / z = 394 [M+H] + .

[1011] Preparation 206: N-(7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinazole (6-Methyl-1-[[( ...-((((-((((-(((-

[1012]

[1013] A solution of N-(4-chloro-7-methoxyquinazolin-6-yl)propanamide (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. under N for 2 h. 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 (20 mg, 19%) as a yellow solid. LCMS: m / z=458[M+H] + .

[1014] Preparation 207: N-(4-(1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazole- 4-yl)-7-methoxyquinazolin-6-yl)-2-fluorobenzamide

[1015]

[1016] 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), Pd2(dba)3 (20 mg, 0.0193 mmol), XPhos (20 mg, 0.0345 mmol), and Cs2CO3 (108 mg, 0.334 mmol) in toluene (10 mL) was stirred at 100°C for 2 h. 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 (84 mg, 73%) as a yellow solid. LCMS: m / z = 598 [M+H] + .

[1017] Preparation 208: N-(4-(1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazole- 4-yl)-7-methoxyquinazolin-6-yl)bicyclo[1.1.1]pentane-1-carboxamide

[1018]

[1019] The title compound (159 mg, 86%) was prepared as a yellow solid 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) using a method similar to that described for Preparation 207. LCMS: m / z = 570 [M+H] + .

[1020] Preparation 209: 6-Chloro-7-methoxypyrido[3,2-d]pyrimidin-4(3H)-one

[1021]

[1022] Formamidine acetate (420 g, 4.04 mol) was added to 3-amino-6-chloro-5-methoxypicolinic acid (220 g, 1.01 mol) in EtOH (2.0 L) at room temperature, and the resulting mixture was heated to 90° C. for 24 h. The solid was collected by filtration to give the title compound (201 g, 94%) as a brown solid. LCMS: m / z = 212 [M+H] + .

[1023] Preparation 210: 7-methoxy-6-((4-methoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4(3H)-one

[1024]

[1025] 1-(4-Methoxyphenyl)methanamine (45.2 g, 330 mmol) was added to 6-chloro-7-methoxypyrido[3,2-d]pyrimidin-4(3H)-one (Preparation 209, 10 g, 47.2 mmol) in DMSO (50 mL) 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 x 50 mL). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO2, 25:1 DCM / MeOH) to give the title compound (8 g, 54%) as a yellow solid. LCMS: m / z=313[M+H] + .

[1026] Preparation 211: 4-chloro-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine

[1027]

[1028] At room temperature, POCl3 (15.7 g, 102 mmol) and N, N-diethylaniline (25.7 g, 153 mmol) were added 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), and the reaction was stirred at 80 ° C for 2 h. The resulting mixture was added to ice water and the pH was adjusted to pH 8 using aqueous Na2CO3 solution (1 M) and extracted with EtOAc (2 x 500 mL). The combined organic extracts were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (10:1 DCM / EtOAc) to give the title compound (7 g, 83%) as a yellow solid. LCMS: m / z=331[M+H] + .

[1029] Preparation 212: 7-methoxy-N-(4-methoxybenzyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyridine 6-Chloro[3,2-d]pyrimidin-2-amine

[1030]

[1031] A mixture of Pd(dppf)Cl2 (1.76 g, 2.11 mmol), K2CO3 (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 under N2 for 2 h. The mixture was diluted with EtOAc (200 mL) and washed with water (2 x 50 mL). The combined organics were dried (Na2SO4) 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] + .

[1032] Preparation 213: 4-(3-(2,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxy benzyl)pyrido[3,2-d]pyrimidin-6-amine

[1033]

[1034] The title compound (550 mg, 80%) was prepared as an off-white solid 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) using a method similar to that described for Preparation 212. LCMS: m / z = 489 [M+H] + .

[1035] Preparation 214: 4-(3-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxybenzyl)- 1-[3,2-d]pyrimidin-6-amine

[1036]

[1037] The title compound (600 mg, 85%) was prepared as a yellow solid 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) using a method similar to that described for Preparation 212. LCMS: m / z = 471 [M+H] + .

[1038] Preparation 215: 4-(3-(3-((tert-Butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-pyrazole-4- 7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine

[1039]

[1040] A mixture of Pd(PPh3)4 (138 mg, 0.120 mmol), K3PO4 (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. under N2 for 2 h. The resulting solution was extracted with EtOAc (3×50 mL) and the combined organic extracts were dried (Na2SO4) 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] + .

[1041] Preparation 216: 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-amine

[1042]

[1043] At room temperature, 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), and the mixture was stirred at 60 ° C for 3 h. The mixture was diluted with EtOAc (100 mL), washed with brine (2 x 50 mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (18: 1 DCM / MeOH) to give the title compound (2.5 g) as a yellow solid. LCMS: m / z = 333 [M + H] + .

[1044] Preparation 217: 4-(3-(2,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2- d]pyrimidin-6-amine

[1045]

[1046] 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. under N 2 for 3 h. The mixture was diluted with EtOAc (100 mL) and washed with NaHCO 3 (aq.) (2 x 50 mL). The combined organics were dried (Na 2 SO 4 ), evaporated to dryness in vacuo, and the residue was purified by silica gel chromatography (18:1 DCM / EtOAc) to give the title compound (320 mg, 78%) as a yellow solid. LCMS: m / z=369 [M+H] + .

[1047] Preparation 218: 4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidine 6-pyridinamine

[1048]

[1049] The title compound (400 mg, 90%) was prepared as a yellow solid 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) using a method similar to that described for Preparation 217. LCMS: m / z = 351 [M+H] + .

[1050] Preparation 219: 3-(4-(6-amino-7-methoxypyrido[3,2-d]pyrimidin-4-yl)-1-methyl-1H-pyrazole- 3-aminophenyl)phenol

[1051]

[1052] 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 x 50 mL) and the combined extracts were dried (Na2SO4) and evaporated to dryness. The residue was purified by preparative TLC (15:1 DCM / MeOH) to give the title compound (140 mg, 63%) as a yellow solid. LCMS: m / z = 349 [M+H] + .

[1053] Preparation 220: 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxybenzyl)- 1-[3,2-d]pyrimidin-6-amine

[1054]

[1055] A mixture of 4-chloro-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 211, 800 mg, 2.4 mmol), K2CO3 (672 mg, 4.8 mmol), Pd(dppf)Cl2 (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 / H2O (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 (SiO2, 5% MeOH / DCM) to give the title compound (800 mg, 71%) as an off-white solid. LCMS m / z=471[M+H] + .

[1056] Preparation 221: 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidine 6-pyridinylamine trifluoroacetate

[1057]

[1058] 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 h. The solution was concentrated to dryness to give the title compound as a yellow oil (600 mg, 90%). LCMS m / z = 351 [M+H] + .

[1059] Preparation 222: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxy benzyl)pyrido[3,2-d]pyrimidin-6-amine

[1060]

[1061] The title compound (560 mg, 43%) was obtained as a light yellow solid from 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) following the procedure described in Preparation 220. LCMS m / z = 503 [M+H] + .

[1062] Preparation 223: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2- d]pyrimidine-6-amine trifluoroacetate

[1063]

[1064] The title compound (400 mg, crude) was obtained as a pale yellow oil from 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) following the procedure described in Preparation 221. LCMS m / z = 383 [M+H] + .

[1065] Preparation 224: 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine

[1066]

[1067] At room temperature, N,N-diethylaniline (986g, 6.61mol) was added to 6-chloro-7-methoxypyrido[3,2-d]pyrimidin-4(3H)-one (Preparation 209, 200g, 945mmol) and POCl3 (722g, 4.72mol) in MeCN (2000mL), and the resulting mixture was heated at 80°C for 2h. The reaction mixture was added to ice water and Na2CO3 (5M) was added until pH=8. The solution was extracted with EtOAc and the combined organics were concentrated under vacuum. The residue was purified by silica gel chromatography (5:1DCM / EtOAc) to give the title compound (178g, 82%) as a yellow solid. LCMS: m / z=230[M+H] + .

[1068] Preparation 225: 2-Bromo-5-ethoxypyridin-3-amine

[1069]

[1070] At room temperature, NaOEt (45 mL) was added to a solution of 2-bromo-5-fluoropyridin-3-amine (6 g, 31.4 mmol) in EtOH (45 mL), 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 2 , 5:1 PE / EtOAc) to give the title compound (5.1 g, 75%) as an off-white solid. LCMS: m / z=217 [M+H] + .

[1071] Preparation 226: Methyl 3-amino-5-ethoxypicolinate

[1072]

[1073] 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) Cl2 (1.84 g, 2.53 mmol) in MeOH (100 mL) was stirred at 80 ° C under a CO atmosphere (10 atm) for 16 h. The reaction mixture was diluted with EtOAc (200 mL), washed with water (3 x 200 mL) and saturated brine (200 mL). The organic layer was dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (20% EtOAc / PE) to give the title compound (1.5 g, 30%) as a yellow solid. LCMS: m / z = 197 [M + H] + .

[1074] Preparation 227: Methyl 3-amino-6-chloro-5-ethoxypicolinate

[1075]

[1076] At room temperature, 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), and the resulting mixture was heated to 80 ° C and maintained for 16 h. The reaction mixture was diluted with EtOAc (150 mL), washed with water (3 x 150 mL) and saturated brine (150 mL). The organic layer was dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (2: 1PE / EtOAc) to give the title compound (1.6 g, 69%) as a light yellow solid. LCMS: m / z = 231 [M + H] + .

[1077] Preparation 228: 3-Amino-6-chloro-5-ethoxypicolinic acid

[1078]

[1079] At room temperature, 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 / H2O (15 mL / 5 mL), and the resulting mixture was stirred at room temperature for 16 h. 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 (Na2SO4) and evaporated to dryness in vacuo to give the title compound (1.4 g, 93%) as an off-white solid. LCMS: m / z=217 [M+H] +.

[1080] Preparation 229: 6-Chloro-7-ethoxypyrido[3,2-d]pyrimidin-4(3H)-one

[1081]

[1082] Formamidine acetate (5.75 g, 55.3 mmol) was added to 3-amino-6-chloro-5-ethoxypicolinic acid (Preparation 228, 1.5 g, 6.92 mmol) in EtOH (50 mL) at room temperature, and the resulting mixture was heated to 80° C. for 16 h. The reaction mixture was diluted with water (200 mL) and the solid was collected by filtration to give the title compound (1.5 g, 96%) as a white solid. LCMS: m / z = 226 [M+H] + .

[1083] Preparation 230: 4,6-dichloro-7-ethoxypyrido[3,2-d]pyrimidine

[1084]

[1085] At room temperature, POCl3 (5.11 g, 33.2 mmol) was added to 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), and the resulting mixture was heated to 80 ° C and maintained for 2 h. The solution was poured into ice water and the pH was adjusted to pH 8 by adding aqueous NaHCO3 solution (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 (1.4 g, 86%) as an off-white solid. LCMS: m / z = 244 [M + H] + .

[1086] Preparation 231: 6-Chloro-7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine

[1087]

[1088] At room temperature, Pd (PPh ) (235 mg, 0.204 mmol) and K PO (864 mg, 4.08 mmol) are added to 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 / H O (16 mL / 4 mL), and the resulting mixture is heated to 80 ° C and maintained for 2 h under N . The reaction mixture is diluted with EtOAc (200 mL), washed with water (3 x 100 mL) and saturated brine (100 mL). The combined organic matter is dried (Na SO ) and evaporated to dryness in a vacuum. The residue was purified by silica gel column chromatography (20:1 DCM / MeOH) to afford the title compound (290 mg, 39%) as an off-white solid. LCMS: m / z = 366 [M+H] + .

[1089] Preparation 232: 6-Chloro-7-ethoxy-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrido[3,2- d]pyrimidine

[1090]

[1091] The title compound (1 g, 32%) was obtained as a yellow solid from 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) following a procedure similar to that described in Preparation 97. LCMS: m / z = 385 [M+H] + .

[1092] Preparation 233: 6-Chloro-7-ethoxy-4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrido[3,2- d]pyrimidine

[1093]

[1094] The title compound (500 mg, 20%) was obtained as a yellow solid from 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) following a procedure similar to that described in Preparation 231. LCMS: m / z = 384 [M+H] + .

[1095] Preparation 234: 6-Chloro-7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrrolidone Imido[3,2-d]pyrimidine

[1096]

[1097] The title compound (4.2 g, 42% yield) was obtained as a yellow solid from 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) following a procedure similar to that described in Preparation 231. LCMS: m / z = 442 [M+H]. + .

[1098] Preparation 235: 6-Chloro-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine

[1099]

[1100] 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 under N2 for 3 h. The reaction mixture was diluted with EtOAc (120 mL) and washed with H2O (60 mL). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by preparative TLC (50% DCM / EtOAc) to give the title compound (1.5 g, 94%) as a yellow solid. LCMS: m / z=338[M+H] + .

[1101] 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

[1102]

[1103] 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 under N2 for 3 h. 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 afford 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] + .

[1104] Preparation 237: 6-Chloro-4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2- d]pyrimidine

[1105]

[1106] The title compound (150 mg, 47%) was obtained as a white solid from 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) following a procedure similar to that described in Preparation 231. LCMS: m / z = 370 [M+H] + .

[1107] Preparation 238: 6-Chloro-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2- d]pyrimidine

[1108]

[1109] The title compound (300 mg, 37%) was obtained as a yellow solid from 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) following a procedure similar to that described in Preparation 231. LCMS: m / z = 370 [M+H] + .

[1110] Preparation 239: 6-Chloro-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidine

[1111]

[1112] At room temperature, K 3 PO 4 (5.0 g, 23.6 mmol) was added to Pd (dppf) Cl 2.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 / H 2 O, 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 Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 5:1 DCM / EtOAc) to afford the title compound (1.6 g, 23%) as a yellow solid. LCMS m / z = 366 [M+H]+.

[1113] Preparation 240: 6-Chloro-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxypyrido [3,2-d]pyrimidine

[1114]

[1115] The title compound (852 mg, 24% yield) was obtained as a yellow solid from 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) following the procedure described in Preparation 239. LCMS m / z = 402 [M+H] + .

[1116] Preparation 241: 5-(6-chloro-7-methoxypyrido[3,2-d]pyrimidin-4-yl)-2-methyl-4-phenylthiazole

[1117]

[1118] The title compound (40 mg, 16% yield) was obtained as a yellow solid from 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 following a procedure similar to that described in Preparation 231. LCMS: m / z = 369 [M+H] + .

[1119] Preparation 242: 6-Chloro-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine

[1120]

[1121] At room temperature, K PO (250g, 1.18mol) is added to Pd (dppf) Cl in dioxane / H O.DCM (70.5g, 86.4mmol), 4,6-dichloro-7-methoxypyrido [3,2-d] pyrimidine (preparation 224, 250g, 1.08mol) and 1-methyl-3-phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (276g, 972mmol), and the resulting mixture is stirred at 60 ° C for 16h. The reactant is diluted with EtOAc (3L) and washed with brine (2x1L). The combined organics are dried (Na SO ) and evaporated to dryness in vacuo and the residue is purified by silica gel chromatography (5:1DCM / EtOAc) to give the title compound (66g, 17%) as a yellow solid. LCMS: m / z=352[M+H] + .

[1122] Preparation 243: 6-chloro-4-(3-(2,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido [3,2-d]pyrimidine

[1123]

[1124] Under N2, 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 (PPh3) 4 (300 mg, 0.260 mmol) and K3PO4 (1.10 g, 5.20 mmol) in dioxane (10 mL) and H2O (2 mL), and the mixture 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: 1DCM / MeOH) to give the title compound (200 mg, 20%) as a white solid. LCMS: m / z=388[M+H] + .

[1125] Preparation 244: 6-Chloro-4-(1-(difluoromethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2- d]pyrimidine

[1126]

[1127] 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 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 (60 mg, 26%) as a yellow solid. LCMS: m / z=487 [M+H] + .

[1128] Preparation 245: 6-chloro-4-(1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2-d]pyrimidine pyridine

[1129]

[1130] A mixture of Cu(OAc)2 (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 Na2CO3 (62.7 mg, 0.592 mmol) were added, and the resulting mixture was stirred at 80°C under N2 for 4 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 (60 mg, 86%) as a yellow solid. LCMS: m / z = 378 [M+H] + .

[1131] Preparation 246: 6-chloro-4-(1-(cyclopropylmethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxypyrido[3, 2-d]pyrimidine

[1132]

[1133] 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 (80 mg, 35%) as a yellow solid. LCMS: m / z=392 [M+H] + .

[1134] Preparation 247: 4-(1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazole-4- 1-Methyl-6-chloro-7-methoxypyrido[3,2-d]pyrimidine

[1135]

[1136] The title compound (120 mg, 41%) was prepared as a yellow solid 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 using a method similar to that described for Preparation 246. LCMS: m / z = 496 [M+H] + .

[1137] Preparation 248: N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)propanamide

[1138]

[1139] 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 propionic acid (1.66 g, 22.6 mmol) in THF (50 mL) was added (10 mL, 50% solution in EtOAc) and pyridine (1.18 g, 15.0 mmol). The reaction was stirred at room temperature for 2 h and quenched with water. The reaction mixture was extracted with EtOAc, the organic layer was dried over Na2SO4, and then concentrated in vacuo. The residue was purified by column chromatography (SiO2, 20:1 DCM / MeOH) to give the title compound (5.81 g, 99%) as a yellow solid. LCMS m / z=388[M+H] + .

[1140] Preparation 249: N-(7-Hydroxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)propanamide

[1141]

[1142] To N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)propanamide (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 (200 mg, 52%) as a yellow oil. LCMS m / z=374 [M+H] + .

[1143] Preparation 250: 4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-propionylaminoquinazoline-7-trifluoromethanesulfonate esters

[1144]

[1145] To N-(7-hydroxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)propanamide (Preparation 249, 200 mg, 0.535 mmol) and TEA (226 mg, 0.802 mmol) in DCM (2 mL) was added Tf2O (226 mg, 0.802 mmol) dropwise at 0 ° C. under N2, 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 (100 mg, 37%) as a yellow solid. LCMS m / z=506[M+H] + .

[1146] Preparation 251: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-amine

[1147]

[1148] The title compound (300 mg, 56%) was prepared as a yellow solid 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) using a two-part procedure analogous to that described for Preparation 190. LCMS: m / z = 382 [M+H] + .

[1149] Preparation 252: 4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-amine

[1150]

[1151] The title compound (120 mg) was prepared as a white solid 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) using a two-part procedure analogous to that described for Preparation 190. LCMS: m / z = 346 [M+H] + .

[1152] Preparation 253: 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-amine

[1153]

[1154] The title compound (80 mg, 77%) was prepared as a white solid 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) using a two-part procedure analogous to that described for Preparation 190. LCMS: m / z = 350 [M+H] + .

[1155] Preparation 254: 4-(3-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-amine

[1156]

[1157] The title compound (100 mg, 54%) was prepared as a yellow solid 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) using a two-part procedure analogous to that described for Preparation 190. LCMS: m / z = 380 [M+H] + .

[1158] Preparation 255: 4-(1-ethyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-amine

[1159]

[1160] 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 H2O (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 (80 mg, 73%) as a yellow solid. LCMS: m / z = 364 [M + H] + .

[1161] Preparation 256: 5-Fluoro-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine

[1162]

[1163] At room temperature, 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), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (100 mL) and washed with brine (2 x 50 mL). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO2, 15:1 DCM / MeOH) to give the title compound (180 mg, 37%) as a yellow solid. LCMS: m / z=350 [M+H] + .

[1164] Preparation 257: 1-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)carbamyl tert-Butyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[1165]

[1166] The title compound (310 mg, 95%) was prepared as a yellow solid 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) using a method similar to that described for Example 205. LCMS: m / z = 541 [M+H] + .

[1167] Preparation 258: 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-carboxylic acid tert-butyl ester

[1168]

[1169] 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. under N2 for 3 h. The reaction mixture was diluted with water, 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 (100 mg, 47%) as a yellow solid. LCMS: m / z = 560 [M+H] + .

[1170] Preparation 259: 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-carboxylic acid tert-butyl ester

[1171]

[1172] The title compound (320 mg, 71%) was prepared as a yellow solid 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) using a method similar to that described for Preparation 258. LCMS: m / z = 574 [M+H] + .

[1173] Preparation 260: 6,6-difluoro-1-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3, tert-Butyl (2-d]pyrimidin-6-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[1174]

[1175] 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), Pd2(dba)3 (5 mg, 5.46 μmol), XantPhos (180 mg, 0.312 mmol) and Cs2CO3 (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 (70 mg, 39%) as a yellow solid. LCMS: m / z=578[M+H] + .

[1176] Preparation 261: N-(4-(1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazole- 4-yl)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)bicyclo[1.1.1]pentane-1-carboxamide

[1177]

[1178] The title compound (80 mg, 58%) was prepared as a yellow solid 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) using a method similar to that described for Preparation 260. LCMS: m / z = 571 [M+H] + .

[1179] Preparation 262: N-(4-(1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazole- 4-yl)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)-1-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[1180]

[1181] The title compound (60 mg, 47%) was prepared as a yellow solid 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) using a method similar to that described for Preparation 260. LCMS: m / z = 639 [M+H] + .

[1182] Preparation 263: (1R,3S,5R)-3-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido tert-Butyl [3,2-d]pyrimidin-6-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

[1183]

[1184] The title compound (100 mg, 43%) was prepared as a yellow solid 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) using a method similar to that described for Preparation 260. LCMS: m / z = 542 [M+H] + .

[1185] Preparation 264: (1R,3R,5R)-3-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido tert-Butyl [3,2-d]pyrimidin-6-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

[1186]

[1187] The title compound (100 mg, 43%) was prepared as a yellow solid 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) using a method similar to that described for Preparation 260. LCMS: m / z = 542 [M+H] + .

[1188] Preparation 265: 7-(1-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one

[1189]

[1190] Under N2, 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), KHCO3 (3.71 mg, 26.7 mmol) and Pd(dppf)Cl2 (975 mg, 1.33 mmol) in dioxane (100 mL) and H2O (20 mL) were placed in a round-bottom flask and the resulting solution was stirred at 100 ° C for 1 h. The reaction mixture was diluted with H2O (50 mL), the solids were removed by filtration and the resulting solution was extracted with EtOAc (3x50 mL). The organic layer was concentrated in vacuo. The residue was purified by column chromatography (SiO2, 20:1 DCM / MeOH) to give the title compound (1.70 g, 56%) as a light yellow solid. LCMS m / z=227[M+H] + .

[1191] Preparation 266: 4-Chloro-7-(1-methyl-1H-pyrazol-4-yl)quinazoline

[1192]

[1193] Under N2, 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 and the resulting solution was stirred at 100 ° C for 2 h. The mixture was concentrated under vacuum and the residue was diluted with water (10 mL). The resulting solution was extracted with DCM (3x10 mL) and the combined organic layers were concentrated in vacuo to give the title compound (1.30 g, 71%) as a light yellow solid. LCMS m / z=245[M+H] + .

[1194] Preparation 267: 7-(1-methyl-1H-pyrazol-4-yl)-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)- oxazol-4-yl)quinazoline

[1195]

[1196] 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(PPh3)4 (47.1 mg, 0.0408 mmol), and K3PO4 (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 x 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 (65 mg, 36%) as a white solid. LCMS m / z=437[M+H] + .

[1197] Preparation 268: 4-(3-(2-Fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7-(1-methyl (4-(2-(2-pyrazol-1H-yl)quinazoline)

[1198]

[1199] The title compound (80 mg, 54% yield) was obtained as a light yellow solid from 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) following the procedure described in Preparation 267. LCMS m / z = 455 [M+H] + .

[1200] 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

[1201]

[1202] The title compound (60 mg) was obtained as a white solid from 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) following a procedure similar to that described in Preparation 267.

[1203] Preparation 270: 4-Chloro-7-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)quinazoline

[1204]

[1205] 7-Bromo-4-chloroquinazoline (100 mg, 0.410 mmol), 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)Cl2.DCM (33.4 mg, 0.041 mmol), and K2CO3 (113 mg, 0.820 mmol) in DMF (1.2 mL) 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.

[1206] Preparation 271: 7-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-4-(3-phenyl-1-(tetrahydro-2H-pyrazol-4-yl)-1H-pyrazol-4-yl)- (pyran-2-yl)-1H-pyrazol-4-yl)quinazoline

[1207]

[1208] The title compound (25 mg, 16% yield) was obtained as a yellow solid from 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) following a procedure similar to that described in Preparation 267. LCMS m / z = 437 [M+H] + .

[1209] Preparation 272: 5-Fluoro-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one

[1210]

[1211] The title compound (400 mg, 80% yield) was obtained as a white solid from 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 7-bromo-5-fluoroquinazolin-4(3H)-one following a procedure similar to that described in Preparation 265. LCMS m / z = 245 [M+H] + .

[1212] Preparation 273: 4-Chloro-5-fluoro-7-(1-methyl-1H-pyrazol-4-yl)quinazoline

[1213]

[1214] The title compound (200 mg, 47% yield) was obtained as a white solid from 5-fluoro-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one (Preparation 272) following a procedure similar to that described in Preparation 266. LCMS m / z = 263 [M+H] + .

[1215] Preparation 274: 6-(Benzyloxy)-7-bromo-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)quinone Oxazoline

[1216]

[1217] Under N2, 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 H2O (5 mL) was added Pd(dppf)Cl2 (209 mg, 0.286 mmol) and K2CO3 (789 mg, 5.72 mmol), and the reaction was stirred at 80 ° C for 4 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative TLC (10:1 DCM / MeOH) to afford the title compound (700 mg, 74%) as a yellow solid. LCMS m / z = 521 [M+H] + .

[1218] Preparation 275: 6-(Benzyloxy)-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(1-methyl (4-(2-(2-pyrazol-1H-yl)quinazoline)

[1219]

[1220] The title compound (550 mg, 79% yield) was obtained as a white solid from 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 following a procedure similar to that described in Preparation 274. LCMS m / z = 523 [M+H] + .

[1221] Preparation 276: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol-4-yl)- quinazolin-6-ol

[1222]

[1223] 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. under an atmosphere of H 2 for 4 h. The mixture was filtered and the filtrate was evaporated to dryness to give the title compound (400 mg, 88.1%) as a yellow solid.

[1224] Preparation 277: Trifluoromethanesulfonic acid 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(1-methyl- 1H-pyrazol-4-yl)quinazolin-6-yl ester

[1225]

[1226] 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. Tf2O (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 (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 1:1DCM / EtOAc) to give the title compound (500 mg, 96%) as a yellow solid. LCMS m / z=565[M+H] + .

[1227] Preparation 278: 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6-(1-ethoxyvinyl)- 7-(1-methyl-1H-pyrazol-4-yl)quinazoline

[1228]

[1229] 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 N2. 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 x 40 mL). The combined organic layers were washed with brine (20 mL), then dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 1:1 PE / EtOAc) to afford the title compound (400 mg, 93%) as a yellow solid. LCMS m / z = 487 [M+H] + .

[1230] Preparation 279: 1-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol- oxazol-4-yl)quinazolin-6-yl)ethan-1-one

[1231]

[1232] 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] + .

[1233] Preparation 280: 7-Bromo-4-chloro-6-methoxyquinazoline

[1234]

[1235] At room temperature, TEA (479 mg, 4.70 mmol) was added to POCl3 (599 mg, 3.92 mmol) and 7-bromo-6-methoxyquinazolin-4 (3H) -one (200 mg, 0.784 mmol) in MeCN (1 mL). The reaction mixture was heated to 80 ° C and maintained for 2 h. The resulting solution was added to ice water and then Na2CO3 (1 M) was added to adjust to pH 8. 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 (60 mg, 28%) as a yellow solid. LCMS m / z = 273 [M + H] + .

[1236] Preparation 281: 7-Bromo-6-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline

[1237]

[1238] The title compound (40 mg, 46%) was obtained as a yellow solid from 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 following the procedure described in Preparation 231. LCMS m / z = 395 [M+H] + .

[1239] Preparation 282: 7-(1-methyl-1H-pyrazol-3-yl)-6-nitroquinazolin-4(3H)-one

[1240]

[1241] To a solution of 7-bromo-6-nitro-3,4-dihydroquinazolin-4-one (500 mg, 1.85 mmol) in dioxane and water was added 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), and the reaction was stirred at 100 ° C for 2 h. The mixture was extracted with EtOAc (20 mL x 3) and washed with brine (10 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the title compound (400 mg, 80%) as a yellow solid. LCMS: m / z=272[M+H] + .

[1242] Preparation 283: 4-Bromo-7-(1-methyl-1H-pyrazol-3-yl)-6-nitroquinazoline

[1243]

[1244] 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 POBr3 (400 mg, 2.20 mmol) in MeCN (5 mL) was stirred at 80 ° C for 2 h. The mixture was poured into ice-NaHCO3, extracted with EtOAc (3x20 mL) and washed with brine (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (10:1 DCM / MeOH) to give the title compound (280 mg, 57%) as a yellow solid. LCMS m / z=334[M+H] + .

[1245] Preparation 284: 4-(3-(2,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]-7-(1-methyl-1H-pyrazol-3-yl)- 6-nitroquinazoline

[1246]

[1247] The title compound (40 mg, 25% yield) was obtained as a yellow solid from 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) following a procedure similar to that described in Preparation 274. LCMS m / z = 448 [M+H] + .

[1248] Preparation 285: 4-(3-(2,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol-3-yl)- quinazolin-6-amine

[1249]

[1250] 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 NHCl (47.8 mg, 0.894 mmol) in EtOH (3 mL) and H2O (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 (30 mg, 80%) as a yellow solid.

[1251] Preparation 286: Methyl 3-amino-5,6-dichloropicolinate

[1252]

[1253] At room temperature, 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). The resulting mixture was heated to 80 ° C and maintained for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL x 3) and saturated brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to obtain a crude product. This crude product was purified by silica gel column eluting with PE:EtOAc=4:1 to obtain the title compound as a yellow solid (1.1 g, yield: 98.2%). LCMS m / z=221[M+H] + .

[1254] Preparation 287: 6,7-Dichloropyrido[3,2-d]pyrimidin-4(3H)-one

[1255]

[1256] At room temperature, AcOH (1 mL) was added to methyl 3-amino-5,6-dichloropicolinate (preparation 286, 1.1 g, 4.97 mmol) in formamide (10 mL), and the reactants were heated to 120 ° C and kept for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mLx3) and saturated brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column using DCM:MeOH=20:1 to obtain the title compound (900 mg, yield: 84.1%) as a brown solid. LCMS m / z=215[M+H] + .

[1257] Preparation 288: 7-Chloro-6-((4-methoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4(3H)-one

[1258]

[1259] 1-(4-methoxyphenyl)methylamine (2.85 g, 20.8 mmol) was added to 6,7-dichloropyrido[3,2-d]pyrimidin-4(3H)-one (preparation 287, 900 mg, 4.16 mmol) in DMSO (10 mL), and the resulting mixture was heated at 80 ° C for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mLx3) and saturated brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative TLC using DCM:MeOH=20:1 to give the title compound (900 mg, yield: 68.7%) as a brown solid. LCMS m / z=317[M+H] + .

[1260] Preparation 289: 4,7-Dichloro-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine

[1261]

[1262] At room temperature, N,N-diethylaniline (2.95 g, 19.8 mmol) was added to 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) in MeCN (15 mL). The resulting mixture was heated at 80 ° C for 2 h. The resulting solution was added to ice water and then 1M Na2CO3 was added until pH = 8. The solution was extracted with EtOAc and concentrated under vacuum. The residue was purified by silica gel column using DCM:EtOAc=3:1 to give the title compound (360 mg, yield: 37.8%) as a yellow solid. LCMS m / z=335[M+H] +.

[1263] Preparation 290: 7-Chloro-N-(4-methoxybenzyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3, 2-d]pyrimidin-6-amine

[1264]

[1265] A mixture of Pd(dppf)Cl2 (76.0 mg, 0.104 mmol), K3PO4 (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. under N2 for 16 h. 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 by silica gel column using DCM:MeOH=20:1 to give the title compound as a yellow solid (350 mg, yield: 73.6%). LCMS m / z=457 [M+H] + .

[1266] Preparation 291: 7-Chloro-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-amine

[1267]

[1268] 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 and maintained for 2 h. The mixture was concentrated under vacuum. The crude product was purified by preparative TLC using DCM:MeOH=10:1 to give the title compound (160 mg, yield: 64.0%) as a yellow solid. LCMS m / z=337[M+H] + .

[1269] Preparation 292: N-(7-chloro-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine-6-yl)- 1-Hydroxy-3-oxabicyclo[3.1.0]hexane-1-carboxamide

[1270]

[1271] At 0 ° C, 2,4,6-trichlorobenzoyl chloride (324 mg, 1.33 mmol) was added to 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). 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 stirred at 80 ° C for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL x 3) and brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give a crude product. The crude product was purified by preparative TLC using DCM: MeOH = 20: 1. The residue was purified by preparative HPLC (column: XBridge Preparative OBD C18 column, 30*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) to give the title compound (34.1 mg, 17.2%) as a white solid. LCMS: m / z = 447 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ10.10(s,1H),9.03(s,1H),8.94(s,1H),8.64(s,1H),7.52-7.45(m,2H),7.31(q,J=2.9H z, 3H), 4.06-3.98 (m, 5H), 3.80 (s, 2H), 2.36 (t, J = 6.5Hz, 1H), 1.56 (dd, J = 8.3, 4.5Hz, 1H), 0.99 (t, J = 4.9Hz, 1H).

[1272] Preparation 293: 6-((4-methoxybenzyl)amino)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido [3,2-d]pyrimidin-7-ol

[1273]

[1274] L-Selectride (1.67 g, 8.82 mmol) 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, 2 g, 4.41 mmol) in THF (16 mL), and the reaction mixture was stirred at 80 ° C for 2 h, then diluted with EtOAc (200 mL) and washed with brine (2x10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 25:1 DCM / MeOH) to give the title compound (1.1 g, 55%) as a white solid. LCMS m / z=439[M+H] + .

[1275] Preparation 294: 6-((4-methoxybenzyl)amino)-4-(1-methyl-3-phenyl-1H-pyrazole-4-yl)-trifluoromethanesulfonic acid yl)pyrido[3,2-d]pyrimidin-7-yl ester

[1276]

[1277] At room temperature, Tf2O (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 (prepared 293, 500 mg, 1.14 mmol), DMAP (137 mg, 0.57 mmol) and pyridine (456 mg, 5.70 mmol) in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 h, then diluted with EtOAc (100 mL) and washed with brine (2x50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 15:1DCM / MeOH) to give the title compound (160 mg, 32%) as a yellow solid. LCMS m / z=571[M+H] + .

[1278] Preparation 295: N-(4-methoxybenzyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-7-(3-morpholinyl Prop-1-yn-1-yl)pyrido[3,2-d]pyrimidin-6-amine

[1279]

[1280] CuI (10.0 mg, 0.524 mmol) is 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 reactants are stirred at 80 ° C under N2 for 2 h. The mixture is diluted with EtOAc (150 mL) and washed with brine (2x75 mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by column chromatography (SiO2, 15:1DCM / EtOAc) to give the title compound (80 mg, 54%) as an off-white solid. LCMS m / z=546[M+H] + .

[1281] 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

[1282]

[1283] At room temperature, 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). The reaction mixture was stirred at 60 ° C for 3 h, then diluted with EtOAc (100 mL) and washed with brine (2x50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 18: 1DCM / MeOH) to give the title compound (50 mg, 63%) as a yellow solid. LCMS m / z=426[M+H] + .

[1284] Preparation 297: 2-(4-(6-bromo-7-methoxyquinazolin-4-yl)-3-phenyl-1H-pyrazol-1-yl)-N,N-dimethyl 1-Methylethylamine

[1285]

[1286] NaH (60%, 66.6 mg, 1.67 mmol) was added to a solution 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) in DMF (15 mL), and the mixture was stirred at 50 ° C for 2 h. 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 (100 mg, 10.5%) as a yellow solid. LCMS m / z = 452,454 [M + H] + .

[1287] Preparation 298: tert-Butyl 3-carbamoyl-3-(trifluoromethyl)pyrrolidine-1-carboxylate

[1288]

[1289] To a solution of 1-(tert-butoxycarbonyl)-3-(trifluoromethyl)pyrrolidine-3-carboxylic acid (300 mg, 1.05 mmol) in DCM (10 mL) was added EDCI (256 mg, 1.65 mmol) and HOBt (222 mg, 1.65 mmol), and the mixture was stirred at room temperature for 2 h, followed by addition of NH (35% aqueous solution, 3 mL). The resulting mixture was stirred at room temperature for 1 h 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 grey solid, which was used without further purification.

[1290] Preparation 299: 6-Chloro-4-(1-ethyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-7-methoxypyrido[3,2- d]pyrimidine

[1291]

[1292] Into a 20 mL pressure tank reactor purged and maintained with an inert nitrogen atmosphere was placed 1-ethyl-3-(4-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1...

Claims

1. A compound of formula (A): or a pharmaceutically acceptable salt thereof, wherein X is CR x or N; R x is H or F; L 1 is a bond, NH, -NHC(O)-*, -NHC(O)O-*, O, or -OC(O)-*; where -* indicates attachment to R 1 point; L 2 is a bond or O; R 1 is H; or C1-C4 alkyl optionally substituted by 1 to 4 groups independently selected from the group consisting of halo, deuterium, OR a NR a R b , C3-C6 cycloalkyl, 4 to 12 membered heterocyclyl, and 5 to 10 membered heteroaryl, wherein the heterocyclyl and the 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, wherein R 1 The cycloalkyl, phenyl, heterocyclic and heteroaryl groups represented by 11 The group substitution; Each R 11 are independently selected from halogen, 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)2R a , C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, wherein R 11 The alkyl, cycloalkyl, phenyl, heterocyclic and heteroaryl groups represented by the present invention are each optionally substituted by 1 to 4 groups selected from deuterium, halogen, C1-C4 alkyl, OR a and NR a R b or two R 11 Together they form = O; R 2 yes: H, C1-C4 alkyl, C3-C8 cycloalkyl, C2-C4 alkenyl or C2-C4 alkynyl, each of which is optionally substituted by 1 to 4 groups independently selected from the following: halo, deuterium, OR a NR a R b and 4 to 12 membered heterocyclyl optionally substituted by 1 to 4 groups independently selected from halo, deuterium and C1-C4 alkyl; or 4 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl, wherein R 2 The heterocyclic group and the heteroaryl group represented by are each optionally substituted by 1 to 4 groups selected from the following groups: deuterium, C1-C4 alkyl, C(O)R a and a 4- to 12-membered heterocyclyl group optionally substituted by 1 to 4 groups selected from the group consisting of halogen, deuterium and C1-C4 alkyl; R 3 is connected 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 heterocyclic group, wherein R 3 The alkyl, cycloalkyl and heterocyclic groups represented by a NR a R b and C3-C6 cycloalkyl groups; Each R 4 independently selected from halo, deuterium and OR a ; R 5 is selected from H, deuterium, halo, and C1-C4 alkyl optionally substituted by 1 to 4 groups independently selected from halo, deuterium, OR a NR a R b , C3-C6 cycloalkyl, 4 to 12 membered heterocyclyl, and 5 to 10 membered heteroaryl, wherein the heterocyclyl and the heteroaryl are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium, and C1-C4 alkyl; Each R a independently selected from H, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl and 4 to 6 membered heterocyclyl; Each R b is independently selected from H, deuterium and C1-C4 alkyl; and n is 0, 1, 2, 3, 4 or 5.

2. The compound of claim 1, wherein the compound has formula (B) or formula (C): or a pharmaceutically acceptable salt thereof.

3. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein when L 1 and L 2 When each is a bond, R 1 Yes H, R 2 Not H.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 2 is C1-C4 alkyl, C3-C8 cycloalkyl, C2-C4 alkenyl or C2-C4 alkynyl, each of which is optionally substituted by 1 to 4 groups independently selected from the following: halo, deuterium, OR a NR a R b and 4 to 12 membered heterocyclyl optionally substituted by 1 to 4 groups independently selected from halo, deuterium and C1-C4 alkyl; or 4 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl, wherein R 2 The heterocyclic group and the heteroaryl group represented by are each optionally substituted by 1 to 4 groups selected from the following groups: deuterium, C1-C4 alkyl, C(O)R a and a 4- to 12-membered heterocyclic group optionally substituted by 1 to 4 groups selected from halogen, deuterium and C1-C4 alkyl.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 5 is H, F or methyl.

6. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is CR x or N; R x is H or F; L 1 is a bond, NH, -NHC(O)-*, -NHC(O)O-*, O, or -OC(O)-*; where -* indicates attachment to R 1 point; L 2 is a bond or O; R 1 is H; or C1-C4 alkyl optionally substituted by 1 to 4 groups independently selected from the group consisting of halo, deuterium, OR a NR a R b , C3-C6 cycloalkyl, 4 to 12 membered heterocyclyl, and 5 to 10 membered heteroaryl, wherein the heterocyclyl and the 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, wherein R 1 The cycloalkyl, phenyl, heterocyclic and heteroaryl groups represented by 11 The group substitution; Each R 11 are independently selected from halogen, 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)2R a , C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, wherein R 11 The alkyl, cycloalkyl, phenyl, heterocyclic and heteroaryl groups represented by the present invention are each optionally substituted by 1 to 4 groups selected from deuterium, halogen, C1-C4 alkyl, OR a and NR a R b or two R 11 Together they form = O; R 2 yes: C1-C4 alkyl, C3-C8 cycloalkyl, C2-C4 alkenyl or C2-C4 alkynyl, each of which is optionally substituted by 1 to 4 groups independently selected from the following: halo, deuterium, OR a NR a R b and 4 to 12 membered heterocyclyl optionally substituted by 1 to 4 groups independently selected from halo, deuterium and C1-C4 alkyl; or 4 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl, wherein R 2 The heterocyclic group and the heteroaryl group represented by are each optionally substituted by 1 to 4 groups selected from the following groups: deuterium, C1-C4 alkyl, C(O)R a and a 4- to 12-membered heterocyclyl group optionally substituted by 1 to 4 groups selected from the group consisting of halogen, deuterium and C1-C4 alkyl; R 3 is H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic group, wherein R 3 The alkyl, cycloalkyl and heterocyclic groups represented by a NR a R b and C3-C6 cycloalkyl group substitution; Each R 4 independently selected from halo, deuterium and OR a ; Each R a independently selected from H, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl and 4 to 6 membered heterocyclyl; Each R b is independently selected from H, deuterium and C1-C4 alkyl; and n is 0, 1, 2, 3, 4 or 5.

7. The compound of claim 6, wherein the compound is represented by one of the following structural formulas: or a pharmaceutically acceptable salt thereof.

8. The compound of claim 6, wherein the compound is represented by one of the following structural formulas: or a pharmaceutically acceptable salt thereof.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R x It's H.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein: R 1 is H; or C1-C3 alkyl optionally substituted by 1 to 2 groups independently selected from the group consisting of halo, OR a NR a R b , C 3- C5 cycloalkyl, 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl, wherein the heterocyclyl and the heteroaryl are each optionally substituted with 1 to 2 groups independently selected from halo and -CH3; or C3-C8 cycloalkyl, phenyl, 4- to 9-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein R 1 The cycloalkyl, phenyl, heterocyclic and heteroaryl groups in the group represented by are each optionally substituted by 1 to 3 groups independently selected from R 11 and Each R a are independently H or -CH3; and each R b It is -CH3.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: R 1 is H; or R 1 Selected from -CH3, -CH2CH3, -CH2CH3CH3 and -CH(CH3)2, each of which is optionally substituted by 1-3 groups selected from the following: F, -OH, -OCH3, -N(CH3)2, cyclopropyl, morpholinyl, oxadiazolyl, oxetanyl, oxazolyl, pyridinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl and triazolyl, wherein the pyridinyl, the thiadiazolyl, the thiazolyl and the triazolyl are each optionally substituted by F, -CH3 or -CH2CH3; or R 1 selected from azabicyclo[3.1.0]hexyl, azetidinyl, 1H-benzo[d]imidazolyl, bicyclo[1.1.1]pentyl, cubanyl, cyclobutyl, cyclopropyl, dihydroisoquinolinyl, dihydropyrrolyl, dihydro-2H-benzo[b][1,4]oxazinyl, dioxepyl, hexahydro-1H-pyrrolazinyl, imidazolidinyl, indazolyl, isoindolinyl, isothiazolyl, morpholinyl, octahydropyrrolo[1,2- a] pyrazinyl, oxabicyclo[3.1.0]hexyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, oxabicyclo[3.3]heptyl, 7-oxa-4-azaspiro[2.5]octyl, oxetanyl, phenyl, piperidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolopyridinyl, tetrahydrofuranyl, tetrahydropyranyl and thiazolyl, each of which is optionally substituted by 1 to 3 independently selected R 11 The group is substituted.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 1 Selected from 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 , 13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: Each R 11 are 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-C4 alkyl, C3-C6 cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, wherein R 11 The alkyl, cycloalkyl, heterocyclic and heteroaryl groups represented by a and NR a R b or two R 11 Together they form = O; Each R a is independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl and 4 to 6 membered heterocyclyl; and Each R b Independently selected from H and C1-C4 alkyl.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein: Each R 11 are 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 , C 1- C3 alkyl, morpholinyl, oxazolyl, oxadiazolyl, oxetanyl, pyridyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl and thiazolyl, wherein R 11 The alkyl, morpholinyl, oxazolyl, oxadiazolyl, oxetanyl, pyridyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl and thiazolyl represented by each are optionally substituted by 1 to 3 groups selected from deuterium, halogen, OR a and NR a R b or two R 11 Together they form = O; Each R a independently selected from H, -CH3, -CH2CH3, -C(CH3)3, and Each R b are independently H or -CH3.

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein each R 11 Independently selected from Cl, F, -OH, -OCH3, -C(O)CH2CH3, -N(CH3)2, -NHC(O)OC(CH3)3, -CH3, -CD3, -CHF2, -CF3, -CH2OH, -CH2OCH3, -CH2-N(CH3)2, -CH2CH3, -CH2CF3, -CH2CH2-N(CH3)2, -CH(CH3)2, -C(CH3)2-OH, or two R attached to the same carbon atom 11 Together they form =O.

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein L 2 It's O.

17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein: R 2 is C1-C4 alkyl, C3-C8 cycloalkyl, C2-C4 alkenyl or C2-C4 alkynyl, each of which is optionally substituted by 1 to 3 independently selected halogen, OR a NR a R b and 4 to 12 membered heterocyclic groups, or 4 to 12 membered heterocyclic groups or 5 to 12 membered heteroaryl groups, wherein R 2 The heterocyclic group and the heteroaryl group represented by are each optionally substituted by 1 to 4 groups selected from the following groups: C1-C4 alkyl, C(O)R a and a 4- to 12-membered heterocyclic group optionally substituted by 1 to 3 groups selected from halo and C1-C4 alkyl; Each R a is independently selected from H and C1-C4 alkyl; and Each R b Independently selected from H and C1-C4 alkyl.

18. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein: R 2 is C1-C3 alkyl, C3-C5 cycloalkyl or C 3- C4 alkynyl, each of which is optionally substituted by 1 to 2 independently selected from halogen, OR a NR a R b and 4 to 6 membered heterocyclic groups, or 5 to 7 membered heterocyclic groups or 5 to 6 membered heteroaryl groups, wherein R 2 The heterocyclic group and the heteroaryl group in the group represented by are each optionally substituted by 1 to 2 groups selected from the following groups: C1-C2 alkyl, C(O)R a and a 6-membered heterocyclic group optionally substituted by a C1-C2 alkyl group; Each R a are independently selected from H and -CH3; and Each R b It is -CH3.

19. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein: R 2 is -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl or each of which is optionally substituted with F, -OCH3, -N(CH3)2, morpholinyl or oxetanyl; or R 2 is diazaspiro[3.3]heptyl, pyrazolyl, pyrimidinyl or tetrahydrofuranyl, each of which is optionally substituted with C1-C2 alkyl, C(O)C1-C4 alkyl or piperidinyl optionally substituted with -CH3.

20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein: R 2 is -CH3, -CHF2, -CH2CH3, -CH2CH2-OCH3, -CH2CH2-N(CH3)2, -CH(CH3)2, cyclopropyl, or R 2 yes Each of which is optionally replaced by -CH3, C(O)CH3 or replace.

21. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein: R 3 is H, C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic group, wherein R 3 The alkyl, cycloalkyl and heterocyclic groups represented by are each optionally substituted by 1 to 3 groups independently selected from the following: halogen, deuterium, OR a NR a R b and C 3- C6 cycloalkyl; Each R a are independently H or C1-C4 alkyl; and Each R b are independently H or C1-C4 alkyl.

22. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein R 3 is H, cyclopropyl, oxetanyl, tetrahydropyranyl or C1-C3 alkyl optionally substituted by 1 to 3 groups independently selected from halo, deuterium, OH, N(CH3)2 and cyclopropyl.

23. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 22, wherein R 3 Selected from H, -CH3, -CHF2, -CD3, -CH2CH3, -CH2CHF2, -CH2CF3, -CH2CH2-OH, -CH2CH2-N(CH3)2, -CH2CH3CH3, -CH(CH3)2, 24. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein: Each R 4 is halogen or OR a ; Each R a is independently selected from H and C1-C4 alkyl; and n is 0, 1, 2 or 3.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein n is 0.

26. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 25, wherein n is 1 or 2, and each R 4 Independently selected from F and OH.

27. The compound of any one of claims 1-4 or 6-26, wherein the compound is represented by one of the following structural formulas: or a pharmaceutically acceptable salt thereof.

28. The compound of any one of claims 1-4 or 6-26, wherein the compound is represented by one of the following structural formulas: or a pharmaceutically acceptable salt thereof.

29. The compound of claim 27 or 28, wherein: R 1 yes: C1-C4 alkyl optionally substituted by 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is optionally substituted by C1-C2 alkyl, or C3-C8 cycloalkyl, 4- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl, wherein R 1 The cycloalkyl, heterocyclic and heteroaryl groups represented by 11 The group substitution; Each R 11 are independently selected from halo, NR a R b , C3-C6 cycloalkyl and C1-C4 alkyl optionally substituted by 1 to 3 halogen groups, and each R a Independently selected from H and C1-C4 alkyl; R 2 and R 3 are each independently C1-C4 alkyl; and R 4 is a halo group, wherein n is 0, 1 or 2.

30. The compound or pharmaceutically acceptable salt thereof according to any one of claims 27 to 29, wherein: R 1 yes: C1-C2 alkyl optionally substituted by 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted by C1-C2 alkyl, or C3-C5 cycloalkyl, 5-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein R 1 The cycloalkyl, heterocyclic and heteroaryl groups represented by 11 The group substitution; Each R 11 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 Each is independently a C1-C2 alkyl group; R 4 is a halogen group; and n is 0, 1 or 2.

31. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 27 to 30, wherein: R 1 is -CH2CH3 substituted by oxadiazolyl, wherein the oxadiazolyl is optionally substituted by -CH3; or R 1 is selected from azabicyclo[3.1.0]hexyl, bicyclo[1.1.1]pentyl, cyclopropyl, 3-oxabicyclo[3.1.0]hexyl, piperidinyl, pyrazolyl and pyridinyl, each of which is optionally substituted by 1 to 2 independently selected R 11 The group substitution, Each R 11 independently selected from F, -N(CH3)2, -CH3, -CF3, 32. A compound according to any one of claims 27 to 31 or a pharmaceutically acceptable salt thereof, Where R 1 Selected from And each R 11 independently selected from F, -N(CH3)2, -CH3, -CF3, 33. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 27 to 32, wherein: R 2 is a C1-C4 alkyl group; R 3 is a C1-C4 alkyl group; Each R 4 are independently halo; and n is 0, 1 or 2.

34. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 27 to 33, wherein: R 2 is -CH3 or -CH2CH3; R 3 is -CH3; R 4 is F; and n is 0 or 1.

35. A compound as described in any one of claims 6, 9 and 16-26, wherein the compound is represented by formula (III): or a pharmaceutically acceptable salt thereof.

36. The compound of any one of claims 6 and 16-26, wherein the compound is represented by formula (III-1) or formula (III-2): or a pharmaceutically acceptable salt thereof.

37. The compound of claim 35 or 36 or a pharmaceutically acceptable salt thereof, wherein L 2 is the key.

38. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof.

39. A method for treating cancer, comprising administering to a subject in need thereof an effective amount of the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 38.

40. The method of claim 39, wherein the cancer is lung cancer, colon cancer, urothelial cancer, breast cancer, prostate cancer, brain cancer (glioma), ovarian cancer, gastric cancer, pancreatic cancer, head and neck cancer, bladder cancer, or mesothelioma.

41. The method of claim 39, wherein the cancer is non-small cell lung cancer.

42. The method of any one of claims 39-41, wherein the cancer in the subject in need thereof has metastasized.

43. The method of any one of claims 39-42, wherein the cancer is characterized by an epidermal growth factor receptor (EGFR) L858R mutation.

44. The method of any one of claims 39-42, wherein the cancer is characterized by epidermal growth factor receptor (EGFR) exon 19 deletion.

45. The method of any one of claims 39-44, wherein the cancer is further characterized by an epidermal growth factor receptor (EGFR) C797S mutation.

46. ​​The method of any one of claims 39-45, wherein the cancer is further characterized by an epidermal growth factor receptor (EGFR) T790M mutation.

47. The method of any one of claims 39-46, further comprising administering to the subject in need thereof an effective amount of afatinib or osimertinib.

48. A method of inhibiting epidermal growth factor receptor (EGFR), the method comprising administering to a subject in need thereof an effective amount of the compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 38.

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