Ire1 degrader compounds and methods of use

Abstract

Provided here are IRE1 degrader compounds comprising a protein target moiety covalently attached by a linker to an E3 ubiquitin ligase-binding moiety. Also provided are intermediate compositions for the preparation of IRE 1 degrader compounds and methods of treating diseases and disorders such as cancer with the IRE1 degrader compounds.

Description

[0001] IRE1 DEGRADER COMPOUNDS AND METHODS OF USE

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U. S. Provisional Application No.

[0004] 63 / 736,041, filed December 19, 2024, and U. S. Provisional Application No. 63 / 767,321, filed on March 5, 2025, the content of each of which is incorporated by reference in its entirety.

[0005] FIELD

[0006] The invention relates generally to bifunctional compounds comprising a target protein binding moiety and an E3 ubiquitin ligase binding moiety, and associated methods of use. The bifunctional compounds are useful as modulators of targeted ubiquitination, especially with respect to IRE1 which are degraded and / or otherwise inhibited by bifunctional compounds according to the present disclosure.

[0007] BACKGROUND

[0008] The Unfolded Protein Response (UPR) sensor IRE la plays an important pathological role in multiple myeloma (MM), based on its known involvement in plasma cell differentiation and in supporting immunoglobulin protein secretion (Wang, M.; Kaufman, R. J. “The impact of the endoplasmic reticulum protein-folding environment on cancer development” (2014) Nat. Rev. Cancer 14:581-597). Inositol requiring enzyme 1-alpha (IREla) is an ER-resident protein, consisting of a luminal domain, a transmembrane domain, and a cytoplasmic kinase-RNase enzymatic module. Genetic and pharmacological evidence has been reported validating IREl as a potential therapeutic target for MM and demonstrating that allosteric inhibition of its RNase activity through the kinase ATP -binding pocket blocks in vitro and in vivo growth of MM tumor xenografts (Harnoss, J. M., et al. “Disruption of IREla through its kinase domain attenuates multiple myeloma” Proc. Natl. Acad. Sci. U. S. A. (2019) 116:16420-16429). IRE1 alpha inhibitors have been reported with activity in a Multiple Myeloma model (Braun, M-G., et al. “Discovery of Potent, Selective, and Orally Available IREla Inhibitors Demonstrating Comparable PD Modulation to IRE1 Knockdown in a Multiple Myeloma Model” (2024) J. Med. Chem. 67(ll):8708-8729; WO 2018166528; WO 2017201449; WO 2020252165; WO 2020056061; WO 2020056089).

[0009] Human E3 ubiquitin ligases confer substrate specificity for ubiquitination and are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates. One E3 ligase with therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor, the substrate recognition subunit of the E3 ligase complex VCB, which also consists of elongins B and C, Cul2 and Rbxl. The primary substrate of VHL is Hypoxia Inducible Factor la (HIF-la), a transcription factor that upregulates genes such as the pro-angiogenic growth factor VEGF and the red blood cell inducing cytokine erythropoietin in response to low oxygen levels. The Von Hippel-Lindau (VHL) protein is among the most widely recruited E3 ligases for protein degradation. Many potent small-molecule VHL binders feature a (A)-hydroxyproline motif (Buckley, D. L.; et al. J. Am. Chem. Soc. (2012) 134 (10):4465-4468; Galdeano, C.; et al. J. Med. Chem. (2014) 57 (20), 8657-8663; Testa, A.; et al. J. Am. Chem. Soc. (2018) 140 (29), 9299-9313; Han, X.; et al. J. Med. Chem. (2019) 62 (24), 11218-11231) which forms an interaction with Seri 10 in the HIF la binding site of VHL but limits passive transport across the cell membrane (Klein, V. G.; et al. ACS Med. Chem. Lett. (2020) 11 (9), 1732-1738; Han, X.; et al. Cell Rep. Phys. Set. (2022) 3 (10): 101062; Shah, R. R.; et al. Bioorg. Med. Chem. (2020) 28 (5), 115326; Diehl, C. J. et al. Chem. Soc. Rev. (2022) 51 (19):8216).

[0010] Bifunctional compounds with a VHL E3 ubiquitin ligase binding moiety and a target protein binding moiety function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation (US 2015 / 0291562; US 2014 / 0356322). In particular, bifunctional or proteolysis targeting chimeric (PROTAC) compounds modulate targeted ubiquitination of a variety of polypeptides and other proteins, which are then degraded and / or otherwise inhibited by the bifunctional compounds. Targeted degradation of pathogenic proteins (TPD) using small molecule degraders is a new modality in the treatment of diseases, including redirecting the activity of E3 ligases such as cereblon (CRBN) or VHL. Proteolysis targeting chimera compounds called PROTAC (Sakamoto, K. M., et al. (2001) Proc. Natl. Acad. Set. USA 98:8554-8559; Sun, X. et al. (2019) Signal Transduct. Target. Ther. 4:64; Schapira, M., et al. (2019) Nat. Rev. DrugDiscov. 18:949-963) and “molecular glue” compounds (Yang, Z., et al. (2021) Cell Research 31:1315-1318; Tan, X. et al. (2007) Nature 446:640-645; Han, T. et al. (2017) Science 356, eaal3755) are two modes of TPD. PROTAC comprise three parts, including a ligand for binding a target protein, another ligand for recruiting an E3 ligase, and a linker to help anchor the target protein to the E3 ubiquitin ligase to promote its ubiquitination and subsequent proteasomal degradation. Protein degraders which ligand the E3 ligase in a covalent manner offer potential advantages over their reversible counterparts by transforming the ternary complex into a simple binary interaction between modified E3 and the substrate.

[0011] An ongoing need exists in the art for effective treatments for disease associated with overexpression, aggregation, and / or overactivation of IREl. Small-molecule therapeutic agents that target IREl and that leverage or potentiate VHL substrate specificity would be very useful. Targeted therapeutic agents to treat hyperproliferative disorders like cancer, and other disease are of interest.

[0012] SUMMARY

[0013] The present disclosure relates to compounds having the formula:

[0014] PTBM-L-E3BM

[0015] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or solvate thereof, wherein:

[0016] the PTBM is an IRE 1 -binding moiety;

[0017] the L is a chemical linking moiety connecting the PTBM and the E3BM; and

[0018] the E3BM is an E3 ubiquitin ligase-binding moiety.

[0019] In one aspect, provided herein are compounds that are useful as IRE1 targeted protein degraders.

[0020] In another aspect provided are methods for making the compounds and intermediates thereof.

[0021] In another aspect, provided herein is a pharmaceutical composition comprising a compound as described herein and a pharmaceutically acceptable excipient.

[0022] In another aspect, provided herein is a method for treating a disease or disorder mediated, at least in part, by IRE1 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition.

[0023] Further provided are methods for treating a disease or disorder such as cancer comprising administering a therapeutically effective amount of a compound or a pharmaceutical composition as described herein to a subject in need thereof.

[0024] The disclosure also provides uses of the compounds or compositions as described herein in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated by, or mediated at least in part, by, IRE1.

[0025] DETAILED DESCRIPTION

[0026] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the invention as defined by the claims.

[0027] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The invention is in no way limited to the methods and materials described.

[0028] DEFINITIONS

[0029] “Alkyl” refers to a straight (linear) or branched, saturated, aliphatic radical having the number of carbon atoms indicated. Alkyl can include any number of carbons, for example from one to six, one to eight, one to twelve, one to twenty, or one to forty. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2 -m ethyl- 1 -propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1 -pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2 -pentyl (-CH(CH3)CH2CH2CH3), 3 -pentyl (-CH(CH2CH3)2), 2-methyl-2 -butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3 -methyl- 1 -butyl (-CH2CH2CH(CH3)2), 2-methyl-l -butyl (-CH2CH(CH3)CH2CH3), 1 -hexyl (-CH2CH2CH2CH2CH2CH3), 2 -hexyl (-CH(CH3)CH2CH2CH2CH3), 3 -hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3 -methyl-3 -pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3 -pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-04(043)0(043)3, 1-heptyl, 1-octyl, and the like. Alkyl groups can be substituted or unsubstituted. “Substituted alkyl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, oxo (=0), alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0030] The term “alkyldiyl” refers to a divalent alkyl radical. Examples of alkyldiyl groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and the like. An alkyldiyl group may also be referred to as an “alkylene” group.

[0031] “Alkenyl” refers to a straight (linear) or branched, unsaturated, aliphatic radical having the number of carbon atoms indicated and at least one carbon-carbon double bond, spl. Alkenyl can include from two to about 12 or more carbons atoms. Alkenyl groups are radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. Examples include, but are not limited to, ethylenyl or vinyl (-CH=CH2), allyl (-CEECEtCEE). butenyl, pentenyl, and isomers thereof. Alkenyl groups can be substituted or unsubstituted. “Substituted alkenyl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, oxo (=0), alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0032] The terms “alkenylene” or “alkenyldiyl” refer to a linear or branched-chain divalent hydrocarbon radical. Examples include, but are not limited to, ethylenylene or vinylene (-CH=CH-), allyl (-CH2CH=CH-), and the like.

[0033] “Alkynyl” refers to a straight (linear) or branched, unsaturated, aliphatic radical having the number of carbon atoms indicated and at least one carbon-carbon triple bond, sp. Alkynyl can include from two to about 12 or more carbons atoms. For example, C2-C6 alkynyl includes, but is not limited to ethynyl (-CACH), propynyl (propargyl, -CH2CACH), butynyl, pentynyl, hexynyl, and isomers thereof Alkynyl groups can be substituted or unsubstituted. “Substituted alkynyl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, oxo (=0), alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0034] The term “alkynylene” or “alkynyldiyl” refer to a divalent alkynyl radical.

[0035] " Heteroalkyl" or “heteroalkylene” refer to a monovalent, straight or branched chain alkyl group, as defined above, comprising at least one heteroatom including but not

[0036] limited to Si, N, O, P or S within the alkyl chain or at a terminus of the alkyl chain. In some embodiments, a heteroatom is within the alkyl chain. In other embodiments, a heteroatom is at a terminus of the alkylene and thus serves to join the alkyl to the

[0037] remainder of the molecule. In some embodiments, a heteroalkyl group may have 1 to 12 carbon atoms (C1-C12 heteroalkyl). In some embodiments, a heteroalkyl group may have 1 to 24 carbon atoms (C1-C24 heteroalkyl). In some embodiments, a heteroalkyl group may have 1 to 40 carbon atoms (C1-C40 heteroalkyl) or 1-60 carbon atoms (Ci-Ceo heteroalkyl). Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted. For example, heteroalkyl groups can be substituted with 1-6 fluoro (F) substituents, for example, on the carbon backbone (as -CHF- or -CF2-) or on terminal carbons of straight chain or branched heteroalkyls (such as -CHF2 or -CF3). Examples of heteroalkyl groups include, but are not limited to, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -C(=O)NHCH2CH2NHCH3, -C(=O)N(CH3)CH2CH2N(CH3)2, -C(=O)NHCH2CH2NHC(=O)CH2CH3, -C(=O)N(CH3)CH2CH2N(CH3)C(=O)CH2CH3, -OCH2CH2CH2NH(CH3), -OCH2CH2CH2N(CH3)2, -OCH2CH2CH2NHC(=O)CH2CH3, -OCH2CH2CH2N(CH3)C(=O)CH2CH3, -CH2CH2CH2NH(CH3), -OCH2CH2CH2N(CH3)2, -CH2CH2CH2NHC(=O)CH2CH3, -CH2CH2CH2N(CH3)C(=O)CH2CH3, -CH2SCH2CH3, -CH2CH2S(O)CH3, -NHCH2CH2NHC(=O)CH2CH3, -CH2CH2S(O)2CH3, - CH2CH2OCF3, and -Si(CH3)3. Up to two heteroatoms may be consecutive, such as, for example, -CH2NHOCH3 and -CH2OSi(CH3)3. A terminal polyethylene glycol (PEG) moiety is a type of heteroalkyl group. Exemplary heteroalkyl groups also include ethylene oxide (e.g., polyethylene oxide), propylene oxide, amino acid chains (i.e., short to medium length peptides such as containing 1-15 amino acids), and alkyl chains connected via a variety of functional groups such as amides, disulfides, ketones, phosphonates, phosphates, sulfates, sulfones, sulfonamides, esters, ethers, -S-, carbamates, ureas, thioureas, anhydrides, or the like (including combinations thereof). In some embodiments, a heteroalkyl group includes a poly amino acid having 1-10 amino acids. In some embodiments, a heteroalkyl group includes a polyamino acid having 1-5 amino acids.

[0038] Heteroalkyl groups include a solubilizing unit comprising one or more groups of polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof.

[0039] " Heteroalkenyl" refers to a heteroalkyl group, as defined above, that contains at least one carbon-carbon double bond. " Heteroalkynyl" refers to a heteroalkyl group, as defined above, that contains at least one carbon-carbon triple bond.

[0040] “Heteroalkyldiyl” refers to a divalent form of a heteroalkyl group as defined above. In some embodiments, a heteroalkyldiyl group may have 1 to 12 carbon atoms (Ci-C12 heteroalkyldiyl). In some embodiments, a heteroalkyldiyl group may have 1 to 24 carbon atoms (C1-C24 heteroalkyldiyl). In some embodiments, a heteroalkyldiyl group may have 1 to 40 carbon atoms (C1-C40 heteroalkyldiyl) or 1-60 carbon atoms (Ci-Ceo heteroalkyldiyl). Examples of heteroalkyldiyl groups include, but are not limited to, -CH2CH2OCH2-, -CH2CH2OCF2-, -CH2CH2NHCH2-, -CH2OC(=O)NH- -CH2OP(=O)(OH)OCH2-, -C(=O)NHCH2CH2NHCH2-, -C(=O)N(CH3)CH2CH2N(CH3)CH2-, -C(=O)NHCH2CH2NHC(=O)CH2CH2-, -C(=O)N(CH3)CH2CH2N(CH3)C(=O)CH2CH2-, -OCH2CH2OCH2CH2-, -OCH2CH2OCH2C(=O)-, -OCH2CH2OCH2CH2C(=O)-, -OCH2CH2NHCH2-, -OCH2CH2N(CH3)CH2-, -OCH2CH2CH2NHCH2-, -OCH2CH2CH2N(CH3)CH2-, -OCH2CH2CH2NHC(=O)CH2CH2-, -OCH2CH2CH2N(CH3)C(=O)CH2CH2-, -CH2CH2CH2NHCH2—, -CH2CH2CH2N(CH3)CH2-, -CH2CH2CH2NHC(=O)CH2CH2-, -CH2CH2CH2N(CH3)C(=O)CH2CH2-, -CH2CH2NHC(=O)-, -CH2CH2N(CH3)CH2-, - CH2CH2N+(CH3)2-, -NHCH2CH2(NH2)CH2- and -NHCH2CH2(NHCH3)CH2-. A divalent polyethylene glycol (PEG) moiety with one to about 50 units of-OCH2CH2- is a type of heteroalkyldiyl group. “Heteroalkenyldiyl” refers to a divalent form of a heteroalkenyl group. “Heteroalkynyldiyl” refers to a divalent form of a heteroalkynyl group.

[0041] The terms “carbocycle”, “carbocyclyl”, “carbocyclic ring” and “cycloalkyl” refer to a saturated or partially unsaturated, monocyclic, fused bicyclic, bridged polycyclic ring, or linked by a bond to form a bicyclic assembly containing from 3 to 20 ring carbon atoms, or the number of carbon atoms indicated. Saturated monocyclic carbocyclic rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. Saturated bicyclic and polycyclic carbocyclic rings include, for example, norbomyl, [2.2.2] bicyclooctanyl, decahydronaphthalyl and adamantyl. Carbocyclic groups can also be partially unsaturated, having one or more double or triple bonds in the ring. Representative carbocyclic groups that are partially unsaturated include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl (1,3- and 1,4-isomers), cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl (1,3-, 1,4- and 1,5-isomers), norbomenyl, and norbomadienyl.

[0042] The term “cycloalkyldiyl” refers to a divalent cycloalkyl radical.

[0043] “Aryl” refers to a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms (Ce-C2o) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene linking group. Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl.

[0044] The terms “arylene” or “aryldiyl” mean a divalent aromatic hydrocarbon radical of 6-20 carbon atoms (Ce-C2o) derived by the removal of two hydrogen atom from a two carbon atoms of a parent aromatic ring system. Some aryldiyl groups are represented in the exemplary structures as “Ar”. Aryldiyl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical aryldiyl groups include, but are not limited to, radicals derived from benzene (phenyldiyl), substituted benzenes, naphthalene, anthracene, biphenylene, indenylene, indanylene, 1,2-dihydronaphthalene, 1, 2,3,4-tetrahydronaphthyl, and the like. Aryldiyl groups are also referred to as “arylene”, and are optionally substituted with one or more substituents described herein. The terms “heterocycle,” “heterocyclyl” and “heterocyclic ring” are used interchangeably herein and refer to a saturated or a partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) carbocyclic radical of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, where one or more ring atoms is optionally substituted independently with one or more substituents described below. Heterocycles can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biheterocyclic such as the 4-(piperidin-4-yl)piperazine group:

[0045]

[0046] A heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system. Heterocycles are described in Paquette, Leo A.; “Principles of Modem Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. “Heterocyclyl” also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, morpholin-4-yl, piperidin-l-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-l-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azocan- 1-yl, azetidin-l-yl, octahydropyrido[l,2-a]pyrazin-2-yl, [l,4]diazepan-l-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl quinolizinyl and N-pyridyl ureas. Spiro heterocyclyl moieties are also included within the scope of this definition.

[0047] Examples of spiro heterocyclyl moieties include azaspiro[2.5]octanyl and azaspiro[2.4]heptanyl. Examples of a heterocyclic group wherein 2 ring atoms are substituted with oxo (=0) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocycle groups herein are optionally substituted independently with one or more substituents described herein. The term “heterocyclyldiyl” refers to a divalent, saturated or a partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) carbocyclic radical of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, where one or more ring atoms is optionally substituted independently with one or more substituents as described. Examples of 5-membered and 6-membered heterocyclyldiyls include morpholinyldiyl, piperidinyldiyl, piperazinyldiyl, pyrrolidinyldiyl, dioxanyldiyl, thiomorpholinyldiyl, and S-dioxothiomorpholinyldiyl.

[0048] The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-, or 7-membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heteroaryls can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biheteroaryl such as the 4-(pyrazol-3-yl)pyridine group:

[0049]

[0050] Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadi azolyl, thiadi azolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups are optionally substituted independently with one or more substituents described herein.

[0051] The term “heteroaryldiyl” refers to a divalent aromatic radical of 5-, 6-, or 7-membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of 5-membered and 6-membered heteroaryl diyls include pyridyldiyl, imidazolyldiyl, pyrimidinyldiyl, pyrazolyl diyl, tri azolyl diyl, pyrazinyldiyl, tetrazolyl diyl, furyldiyl, thienyldiyl, isoxazolyl diyl diyl, thiazolyl diyl, oxadi azolyl diyl, oxazolyl diyl, isothiazolyl diyl, and pyrrolyl diyl.

[0052] The heterocycle or heteroaryl groups may be carbon (carbon-linked), or nitrogen (nitrogen-linked) bonded where such is possible. By way of example and not limitation, carbon bonded heterocycles or heteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.

[0053] By way of example and not limitation, nitrogen bonded heterocycles or heteroaryls are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, IH-indazole, position 2 of a isoindole, or isoindolinone, position 4 of a morpholine, and position 9 of a carbazole, or P-carboline.

[0054] The terms “halo”, “halide” and “halogen,” by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0055] The term “carbonyl,” by itself or as part of another substituent, refers to C(=O) or -C(=O)-, i.e., a carbon atom double-bonded to oxygen and bound to two other groups in the moiety having the carbonyl.

[0056] As used herein, the phrase “quaternary ammonium salt” refers to a tertiary amine that has been quaternized with an alkyl substituent (e.g., a C1-C4 alkyl such as methyl, ethyl, propyl, or butyl).

[0057] The term “fused” refers to a ring which is joint to an adjacent ring and share two adjacent ring atoms that form a covalent bond.

[0058] The term “bridged” refers to a ring fusion wherein non-adjacent atoms on a ring are joined by a divalent substituent, such as alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems.

[0059] The term or prefix “spiro” refers to a ring substituent which is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1 -di ethylcyclopentane, dimethyldioxolane, and 4-benzyl-4- methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents.

[0060] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen. “Optionally substituted” may be zero to the maximum number of possible substitutions, and each occurrence is independent. When the term “substituted” is used, then that substitution is required to be made at a substitutable hydrogen atom of the indicated substituent. An optional substitution may be the same or different from a (required) substitution.

[0061] The term "chiral" refers to molecules which have the property of non-superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.

[0062] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0063] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., " Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0064] " Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.

[0065] " Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0066] The term "salt" refers to acid or base salts of the compounds of the disclosed herein. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Pharmaceutically acceptable salts of the acidic compounds disclosed herein are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts. Similarly acid addition salts, such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure. The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0067] Any compound or Formula given herein, is intended to represent unlabeled forms as well as isotopically labeled forms of the compounds (i.e., "isotopic analogs"). Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,13N,15N,150,17O,18O,31P,32P,35S,18F,36C1,123I and125I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as3H,13C and14C are incorporated. Such isotopically labeled compounds may be useful for enhanced therapeutic activity, in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients. The disclosure also includes "deuterated analogs" of compounds described herein in which from 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium (2H), in which n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, " Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. An18F,3H, or11C labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein. The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as " H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition.

[0068] Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0069] The terms “treat,” “treatment,” and “treating” refer to any indicia of success in the treatment or amelioration of an injury, pathology, condition (e.g., cancer), or symptom (e.g., cognitive impairment), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology, or condition more tolerable to the patient; reduction in the rate of symptom progression; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom. The treatment or amelioration of symptoms can be based on any objective or subjective parameter, including, for example, the result of a physical examination.

[0070] The terms “cancer,” “neoplasm,” and “tumor” are used herein to refer to cells which exhibit autonomous, unregulated growth, such that the cells exhibit an aberrant growth phenotype characterized by a significant loss of control over cell proliferation. Cells of interest for detection, analysis, and / or treatment in the context of the invention include cancer cells (e.g., cancer cells from an individual with cancer), malignant cancer cells, pre-metastatic cancer cells, metastatic cancer cells, and non-metastatic cancer cells. Cancers of virtually every tissue are known. The phrase “cancer burden” refers to the quantum of cancer cells or cancer volume in a subject. Reducing cancer burden accordingly refers to reducing the number of cancer cells or the cancer cell volume in a subject. The term “cancer cell” as used herein refers to any cell that is a cancer cell (e.g., from any of the cancers for which an individual can be treated, e.g., isolated from an individual having cancer) or is derived from a cancer cell, e.g., clone of a cancer cell. For example, a cancer cell can be from an established cancer cell line, can be a primary cell isolated from an individual with cancer, can be a progeny cell from a primary cell isolated from an individual with cancer, and the like. In some embodiments, the term can also refer to a portion of a cancer cell, such as a sub-cellular portion, a cell membrane portion, or a cell lysate of a cancer cell. Many types of cancers are known to those of skill in the art, including solid tumors such as carcinomas, sarcomas, glioblastomas, melanomas, lymphomas, and myelomas, and circulating cancers such as leukemias.

[0071] As used herein, the term “cancer” includes any form of cancer, including but not limited to, solid tumor cancers (e.g., skin, lung, prostate, breast, gastric, bladder, colon, ovarian, pancreas, kidney, liver, glioblastoma, medulloblastoma, leiomyosarcoma, head & neck squamous cell carcinomas, melanomas, and neuroendocrine) and liquid cancers (e.g., hematological cancers); carcinomas; soft tissue tumors; sarcomas; teratomas; melanomas; leukemias; lymphomas; and brain cancers, including minimal residual disease, and including both primary and metastatic tumors.

[0072] The phrases “effective amount” and “therapeutically effective amount” refer to a dose or amount of a substance such as an antibody conjugate that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); Goodman & Gilmans ’ The Pharmacological Basis of Therapeutics, 11thEdition (McGraw-Hill, 2006); and Remington: The Science and Practice of Pharmacy, 22ndEdition, (Pharmaceutical Press, London, 2012)). In the case of cancer, the therapeutically effective amount of the antibody conjugate may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the antibody conjugate may prevent growth and / or kill existing cancer cells, it may be cytostatic and / or cytotoxic. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) and / or determining the response rate (RR) “Recipient,” “individual,” “subject,” “host,” and “patient” are used interchangeably and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired (e.g., humans). “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, camels, etc. In certain embodiments, the mammal is human.

[0073] As used herein, the term “administering” refers to parenteral, intravenous, intraperitoneal, intramuscular, intratumoral, intralesional, intranasal, or subcutaneous administration, oral administration, administration as a suppository, topical contact, intrathecal administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to the subject.

[0074] The terms “about” and “around,” as used herein to modify a numerical value, indicate a close range surrounding the numerical value. Thus, if “X” is the value, “about X” or “around X” indicates a value of from 0.9X to 1.1X, e.g., from 0.95X to 1.05X or from 0.99X to 1.01X. A reference to “about X” or “around X” specifically indicates at least the values X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Accordingly, “about X” and “around X” are intended to teach and provide written description support for a claim limitation of, e.g., “0.98X.”

[0075] IRE1 DEGRADER COMPOUNDS

[0076] The IRE1 degrader compounds of the invention comprise a protein target moiety covalently attached by a linker to an E3 ubiquitin ligase-binding moiety (E3BM). The E3BM is a VHL ligand moiety. The protein target binding moiety (PTBM) modulates IRE1.

[0077] The IRE1 degrader compounds have the formula:

[0078] PTBM-L-E3BM

[0079] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or solvate thereof, wherein:

[0080] the PTBM is an IRE 1 -binding moiety;

[0081] the L is a chemical linking moiety connecting the PTBM and the E3BM; and

[0082] the E3BM is an E3 ubiquitin ligase-binding moiety.

[0083]

[0084] wherein

[0085] dashed lines - indicate attachment of any carbon or nitrogen atom of E3BM to L; Ring B is a 5-membered heteroaryl;

[0086] Y is selected from a bond, C1-C12 alkyl, C1-C12 heteroalkyl, C3-C20 cycloalkyl, and C1-C20 heteroaryl;

[0087] (R6)O

[0088] X is selected from a bond, H, C1-C12 alkyl, a

[0089]

[0090] nd

[0091] Ring A is optionally substituted cyclohexyl or optionally substituted phenyl;

[0092] R1is selected from a bond, H, C1-C12 alkyl, and C3-C20 cycloalkyl;

[0093] R2is selected from H, C1-C12 alkyl, C1-C12 haloalkyl, C1-C12 alkoxy, and -CONR2aR2b, or when X is:

[0094] (R6)O

[0095] -^ A )-R5

[0096] ', then R2together with Ring A form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring;

[0097] R2aand R2bare each independently H or Ci-Ce alkyl, or R2aand R2btogether with the nitrogen atom they are attached to form a heterocyclyl;

[0098] R3is H;

[0099] R5is selected from CN, C1-C12 haloalkyl, and a five-, six-, or seven-membered heteroaryl or heterocyclyl ring;

[0100] each R6is independently selected from hydroxy, halo, CN, C1-C12 haloalkyl, and C1-C12 alkyl; where o is 0, 1 or 2; and

[0101] each alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkoxy, alkynyl, alkynyldiyl, haloalkyl, heteroalkyl, heteroalkyldiyl, aryl, aryldiyl, cycloalkyl, cycloalkyldiyl, haloalkyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryl diyl, is independently and optionally substituted with one or more groups selected from F, Cl, Br, I, -CN, -CH3, -CH2CH3, -CH=CH2, -C=CH, - C =CCH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CH2OP(O)(OH)2, -CH2F, -CHF2, -CF3, -CH2CF3, -CH2CHF2, -CH(CH3)CN, -C(CH3)2CN, -CH2CN, -CH2NH2, -CH2NHSO2CH3, -CH2NHCH3, -CH2N(CH3)2, -CO2H, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, -C0NH2, -C0NHCH3, -CON(CH3)2, - C(CH3)2CONH2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3, -NHS(O)2CH2CH2CF3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, -NHC(=NH)H, -NHC(=NH)CH3, -NHC(=NH)NH2, -NHC(=O)NH2, -NO2, =0, -OH, -OCH3, -OCH2CH3, -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, -0CH2F, -0CHF2, -OCF3, -OP(O)(OH)2, -S(O)2N(CH3)2, -SCH3, -S(O)2CH3, and -S(O)3H.

[0102] In some embodiments, the E3BM is selected from the formulas:

[0103] and

[0104]

[0105] wherein R4is C1-C12 alkyl or C3-C20 cycloalkyl; and

[0106] wherein a dashed line ''' indicates the attachment point in E3BM to the L. In some embodiments, E3BM is:

[0107] In some embodiments, E3BM is:

[0108]

[0109] In some embodiments, E3BM is:

[0110] In some embodiments, E3BM is:

[0111]

[0112] In some embodiments, E3BM is: In some embodiments, E3BM is:

[0113]

[0114] wherein R4is optionally substituted C3-C6 cycloalkyl.

[0115] In some embodiments, E3BM is:

[0116] (R6)O

[0117]

[0118] OH

[0119] In some embodiments, E3BM is:

[0120] (R6)O

[0121]

[0122] OH

[0123] In some embodiments, R4is selected from cyclopropyl and 1 -fluorocyclopropyl. In some embodiments, Ring B is selected from optionally substituted 1,2,3-triazolyl and optionally substituted isoxazolyl.

[0124] In some embodiments, Ring B is substituted with one or more groups independently selected from -CH3, -CH(CH3)2, -C(CH3)3, and optionally substituted cyclopropyl.

[0125] In some embodiments, Y is selected from C1-C12 alkyl and C1-C12 heteroalkyl.

[0126] In some embodiments, Y is C3-C20 cycloalkyl.

[0127] In some embodiments, Y is selected from cyclopropyl and 1-fluorocyclopropyl.

[0128] In some embodiments, X is:

[0129]

[0130] In some embodiments, A is cyclohexyl.

[0131] In some embodiments, A is phenyl.

[0132] In some embodiments, R5is selected from an optionally substituted ring selected from thiazole, pyridine, and pyrazole.

[0133] In some embodiments, R5is thiazole substituted with -CH3.

[0134] In some embodiments, R6is independently selected from F and -CH3, and o is 1 or 2.

[0135]

[0136] In some embodiments, R1is selected from H, -CH3, -CH(CH3)2, and -C(CH3)3. In some embodiments, R2is selected from H, -CH3, -CH(CH3)2, and -C(CH3)3. In some embodiments, R2together with Ring A form a ring selected from cyclopentyl, cyclohexyl, and cycloheptyl.

[0137] In some embodiments, R2together with Ring A form:

[0138]

[0139] In some embodiments, R4is selected from cyclopropyl and 1-fluorocyclopropyl. In some embodiments, L is selected from the group consisting of O, NH, C1-C12 alkyldiyl, Ci-Ceo heteroalkyl diyl, C3-C20 carbocyclyldiyl, C2-C20 heterocyclyldiyl, C6-C20 aryldiyl, C1-C40 heteroaryl diyl, -(C3-C20 carbocyclyldiyl)-(Ci-C6o heteroalkyldiyl)-, -(C3-C20 carbocyclyldiyl)-(Ci-Ci2 alkyldiyl)-, -(C2-C20 heterocyclyldiyl)-(Ci-C6o heteroalkyldiyl)-, -(C2-C20 heterocyclyldiyl)-(Ci-Ci2 alkyldiyl)-, -(C2-C20 heterocyclyldiyl)-(C2-C20 heterocyclyldiyl)-, and -(C1-C20 heteroaryldiyl)-(C3-C20 carbocyclyldiyl)-(Ci-C6o heteroalkyl diyl)-.

[0140] In some embodiments, L is selected from the structures:

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147] o

[0148]

[0149] where the single asterisk * indicates the point of attachment to E3BM, and the double asterisk ** indicates the point of attachment to PTBM.

[0150] In some embodiments, PTBM is selected from the formula:

[0151] R7

[0152]

[0153] wherein

[0154] the dashed line indicates the attachment to L;

[0155] R7is selected from H and C1-C12 alkyl;

[0156] X1and X2are independently selected from H, C1-C12 alkyl, C1-C20 heteroalkyl, C1-C20 heteroaryl and C2-C20 heterocyclyl; or X1and X2together form a five, six, or seven-membered heteroaryl or heterocyclyl ring.

[0157] In some embodiments, X1and X2together form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring.

[0158] In some embodiments, PTBM is selected from the formulas:

[0159]

[0160] wherein R8is selected from H, C1-C12 alkyl, C1-C20 heteroalkyl, C3-C20 carbocyclyl, C6-C20 aryl, and C2-C20 heterocyclyl; and

[0161] each R9is independently selected from H, halide, C1-C12 alkyl, -N(R8)2, -OR8, C1-C20 heteroalkyl, C6-C20 aryl, C3-C20 carbocyclyl, and C2-C20 heterocyclyl.

[0162] In some embodiments, the PTBM is:

[0163]

[0164]

[0165] another embodiment, the

[0166]

[0167] PTBM is

[0168] R7

[0169] In some embodiments, the

[0170]

[0171] PTBM is. In some embodiments, the

[0172]

[0173] In one embodiment, the PTBM is

[0174]

[0175] In some embodiments, R8is H or C1-C12 alkyl. In some embodiments, R8is H. In some embodiments, R8is C1-C12 alkyl. In some embodiments, R8is Ci-Ce alkyl. In some embodiments, R8is C1-C3 alkyl. In one embodiment, R8is methyl. In another embodiment, R8is ethyl. In another embodiment, R8is n-propyl. In another embodiment, R8is i-propyl.

[0176] In some embodiments, each R9is independently selected from H, halide, C1-C12 alkyl, C6-C20 aryl, and C3-C20 carbocyclyl. In some embodiments, each R9is independently selected from H, C1-C12 alkyl, and C6-C20 aryl.

[0177] In some embodiments, one R9is H. In some embodiments, each R9is H. In some embodiments, one R9is: In some embodiments, one R9is H, and another R9is

[0178]

[0179] In some embodiments, the PTBM is selected from:

[0180]

[0181] In some embodiments, one of X1and X2is H and the other is C1-C20 heteroaryl.

[0182] In some embodiments, one of X1and X2is H and the other is selected from pyridinyl and pyrimidinyl.

[0183] In some embodiments, the pyridinyl or pyrimidinyl are substituted with one or more groups selected from -O-(C3-C20 carbocyclyldiyl), -O-(C6-C20 aryl), -O-(C1-C20 heteroaryl), and - O- (C2- C20 heterocyclyl).

[0184] In some embodiments, the pyridinyl or pyrimidinyl are substituted with: - O- (Ce- C20 aryl) where C6-C20 aryl is naphthyl substituted with -NHS(O)2R10; or - O- (C3- C20 carbocyclyldiyl) where C3-C20 carbocyclyldiyl is cyclopropyl substituted with -NHS(O)2R10;

[0185] where R10is selected from the group consisting of C1-C12 alkyl, C1-C20 heteroalkyl, C6-C20 aryl, C3-C20 carbocyclyl, -(C1-C12 alkyldiyl)-(C6-C20 aryl), -(C1-C12 alkyldiyl)— ( C3-C20 carbocyclyl).

[0186] In some embodiments, PTBM is

[0187] R7

[0188] I

[0189]

[0190] wherein R11is -O-(C3-C20 carbocyclyldiyl)-(C1-C6 alkyldiyl)-(C6-C20 aryl).

[0191] In some embodiments, R11is cyclopropyl substituted with -(Ci-Ce alkyldiyl)-(C6-C20 aryl).

[0192] In some embodiments, R11is:

[0193]

[0194] In some embodiments, PTBM is selected from the structures:

[0195]

[0196]

[0197]

[0198]

[0199] wherein any carbon or nitrogen atom of the structures is the point of attachment to L. In some embodiments, the PTBM is attached to L at any carbon or nitrogen that is solvent exposed.

[0200] In some embodiments, PTBM-L is selected from the structures:

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208] where the asterisk * indicates the point of attachment of the PTBM-L to the E3BM.

[0209] In some embodiments, the IRE1 degrader compound is selected from Table 1.

[0210] Exemplary IRE1 degrader compounds of Table 1 were prepared and characterized according to the Examples herein. Each compound in Table 1 was characterized by mass spectrometry and demonstrated to have the correct parent ion and mass. Table 1 Exemplary IRE1 degrader compounds

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217] 1011.3

[0218] o

[0219] T O

[0220] &

[0221] Z I

[0222] p Q, C

[0223] 897.2 0 Z' Z I '

[0224] Z^ y ^ o=

[0225] > Z—

[0226] \ Z —

[0227] z — ' ^ ^ o= Wz

[0228] lZ 1 / \-^ b ^‘■ / o

[0229] zr 884.2 <Z1 o I

[0230] H (Tj

[0231] Y lblX Q. b

[0232] JkN^\

[0233] 0' - k

[0234] 1OH

[0235] H 919.2 Ho^-bX rXW

[0236] THo VXz. U

[0237] ^-NH __ \

[0238] 0

[0239] " \-b \J

[0240] H 919.2 — / , N=NJOANTNINT°

[0241] | \ JL 1 J

[0242] NH _>\

[0243] 0

[0244]

[0245]

[0246]

[0247]

[0248]

[0249] 1228.5 9? X X

[0250] Z« ZC -n nfl TI -n-^-— < \ / \ / \ II ii / \ ✓

[0251] H "" ° — ° ' v < \ /

[0252] / ° /

[0253] x _ N

[0254] V 1229.5 p X z I z* X v> X Q C

[0255] 1 Q z^..0 O=S=O F HN-^

[0256] H" Y\ O A z

[0257] 11 1 i i W °

[0258] \ AXNA JL

[0259] fM °h

[0260] A AVL J CT N N N'N=N ) / —H

[0261] f i z < \ / -> \ z <

[0262] XX°A V z \ _ N 1184.4 _ A

[0263] I

[0264] i A

[0265] 0=S=0 F HN— I HNk x / z_ o

[0266] T il ^J1'AOL.

[0267] L X N A N v' L Jn'n" / / —

[0268] 1 H

[0269] 1184.4

[0270]

[0271]

[0272] 883.2 O X O x o

[0273] y< %.°

[0274] 0

[0275] 00

[0276] Q T z vPP

[0277] Z I ^XO=W Z x°

[0278] \

[0279] X

[0280] ^ ^XO'=OTZ

[0281] 1136.4 o / z.—

[0282] Z.—' '

[0283] 0

[0284] 6

[0285] 0

[0286] X z

[0287] o=\ N _ x 867.2 0C ^z

[0288] <Z1

[0289] 00

[0290] i z\ °= hU 0

[0291] M S L JL ^ N L JL HN1~ o,r O N - ' >H0

[0292] JU

[0293] — iTN>

[0294] 0' — L

[0295] 1OH

[0296] 1180.4

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317] 911.2HV JA

[0318] f r "n rOA

[0319] v

[0320] 0r Y0 NY\ —> (

[0321] 1 OH

[0322] H S881.1

[0323] / Y

[0324] / f| V TN \A o / 'V'^N'^|H0 -V-NH

[0325] Yr r^. / VMYi

[0326] 0o / K \

[0327] 1OH

[0328] H_ _,sr\ 881.1 fNTN"v-i xyv [f y NH 0°^NH

[0329] Yr

[0330] ° ° A \

[0331] 1OH

[0332] Ho Y 1166.4Ff Y Y-N O H-^OH

[0333] H O°^N rHxY i

[0334] OYrYnJ° ^ Y

[0335] H 1152.4

[0336] HAAN-VH 0O^NH,H F

[0337] / S^ 1115.3

[0338] H HrOA

[0339] 0 °^NHN

[0340] ,.. r?. Y -Q

[0341] cY1, 1

[0342]

[0343]

[0344] 854.1

[0345] z z —

[0346] (^= z—

[0347] ' Z I

[0348] 840.1hjTVvN

[0349] NX / Nv^x1

[0350] JUS UhH? UNH

[0351] ) I

[0352] U

[0353] 0OH

[0354] 0 2=

[0355] I z,

[0356] 868.1 H 'o=\;_ / A

[0357] f rAN, NYNyx A\A 1

[0358] Z'\ ° / x

[0359] £1 L UH? °VN 1zH^

[0360] 1 I

[0361] V.. -'ll ’1

[0362] o1V OH o

[0363] HO^H

[0364] 05Vs_

[0365] ^Z

[0366] 951.2 N^HN,,, / S^

[0367] hyNHo °VNH

[0368] FUhNv^ k / Nx^x^x. N^AN / ;

[0369] FF O 1 o 0 / K h

[0370] A OH H OH

[0371] 911.2. NHN,,. fj'' / SAN< yNH oCVNH

[0372] o 1 o A\ ^—Z

[0373] 1OH

[0374] 911.2, N^HN / SA lf yNA<NyLH 0°VNH

[0375] tyy ^N^^fNvANA

[0376] o 1 o A\ 'U

[0377] 1OH

[0378]

[0379] 895.2 rNrNni rOV

[0380] [f y NHOO^NH

[0381] YYl^N^^fNvXNA

[0382] o 1 o A '-V

[0383] 1OH

[0384] H / S“^ 1166.4. N^N,, J — |N

[0385] FH O°^NH

[0386] O7:VnJ° ^ Y

[0387] 923.2 H / S-^

[0388] (| YNH 0 °V-NH

[0389] V / Y T Y =

[0390] vN?

[0391] o 1 o ' — /

[0392] 1OH

[0393] 897.2H1 / SY

[0394] N^Nz, Jj'' V-YyN< yNH 0 °VNH ^N^^YNYNA

[0395] o 1 o / k '~Y

[0396] 1OH

[0397] 911.2H\ / / S~^

[0398] [f TNH 0 °VNH

[0399] lyNy

[0400] o 1 o Y\L~~ /

[0401] 1OH

[0402] 909.2H / S~^ N^N,,.^^ r^\ J ^ TN[f y N H O °VNH

[0403] 1yNYl^N^^fNvAN^

[0404] o 1 o Y\

[0405] 1OH

[0406]

[0407] H _,S~ft 895.2

[0408] A / Nho VNH

[0409] o 1 o / k

[0410] 1OH

[0411] H |_i S— n 881.2

[0412] if lNH O °VNH

[0413] 00 / k

[0414] 1OH

[0415] 840.1 _ 7S~^

[0416] H / / V''ZUN

[0417] NV / Nvx\ / " \=V T XJ Uhh? VNH

[0418] Vr '— rX’l

[0419] 0OH

[0420] ^YN H^. OH 854.1

[0421] hr0'1- '" h?..

[0422] 0° UU 1

[0423] — Y N

[0424] 868.2 _ 7S~^

[0425] H / / V^VN

[0426] JL NN VN rH\^ T

[0427] kU H O

[0428] Vr -~^ Y 7

[0429] 0OH

[0430] H 1152.4

[0431] <v- -pF / r° ui

[0432] rr> N v "^N^ »hX °,

[0433] H F9

[0434]

[0435]

[0436] Certain exemplary IRE1 degrader compounds of Table 1 were tested for their target protein degradation effects in the IRE-1 MSD Assay of Example 201 by measuring the IRE1 levels in RPMI 8226 IRE1 sh5-l cell lysates through an antibody sandwich assay. DC50 and Sinf % values were measured and reported as bracketed data in Table 2. The DC50 is a measure of potency and is the concentration at which 50% of the target protein is degraded. RPMI-8226-IRE1 MSD DC50 (pM) activity of groups: Al < 0.5 uM; Bl 0.5 - 1 uM; Cl 1 - 5 uM; and DI > 5 uM. RPMI-8226-IRE1 MSD Sinf (%) activity of groups: A2 < -90%; B2 -90% - -60%; C2 - 60% - -30%; and D2 > -30%. N / A denotes inactive compounds for which Sinf was not reported. Compounds in Table 2 in groups Al and A2 were the most potent. Table 2 Activity of Table 1 IRE1 degrader compounds Ex. No. RPMI-8226-IRE1 MSD RPMI-8226-IRE1 MSD DC50 Sinf

[0437] 1 Al D2

[0438] 2 DI A2

[0439] 3 Bl B2

[0440] 4 DI D2

[0441] 5 Bl B2

[0442] 6 Bl B2

[0443] 7 DI A2

[0444] 8 Bl B2

[0445] 9 Cl A2

[0446] 10 Al C2

[0447] 11 DI A2

[0448] 12 Bl C2

[0449] 13 DI A2

[0450] 14 DI D2

[0451] 15 Bl A2

[0452] 16 DI A2

[0453] 17 Cl A2

[0454] 18 DI A2

[0455] 19 Cl A2

[0456] 20 Bl C2

[0457] 21 DI D2

[0458] 22 Al B2

[0459] 23 Bl A2

[0460] 24 Bl B2

[0461] 25 Al A2

[0462] 26 Cl A2

[0463] 27 Al A2

[0464]

[0465] Ex. No. RPMI-8226-IRE1 MSD RPMI-8226-IRE1 MSD DC50 Sinf

[0466] 28 Al A2

[0467] 29 Al A2

[0468] 30 Al C2

[0469] 31 Al C2

[0470] 32 Al B2

[0471] 33 DI D2

[0472] 34 Al A2

[0473] 35 Bl B2

[0474] 36 Al A2

[0475] 37 Al C2

[0476] 38 Al A2

[0477] 39 Al C2

[0478] 40 Al B2

[0479] 41 Al B2

[0480] 42 Al B2

[0481] 43 Al B2

[0482] 44 Al B2

[0483] 45 Al B2

[0484] 46 Al B2

[0485] 47 Al A2

[0486] 48 Cl C2

[0487] 49 Al B2

[0488] 50 Al A2

[0489] 51 Al B2

[0490] 52 DI C2

[0491] 53 Bl B2

[0492] 54 Bl A2

[0493] 55 Bl B2

[0494]

[0495] Ex. No. RPMI-8226-IRE1 MSD RPMI-8226-IRE1 MSD DC50 Sinf

[0496] 56 Bl C2

[0497] 57 DI A2

[0498] 58 Cl A2

[0499] 59 Al A2

[0500] 60 Al A2

[0501] 61 Bl A2

[0502] 62 Al A2

[0503] 63 Cl A2

[0504] 64 Al B2

[0505] 65 Al B2

[0506] 66 DI A2

[0507] 67 Cl A2

[0508] 68 Bl A2

[0509] 69 Cl A2

[0510] 70 Cl A2

[0511] 71 Al A2

[0512] 72 Bl A2

[0513] 73 Cl B2

[0514] 74 DI A2

[0515] 75 Al C2

[0516] 76 Cl A2

[0517] 77 DI A2

[0518] 78 Cl A2

[0519] 79 Cl A2

[0520] 80 Bl A2

[0521] 81 DI D2

[0522] 82 Al B2

[0523] 83 Bl B2

[0524]

[0525] Ex. No. RPMI-8226-IRE1 MSD RPMI-8226-IRE1 MSD DC50 Sinf

[0526] 84 Al A2

[0527] 85 DI A2

[0528] 86 Al B2

[0529] 87 Al C2

[0530] 88 Al A2

[0531] 89 Al C2

[0532] 90 Al A2

[0533] 91 Al A2

[0534] 92 Al A2

[0535] 93 Al A2

[0536] 94 Al A2

[0537] 95 DI A2

[0538] 96 DI A2

[0539] 97 DI A2

[0540] 98 DI A2

[0541] 99 DI A2

[0542] 100 Bl C2

[0543] 101 DI D2

[0544] 102 Cl B2

[0545] 103 Al A2

[0546] 104 Al D2

[0547] 105 DI A2

[0548] 106 Al A2

[0549] 107 DI A2

[0550] 108 Al A2

[0551] 109 DI A2

[0552] 110 DI D2

[0553] 111 DI D2

[0554]

[0555] Ex. No. RPMI-8226-IRE1 MSD RPMI-8226-IRE1 MSD DC50 Sinf

[0556] 112 DI D2

[0557] 113 Cl A2

[0558] 114 DI D2

[0559] 115 DI D2

[0560] 116 DI A2

[0561] 117 DI D2

[0562] 118 DI A2

[0563] 119 DI D2

[0564] 120 Cl D2

[0565] 121 DI A2

[0566] 122 DI A2

[0567] 123 DI A2

[0568] 124 Cl B2

[0569] 125 Cl B2

[0570] 126 DI D2

[0571] 127 DI D2

[0572] 128 Al A2

[0573] 129 Al A2

[0574] 130 DI D2

[0575] 131 DI D2

[0576] 132 DI D2

[0577] 133 DI A2

[0578] 134 DI A2

[0579] 135 Cl A2

[0580] 136 Bl A2

[0581] 137 DI A2

[0582] 138 Bl A2

[0583] 139 DI D2

[0584]

[0585] PHARMACEUTICAL COMPOSITIONS OF IRE1 DEGRADER COMPOUNDS Provided herein are pharmaceutically or pharmacologically acceptable compositions or formulations, comprising a therapeutically effective amount of an IRE1 degrader compound of as described herein and a pharmaceutically acceptable diluent, vehicle, carrier or excipient.

[0586] In some embodiments, the pharmaceutical compositions comprises a pharmaceutically acceptable salts, in particular, acid or base addition salts of an IRE1 degrader compound. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds useful according to this embodiment are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., l,l'-methylene-bis-(2 -hydroxy-3 naphthoate)] salts, among numerous others.

[0587] In some embodiments, the pharmaceutical composition may be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, including transdermally, in liquid, cream, gel, or solid form, or by aerosol form. In some embodiments, the pharmaceutical composition may be administered in single or divided doses by the oral, parenteral or topical routes. Administration of the active compound may range from continuous (intravenous drip) to several oral administrations per day (for example, Q. I. D.) and may include oral, topical, parenteral, intramuscular, intravenous, sub-cutaneous, transdermal (which may include a penetration enhancement agent), buccal, sublingual and suppository administration, among other routes of administration. Enteric coated oral tablets may also be used to enhance bioavailability of the compounds from an oral route of administration. The most effective dosage form will depend upon the pharmacokinetics of the particular agent chosen as well as the severity of disease in the patient. Administration of compounds according to the present disclosure as sprays, mists, or aerosols for intra-nasal, intra-tracheal or pulmonary administration may also be used. The present disclosure therefore also is directed to pharmaceutical compositions comprising an effective amount of an IRE1 degrader compound, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. Pharmaceutical composition may be administered in immediate release, intermediate release or sustained or controlled release forms. Sustained or controlled release forms are preferably administered orally, but also in suppository and transdermal or other topical forms. Intramuscular injections in liposomal form may also be used to control or sustain the release of compound at an injection site.

[0588] An IRE1 degrader compound can be formulated for oral administration as a tablet, pill, capsule, troche, lozenge, or powder.

[0589] An IRE1 degrader compound can be formulated for parenteral administration, such as intradermal, subcutaneous (subcut), intramuscular (IM), or intravenous (IV) injections, infusion, or administration into a body cavity or lumen of an organ. Alternatively, the IRE1 degrader compound can be injected into or otherwise placed into a specific site of the body, such as a tumor. Compositions for injection will commonly comprise a solution of the IRE1 degrader compound dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and an isotonic solution of one or more salts such as sodium chloride, e.g., Ringer's solution. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These compositions desirably are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well known sterilization techniques. The compositions can contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.

[0590] The composition may contain any suitable concentration of the IRE1 degrader compound. The concentration of the IRE1 degrader compound in the pharmaceutical composition can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. In certain embodiments, the concentration of an IRE1 degrader compound in a solution formulation for injection will range from about 0.1% (w / w) to about 10% (w / w).

[0591] The amount of compound in a pharmaceutical composition as described herein that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host and disease treated and the particular mode of administration. Preferably, the compositions should be formulated to contain between about 0.05 milligram to about 750 milligrams or more, more preferably about 1 milligram to about 600 milligrams, and even more preferably about 10 milligrams to about 500 milligrams of active ingredient, alone or in combination with at least one other compound according to the present disclosure.

[0592] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or disorder being treated.

[0593] A patient or subject in need of therapy using compounds according to the methods described herein can be treated by administering to the patient (subject) an effective amount of the compound according to the present disclosure including pharmaceutically acceptable salts, solvates or polymorphs, thereof optionally in a pharmaceutically acceptable carrier or diluent, either alone, or in combination with other known therapeutic agents as otherwise identified herein.

[0594] METHODS OF TREATING

[0595] In one aspect, the pharmaceutical composition comprising an IRE1 degrader compound modulates protein degradation in a patient or subject in need thereof, for example, an animal such as a human, and can be used for treating or ameliorating disease states, such as cancer, or conditions which are modulated through the degraded protein.

[0596] In another aspect, the description provides a method of ubiquitinating and / or degrading an IRE1 target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound as described herein comprising, e.g., a E3BM and a PTBM, linked through a linker moiety L as otherwise described herein, wherein the E3BM recognizes a ubiquitin pathway protein (e.g., an ubiquitin ligase, such as a VHL E3 ubiquitin ligase) and the PTBM recognizes the target protein (e.g., IRE1) such that degradation of the target protein will occur when the target protein is placed in proximity to the ubiquitin ligase, thus resulting in degradation / inhibition of the effects of the target protein and the control of protein levels. The control of protein levels provides treatment of a disease state or condition, which is modulated through the target protein by lowering the level of that protein in the cell, e.g., cell of a patient. In certain embodiments, the method comprises administering an effective amount of an IRE1 degrader compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent or combination thereof.

[0597] By inducing target-specific degradation of tumor-associated proteins and conferring specificity to minimize off-target toxicity effects, the IRE1 degrader compounds provided herein may be useful in the treatment of diseases and disorders mediated, at least in part, by IRE1 such as cancer. A target protein is ubiquitinated and subsequently degraded.

[0598] It is contemplated that the IRE1 degrader compounds provided herein may be used to treat various hyperproliferative diseases or disorders mediated, at least in part, by IRE1. The diseases or disorders may be characterized by the overexpression of a tumor antigen. Exemplary hyperproliferative disorders include benign or malignant solid tumors and hematological disorders such as leukemia and lymphoid malignancies. In some embodiments, the hyperproliferative disorders are cancers.

[0599] In some embodiments, the disease or disorder is a cancer. Examples of cancer to be treated with an IRE1 degrader compound include, but are not limited to, squamous cell carcinoma, small- cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell lung cancer, peritoneum cancer, hepatocellular cancer, stomach cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, and head and neck cancer.

[0600] In some embodiments, the disease or disorder is a hematological disorder. Examples of hematological disorders to be treated with an IRE1 degrader compound include, but are not limited to, lymphoma, lymphocytic leukemia, multiple myeloma (MM), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), and myeloproliferative disease (MPD).

[0601] In some embodiments, the disease or disorder is multiple myeloma.

[0602] In another aspect, the patient treated with the pharmaceutical composition comprising the IRE1 degrader compound provided herein is administered one or more additional therapeutic agents selected from the group consisting of an anti-inflammatory agent, a corticosteroid, an immunomodulatory agent, anti-cancer agent, an apoptosis-enhancer, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, an agent for treating metabolic disorders, an agent for treating autoimmune disorders, and an agent for treating immunodeficiency disorders.

[0603] In another aspect, provided herein are IRE1 degrader compounds = or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in the treatment of an IRE1-mediated disease or disorder. In some embodiments, the disease or disorder is a cancer selected from the group consisting of squamous cell carcinoma, small -cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell lung cancer, peritoneum cancer, hepatocellular cancer, stomach cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, and head and neck cancer. In some embodiments, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, as described herein.

[0604] In yet another aspect, provided herein are uses of the IRE1 degrader compounds in the manufacture of a medicament for the treatment of an IRE1 -mediated disease or disorder. In some embodiments, the disease or disorder is a cancer selected from the group consisting of squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell lung cancer, peritoneum cancer, hepatocellular cancer, stomach cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, and head and neck cancer. In some embodiments, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, as described herein.

[0605] EXAMPLES

[0606] General Synthetic Schemes and Examples

[0607] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art of prepared as described herein.

[0608] Example 1 (2S, 47?)-l-((5)-2-(7-(4-((lr,4r)-4-((4-(2-(l-benzylcyclopropoxy)pyridin- 3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 1 2

[0609] Step 2

[0610]

[0611] Step 1: 7-(((S)-l-((2S, 4 / ?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-l-yl)-3, 3 -dimethyl- l-oxobutan-2-yl) amino)-7-oxoheptanoic acid

[0612] To a stirred solution of methyl 7-(((5)-l-((25,4A)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-7-oxoheptanoate( 100.0 mg, 0.17 mmol) in H2O (2 mL) and THF (6 mL) was added LiOH H2O (20.4 mg, 0.85 mmol) at room temperature. Then reaction mixture was stirred at room temperature for 3 h. The reaction mixture was acidified with 2 M HC1 to pH ~ 3, extracted with EtOAc (30 mL x 3) and washed by brine (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by pre-TLC (50% EtOAc in petroleum ether, Rf = 0.6) to afford the title compound (41 mg, 42%) as a light yellow oil. LCMS (ESI): m / z 573.3 (M+H)+.

[0613] Step 2: (25,4A)-l-((5)-2-(7-(4-((lr,4r)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0614] To a stirred solution of 7-(((5)-l-((25,4A)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-7-oxoheptanoic acid(40.0 mg, 0.07 mmol) and DIEA (27.1 mg, 0.21 mmol) in DMF (1 mL) was added HATU (31.87 mg, 0.08 mmol) at 0 °C. After stirring at 25 °C for 0.5 h, 4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)-N-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)pyrimidin-2-amine (33.9 mg, 0.07 mmol) in DMF (0.5 mL) was added dropwise to the reaction mixture. After stirring at 25°C for 16 h, the reaction mixture was purified by pre-HPLC (acetonitrile 20-50 / 0.225% FA in water) to give the title compound (28.3 mg, 39%) as a yellow solid. LCMS (ESI): m / z 1039.5 (M+H)+. 'H NMR (400 MHz, DMSO-tL) <58.98 (s, 1H), 8.57 (t, J= 6.0 Hz, 1H), 8.37 (dd, J= 2.0, 4.8 Hz, 1H), 8.24 (s, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.87 (d, J= 9.2 Hz, 1H), 7.45 - 7.35 (m, 4H), 7.25 - 7.13 (m, 6H), 7.04 - 6.98 (m, 1H), 6.65 - 6.52 (m, 1H), 5.13 (d, J= 3.2 Hz, 1H), 4.54 (d, J= 9.6 Hz, 1H), 4.47 - 4.39 (m, 2H), 4.37 - 4.30 (m, 1H), 4.21 (dd, J = 5.6, 16.0 Hz, 1H), 3.70 - 3.60 (m, 3H), 3.45 - 3.35 (m, 4H), 3.32 - 3.20 (m, 2H), 2.45 (s, 3H), 2.44 - 2.35 (m, 3H), 2.29 - 2.20 (m, 4H), 2.15 - 1.87 (m, 6H), 1.85 - 1.70 (m, 2H), 1.54 - 1.41 (m, 4H), 1.33 - 1.21 (m, 6H), 0.95 - 0.85 (m, 13H).

[0615] Example 2 (25,4A)-l-((S)-2-(2-(2-(4-((lr,4S)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)-2-oxoethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0616]

[0617] OH

[0618] Step 1: (2S,47?)-l-((S)-2-(2-(2-(4-((lr,4S)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)-2-oxoethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide To a stirred solution of 2-(2-(((5)-l-((25,4A)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3, 3 -dimethyl- l-oxobutan-2-yl)amino)-2-oxoethoxy)acetic acid (101.5 mg, 0.19 mmol) in H2O (0.5 mL) were added 2,6-lutidine (112.8 mg, 1.05 mmol) at 25°C. After stirring at 25°C for 15 min, 4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)-7V-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)pyrimidin-2-amine (100.0 mg, 0.21 mmol) and COMU (97.21 mg, 0.23 mmol) were added to the reaction mixture. The reaction mixture was stirred at 25° for 5 min. Then the reaction mixture was purified by pre-HPLC (acetonitrile 20 - 50 / 0.225% FA in water) to afford the title compound (34.5 mg, 16%) as a white solid. LCMS (ESI): m / z 1013.6 (M+H)+. 'HNMR (400 MHz, DMSO-tfc) 38.98 (s, 1H), 8.60 (t, J= 6.0 Hz, 1H), 8.37 (dd, J = 2.0, 4.8 Hz, 1H), 8.36 (s, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.78 (d, J= 9.6 Hz, 1H), 7.47 - 7.36 (m, 4H), 7.26 - 7.11 (m, 6H), 7.02 (d, J= 7.6 Hz, 1H), 6.59 (s, 1H), 5.16 (s, 1H), 4.55 (d, J= 9.6 Hz, 1H), 4.48 - 4.20 (m, 6H), 4.00 (s, 2H), 3.72 - 3.63 (m, 2H), 3.63 - 3.59 (m, 1H), 3.45 - 3.40 (m, 3H), 3.35 - 3.25 (m, 5H), 2.63 - 2.53 (m, 3H), 2.44 (s, 3H), 2.09 - 1.86 (m, 4H), 1.85 - 1.75 (m, 2H), 1.39 - 1.20 (m, 4H), 1.00 - 0.87 (m, 13H).

[0619] Example s (25,47?)-l-((5)-2-((17?,35)-3-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazine-l-carbonyl )cyclobutane-l -carboxamido)-3, 3 -di methyl butanoyl )-4-hydroxy- / ' / -(4-(4-methyl thi azol -5-yl)benzyl)pyrrolidine-2-carboxamide

[0620] Step 4

[0621]

[0622] Step 1: (25,4A)-l-((5)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine-2-carboxamide

[0623] To a stirred solution of tert-butyl ((5)-l-((2£,4A)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3, 3 -dimethyl- l-oxobutan-2-yl)carbamate (1.6 g, 3.01 mmol) in 1,4-dioxane (2 mL) was added HC1(11.5 mL, 4 M in dioxane) at room temperature. Then the reaction mixture was stirred at 25 °C for 1 h. After that, the solution was concentrated under vacuum and the residue was purified by column chromatography on silica gel eluting with 0 - 15% MeOH in DCM to afford the title compound (1.1 g, 85%) as a yellow solid. LCMS (ESI): m / z 431.1 (M+H)+. Step 2: tert-butyl (LS',3 / j-3-((CS')- l-((2A',4 / )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3, 3 -dimethyl- l-oxobutan-2-yl)carbamoyl)cy cl obutane-1-carboxylate

[0624] To a stirred mixture of (1 / ',3 / j-3-(tert-butoxycarbonyl)cyclobutane- l -carboxylic acid (20.3 mg, 0.1 mmol), (2£,4A)-l-((5)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (50.0 mg, 0.11 mmol) and DIEA(0.03 mL, 0.17 mmol) in DMF (1 mL) was added T3P (0.13 mL, 0.22 mmol) dropwise at 25 °C. Then the reaction was stirred at 40 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with H2O (10 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed by brine (30 mL * 3), dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by pre-TLC (10% MeOH in DCM, Rf = 0.4) to afford the title compound (25 mg, 36%) as a white solid. LCMS (ESI): m / z 613.3 (M+H)+.

[0625] Step 3: (l£,3r)-3-(((5)-l-((2£,4A)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3, 3 -dimethyl- l-oxobutan-2-yl)carbamoyl)cy cl obutane-1 -carboxylic acid

[0626] To a stirred solution of tert-butyl (l£,3r)-3-(((5)-l-((2£,4A)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)carbamoyl)cyclobutane-l-carboxylate (25.0 mg, 0.04 mmol) in DCM (1 mL) was added TFA (0.03 mL, 0.41 mmol) at 25°. After stirring at 25 °C for 1 h, the solution was concentrated and purified by pre-TLC (10% MeOH in DCM, Rf = 0.2) to afford the title compound (13 mg, 57%) as a yellow solid. LCMS (ESI): m / z 579.1 (M+Na)+.

[0627] Step 4: (25,4A)-l-((5)-2-((lA,35)-3-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazine-l-carbonyl)cyclobutane-l-carboxamido)-3,3-dimethylbutanoyl )-4-hydroxy-A-(4-(4-methylthiazol-5-yl (benzyl )pyrrolidine-2-carboxamide To a stirred solution of 4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)-A-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)pyrimidin-2-amine (26.1 mg, 0.05 mmol) in DMF (1 mL) was added DIEA(0.04 mL, 0.22 mmol), T3P (0.05 mL, 0.09 mmol) and (15,3r)-3-(((S)-l-((25,4A)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)carbamoyl)cyclobutane-l -carboxylic acid (25.0 mg, 0.04 mmol) subsequently at room temperature, then the reaction mixture was stirred at 40 °C for 2 h under N2 atmosphere. After cooling to room temperature, the solution was purified by pre-HPLC (acetonitrile 20-50 / 0.225% FAin water) to afford the title compound (15.1 mg, 33%) as a white solid. LCMS (ESI): m / z 1023.6 (M+H)+ 1HNMR (400 MHz, DMSO ) d 8.97 (s, 1H), 8.54 (t, J= 6.0 Hz, 1H), 8.40 - 8.35 (m, 1H), 8.25 (s, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.76 (d, J= 9.2 Hz, 1H), 7.44 - 7.36 (m, 4H), 7.25 - 7.21 (m, 2H), 7.20 - 7.13 (m, 4H), 6.96 (d, J= 7.6 Hz, 1H), 6.60 (s, 1H), 5.13 (d, J= 3.6 Hz, 1H), 4.54 (d, J= 9.2 Hz, 1H), 4.46 - 4.30 (m, 3H), 4.27 - 4.17 (m, 1H), 3.72 - 3.59 (m, 3H), 3.30 - 3.09 (m, 9H), 2.44 (s, 3H), 2.35 - 1.88 (m, 12H), 1.85-1.75 (m, 2H), 1.33 -1.21 (m, 4H), 0.95 - 0.90 (m, 13H).

[0628] Example 4 (25,47?)-l-((5)-2-((15,37?)-3-(4-((lr,47?)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazine-l-carbonyl )cyclobutane-l -carboxamido)-3, 3 -di methyl butanoyl )-4-hydroxy- / ' / -(4-(4-rnethylthi azol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0629]

[0630] The compound was prepared according to the procedures described for Example 3 and obtained as a formate. LCMS (ESI): m / z 1023.6 (M+H)+. 'HNMR (400 MHz, DMSO ) d 8.98 (s, 1H), 8.57 (t, J= 5.8 Hz, 1H), 8.40 - 8.35 (m, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.78 (d, J= 9.2 Hz, 1H), 7.44 - 7.36 (m, 4H), 7.25 - 7.20 (m, 2H), 7.20 - 7.12 (m, 4H), 7.00 (d, J= 7.6 Hz, 1H), 6.60 (s, 1H), 5.14 (s, 1H), 4.52 (d, J= 9.6 Hz, 1H), 4.47 - 4.38 (m, 2H), 4.37 - 4.30 (m, 1H), 4.25 - 4.15 (m, 1H), 3.71-3.31 (m, 3H), 3.30 - 3.09 (m, 9H), 2.44 (s, 3H), 2.35 - 1.85 (m, 12H), 1.85 - 1.75 (m, 2H), 1.34 - 1.22 (m, 4H), 0.95 - 0.85 (m, 13H).

[0631] Example 5 (25,47?)-l-((5)-2-(5-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin- 3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carb oxami de

[0632]

[0633] OH

[0634] The compound was prepared according to the procedures described for Example 3.

[0635] LCMS (ESI): m / z 1025.7 (M+H)+. 'H NMR (400 MHz, CDCl3) d 8.60 (s, 1H), 8.28 (dd, J= 4.8, 2.0 Hz, 1H), 8.20 (s, 1H), 8.00 (d, J= 5.2 Hz, 1H), 7.58 (d, J= 6.8 Hz, 1H), 7.36 - 7.28 (m, 4H), 7.19 - 7.09 (m, 6H), 6.98 (dd, J= 7.6, 4.8 Hz, 1H), 6.73 (d, J= 7.6 Hz, 1H), 6.66 (d, J= 5.2 Hz, 1H), 5.02 (q, J= 7.2 Hz, 1H), 4.68 (t, J= 8.0 Hz, 1H), 4.47 - 4.39 (m, 2H), 4.06 (d, J= 11.6 Hz, 1H), 3.81 - 3.65 (m, 2H), 3.60 - 3.46 (m, 4H), 3.29 (s, 2H), 3.16 - 2.81 (m, 2H), 2.65 - 2.52 (m, 4H), 2.37 - 2.29 (m, 4H), 2.22 - 2.16 (m, 4H), 2.10 - 2.02 (m, 1H), 1.98 - 1.90 (m, 2H), 1.89 - 1.82 (m, 2H), 1.48 - 1.38 (m, 5H), 1.27 - 1.15 (m, 2H), 1.00 (s, 9H), 0.95 - 0.91 (m, 2H), 0.86 -0.81 (m, 2H).

[0636] Exampl e 6 (2,4 / )- 1 -((5)-2-(5 -(4-(( 1 r,45)-4-((6-(3 -fluoro-4-((3,3, 3 -trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0637]

[0638] The compound was prepared according to the procedures described for Example 3. LCMS (ESI): m / z 1122.9 (M+H)+. 'H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.97 (s, 1H), 8.58 (t, J= 6.0 Hz, 1H), 8.21 (s, 1H), 8.04 (d, J= 12.4 Hz, 1H), 7.98 (d, J= 8.4 Hz, 1H), 7.90 (d, J= 9.6 Hz, 1H), 7.53 (t, J= 8.4 Hz, 2H), 7.44 - 7.36 (m, 5H), 5.15 (d, J= 3.6 Hz, 1H), 4.54 (d, J= 9.2 Hz, 1H), 4.46 - 4.40 (m, 2H), 4.40 - 4.33 (m, 1H), 4.22 (dd, J= 5.6, 16.0 Hz, 1H), 3.85 - 3.78 (m, 1H), 3.72 - 3.65 (m, 2H), 2.86 - 2.73 (m, 3H), 2.59 - 2.53 (m, 3H), 2.44 (s, 3H), 2.31 - 2.24 (m, 4H), 2.23 - 2.16 (m, 2H), 2.14 - 2.07 (m, 2H), 2.05 - 1.99 (m, 2H), 1.95 - 1.87 (m, 2H), 1.90 - 1.80 (m, 2H), 1.75 - 1.65 (m, 2H), 1.40 - 1.30 (m, 4H), 1.26 - 1.21 (m, 6H), 0.95 (s, 9H).

[0639] Example 7 (25,47?)-l-((5)-3,3-dimethyl-2-(5-(4-((lr,45)-4-((8-methylpyrido[3,2-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)-5-oxopentanamido)butanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0640]

[0641] The compound was prepared according to the procedures described for Example 3. LCMS (ESI): m / z 875.6 (M+Na)+.XH NMR (400 MHz, DMSO-tL) d 9.05 (s, 1H), 8.97 (s, 1H), 8.57 (t, J= 6.0 Hz, 1H), 8.42 (d, J= 4.4 Hz, 1H), 7.90 (d, J= 9.2 Hz, 1H), 7.52 (d, J= 4.8 Hz, 1H), 7.44 - 7.34 (m, 5H), 5.14 (d, J= 3.6 Hz, 1H), 4.53 (d, J= 9.2 Hz, 1H), 4.49 - 4.37 (m, 3H), 4.38 - 4.30 (m, 1H), 4.21 (dd, J= 5.2, 15.6 Hz, 1H), 3.87 - 3.70 (m, 2H), 3.69 - 3.60 (m, 3H), 2.43 (s, 3H), 2.30 - 2.23 (m, 4H), 2.22 - 2.14 (m, 2H), 2.12 - 1.96 (m, 5H), 1.94 - 1.87 (m, 2H), 1.86 - 1.77 (m, 2H), 1.75 - 1.65 (m, 2H), 1.40 - 1.20 (m, 8H), 0.94 (s, 9H).

[0642] Example 8 (25,47?)- 1 -((S)-2-(5-(4-((lr,45)-4-((6-(3 -fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0643]

[0644] The compound was prepared according to the procedures described for Example 3.

[0645] LCMS (ESI): m / z 1166.4 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.68 - 8.56 (m, 2H), 7.97 - 7.85 (m, 3H), 7.63 (d, J= 12.4 Hz, 1H), 7.52 - 7.48 (m, 1H), 7.44 - 7.37 (m, 6H), 5.73 (s, 1H), 5.15 (d, J= 3.6 Hz, 1H), 4.54 (d, J= 9.6 Hz, 1H), 4.43 (t, J= 8.0 Hz, 2H), 4.38 -4.30 (m, 1H), 4.22 (dd, J= 5.6, 15.6 Hz, 1H), 3.70 - 3.60 (m, 2H), 2.90 - 2.75 (m, 2H), 2.50 -2.42 (m, 6H), 2.35 - 2.15 (m, 6H), 2.08 - 1.98 (m, 4H), 1.94 - 1.84 (m, 3H), 1.75 - 1.62 (m, 3H), 1.60 - 1.48 (m, 6H), 1.40 - 1.22 (m, 9H) 0.95 (s, 9H).

[0646] Example 9 (2S,4R)-4-hydroxy-l-((S)-2-(5-(4-((lr,4S)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0647]

[0648] The compound was prepared according to the procedures described for Example 3.

[0649] LCMS (ESI): m / z 897.4 (M+H)+. 'H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.61 - 8.52 (m, 2H), 7.90 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.45 - 7.35 (m, 5H), 6.23 - 6.10 (m, 1H), 5.75 - 5.55 (m, 1H), 5.14 (d, J= 3.6 Hz, 1H), 4.54 (d, J= 9.2 Hz, 1H), 4.48 - 4.39 (m, 2H), 4.37 - 4.30 (m, 1H), 4.22 (dd, J= 5.6, 16.0 Hz, 1H), 3.70 - 3.60 (m, 3H), 2.44 (s, 3H), 2.35 - 2.16 (m, 6H), 2.10 - 1.98 (m, 4H), 1.97 - 1.79 (m, 5H), 1.75 - 1.60 (m, 2H), 1.53 - 1.40 (m, 6H), 1.35 - 1.20 (m, 7H), 0.94 (s, 9H).

[0650] Exampl e 10 (25,47?)- 1 -((5)-2-(7-(4-(( 1 r,4r)-4-((6-(3 -fluoro-4-((3,3, 3 -trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0651] Stepl

[0652]

[0653] Step 1: 7-(((5)-l-((25,47?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-7-oxoheptanoic acid

[0654] To a stirred solution of methyl 7-(((5)-l-((25,47?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-7-oxoheptanoate (300.0 mg, 0.51 mmol) in H2O (2 mL) and THF (6 mL) was added LiOH·H₂O (30.6 mg, 1.28 mmol) at 25 °C. Then the reaction mixture was stirred at 25 °C for 3 h. After that, the mixture was acidified with 2M HC1 aqueous to pH ~ 3, extracted with EtOAc (30 mL x 3). The combined organic layer was washed by brine (30 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (220 mg, 75%) as a white solid.

[0655] LCMS (ESI): m / z 595.1 (M+Na)+.

[0656] Step 2: (25,47?)- 1 -((5)-2-(7-(4-(( 1 r,4r)-4-((6-(3 -fluoro-4-((3,3, 3 -trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0657] To a stirred mixture of3,3,3-trifluoro-3,3,3-trifluoro-N-(2-fluoro-4-(8-methyl-2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl)amino)pyrido[3,2-t7]pyrimidin-6-yl)phenyl)propane-l-sulfonamide (24.28 mg, 0.04 mmol), 7-(((5)-l-((25,47?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-7-oxoheptanoic acid (20.0 mg, 0.03mmol) and Et3N (0.03 mL, 0.21 mmol) in DCM (2 mL) was added and T3P (0.02 mL, 0.07 mmol) at 25 °C. Then the reaction mixture was stirred at 40 °C for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (acetonitrile 58-88 / 0.225% FA in water) to afford the title compound (12 mg, 29%) as a white solid. LCMS (ESI): m / z 576.1 (M / 2+H)+. 'H NMR (400 MHz, DMSO-tL) 39.12 (s, 1H), 8.98 (s, 1H), 8.57 (t, J= 6.0 Hz, 1H), 8.23 (s, 1H), 8.08 (d, J = 12.0 Hz, 1H), 8.02 (d, J= 8.8 Hz, 1H), 7.87 (d, J= 9.2 Hz, 1H), 7.65 (s, 1H), 7.55 (t, J= 8.4 Hz, 1H), 7.46 - 7.35 (m, 4H), 5.15 (s, 1H), 4.55 (d, J= 9.2 Hz, 1H), 4.48 - 4.39 (m, 2H), 4.37 - 4.30 (m, 1H), 4.22 (dd, J= 16.0, 5.2 Hz, 1H), 3.80 (s, 1H), 3.71 - 3.63 (m, 2H), 3.56 - 3.49 (m, 2H), 2.89 - 2.74 (m, 2H), 2.57 (s, 3H), 2.54 - 2.53 (m, 1H), 2.48 - 2.44 (m, 6H), 2.31 - 2.20 (m, 4H), 2.15 - 1.95 (m, 5H), 1.96 - 1.74 (m, 4H), 1.57 - 1.43 (m, 5H), 1.42 - 1.30 (m, 4H), 1.30 - 1.18 (m, 3H), 1.01 - 0.88 (m, 9H).

[0658] Example 11 (25,4 / ?)-l-((5)-3,3-dimethyl-2-(7-(4-((lr,4r)-4-((8-methylpyrido[3,2- J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)-7-oxoheptanamido)butanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0659]

[0660] The compound was prepared according to the procedures described for Example 10. LCMS (ESI): m / z 881.4 (M+H)+. 'H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.98 (s, 1H), 8.57 (t, J= 5.6 Hz, 1H), 8.42 (d, J= 4.4 Hz, 1H), 7.87 (d, J= 9.2 Hz, 1H), 7.60 - 7.50 (m, 2H), 7.45 - 7.33 (m, 4H), 4.54 (d, J= 9.2 Hz, 1H), 4.48 - 4.40 (m, 2H), 4.40 - 4.32 (m, 1H), 4.22 (dd, J= 15.2, 5.2 Hz, 1H), 3.85 - 3.70 (m, 2H), 3.70 - 3.60 (m, 4H), 2.65 - 2.50 (m, 5H), 2.47 - 2.41 (m, 6H), 2.31 - 2.21 (m, 4H), 2.18 -2.07 (m, 3H), 1.97 - 1.79 (m, 4H), 1.55 - 1.43 (m, 4H), 1.40 - 1.30 (m, 4H), 1.29 - 1.21 (m, 3H), 0.94 (s, 9H).

[0661] Exampl e 12 (25,47?)- 1 -((5)-2-(7-(4-(( 1 r,4r)-4-((6-(3 -fluoro-4-((3,3, 3 -trifluoropropyl)sulfonamido)phenyl)-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0662]

[0663] The compound was prepared according to the procedures described for Example 10. LCMS (ESI): m / z 1194.6 (M+H)+. 'H NMR (400 MHz, DMSO-tL) d 8.97 (s, 1H), 8.68 - 8.60 (m, 1H), 8.57 (t, J= 5.6 Hz, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.86 (d, J= 9.6 Hz, 2H), 7.63 (d, J = 12A Hz, 1H), 7.55 - 7.36 (m, 6H), 5.85 - 5.70 (m, 1H), 5.15 (d, J= 3.2 Hz, 1H), 4.54 (d, J= 9.2 Hz, 1H), 4.47 - 4.40 (m, 2H), 4.40 - 4.30 (m, 1H), 4.26 - 4.18 (m, 1H), 3.71 - 3.61 (m, 2H), 3.61 - 3.57 (m, 2H), 2.87 - 2.75 (m, 2H), 2.56 - 2.54 (m, 4H), 2.47 - 2.42 (m, 6H), 2.31 - 2.22 (m, 4H), 2.18 - 2.10 (m, 1H), 2.08 - 1.98 (m, 3H), 1.96 - 1.79 (m, 8H), 1.58 - 1.43 (m, 6H), 1.40 -1.20 (m, 7H), 1.01 - 0.87 (m, 9H).

[0664] Example 13 (25',47?)-4-hydroxy-l-((5)-2-(7-(4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0665]

[0666] The compound was prepared according to the procedures described for Example 10. LCMS (ESI): m / z 925.5 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.60 - 8.50 (m, 2H), 7.86 (d, J= 9.2 Hz, 1H), 7.73 (s, 1H), 7.64 (d, J= 8.8 Hz, 1H), 7.45 - 7.38 (m, 4H), 6.25 -6.15 (m, 1H), 5.72 - 5.55 (m, 1H), 5.14 (d, J= 3.2 Hz, 1H), 4.54 (d, = 9.2 Hz, 1H), 4.49 - 4.40 (m, 2H), 4.40 - 4.32 (m, 1H), 4.22 (dd, J= 16.4, 5.6 Hz, 1H), 3.70 - 3.60 (m, 3H), 3.39 - 3.38 (m, 2H), 2.50 - 2.45 (m, 8H), 2.32 - 2.22 (m, 5H), 2.18 - 2.09 (m, 2H), 2.03 - 1.97 (m, 3H), 1.96 - 1.85 (m, 4H), 1.53 - 1.42 (m, 8H), 1.40 - 1.30 (m, 3H), 1.30 - 1.20 (m, 3H), 0.94 (s, 9H).

[0667] Example 14 (25,47?)-l-((S)-2-(2-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide Step 1

[0668] OH

[0669]

[0670] Step 1: (2S, 47?)-l-((5)-2-(2-bromoacetamido)-3, 3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide

[0671] To a stirred mixture of 2-bromoacetic acid (0.07 mL, 0.93 mmol) and T3P (0.55 mL, 0.93 mmol) in DCM (1.0 mL) was added Et3N (0.32 mL, 2.32 mmol) and (2S,4R)-l-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (200.0 mg, 0.46 mmol) in sequence at 25 °C. Then the reaction mixture was stirred at 40 °C for 2 h. After cooled to room temperature, the reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (25 mL x 2). The combined organic layer was washed with brine (100 mL), dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by pre-TLC (10% MeOH in DCM, Rf = 0.5) to afford the title compound (50 mg, 19%) as a white solid. LCMS (ESI): m / z 552.9 (M+H)+.

[0672] Step 2: (25,4A)-l-((S)-2-(2-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0673] To a stirred mixture of 4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)-A-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)pyrimidin-2-amine (40.0 mg, 0.08 mmol) and (2S,4R)-l-((S)-2-(2-bromoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (50.1 mg, 0.09 mmol) in DMF (1 mL) was added K2CO3 (0.08 mL, 0.41 mmol) at 25 °C. After stirred at 25 °C for 2 h, the reaction mixture was filtered to remove undissolved solid and the filtrate was purified by pre-HPLC (MeCN 15 - 45 / 0.225% FA in water) to afford the title compound (16.9 mg, 20%) as a white solid. LCMS (ESI): m / z 955.4 (M+H)+. 'H NMR (400 MHz, DMSO-tfc) <58.98 (s, 1H), 8.62 (t, J= 6.0 Hz, 1H), 8.37 (dd, J = 2.0, 4.8 Hz, 1H), 8.31 - 8.18 (m, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.76 (d, J = 9.6 Hz, 1H), 7.46 -7.35 (m, 4H), 7.27 - 7.21 (m, 2H), 7.20 - 7.11 (m, 4H), 6.97 (d, J= 7.6 Hz, 1H), 6.60 (s, 1H), 5.15 (s, 1H), 4.49 (d, J= 9.6 Hz, 1H), 4.46 - 4.32 (m, 3H), 4.30 - 4.23 (m, 1H), 3.71 - 3.56 (m, 2H), 3.35 - 3.25 (m, 5H), 3.02 (d, J= 16.0 Hz, 2H), 2.89 (d, J= 16.0 Hz, 2H), 2.46 - 2.41 (m, 5H), 2.30 - 2.17 (m, 1H), 2.13 - 1.98 (m, 2H), 1.97 - 1.85 (m, 3H), 1.83 - 1.75 (m, 2H), 1.40 - 1.15 (m, 4H), 0.98 - 0.89 (m, 13H).

[0674] Example 15 (25,45)-l-((5)-2-(5-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy -N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0675]

[0676] OH

[0677] The compound was prepared according to the procedures described for Example 14. LCMS (ESI): m / z 997.6 (M+H^HNMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.57 (t, J= 5.6 Hz, 1H), 8.37 (d, J= 3.2 Hz, 1H), 8.18 (s, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.86 (d, J= 9.2 Hz, 1H), 7.45 - 7.30 (m, 4H), 7.25 - 7.05 (m, 6H), 6.99 (d, J= 7.6 Hz, 1H), 6.59 (s, 1H), 4.54 (d, J = 9.2 Hz, 1H), 4.45 - 4.39 (m, 2H), 4.37 - 4.28 (m, 1H), 4.21 (dd, J= 5.2, 15.6 Hz, 1H), 3.67 -3.64 (m, 3H), 2.50 - 2.38 (m, 8H), 2.40 - 2.10 (m, 10H), 2.08 - 1.85 (m, 5H), 1.82-1.72 (m, 2H), 1.54 - 1.34 (m, 4H), 1.29 - 1.21 (m, 4H), 0.93 (s, 13H).

[0678] Example 16 (25,45)-l-((5)-2-(5-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy -N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0679]

[0680] The compound was prepared according to the procedures described for Example 14. LCMS (ESI): m / z 997.4 (M+H)+. 'H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.63 (t, J= 6.4 Hz, 1H), 8.37 (dd, J= 2.0, 4.8 Hz, 1H), 8.18 (s, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.85 (d, J= 9.2 Hz, 1H), 7.43 - 7.36 (m, 4H), 7.27 - 7.11 (m, 6H), 6.97 (d, J= 7.6 Hz, 1H), 6.59 (s, 1H), 4.49 - 4.41 (m, 2H), 4.35 (dd, J= 6.4, 8.4 Hz, 1H), 4.29 - 4.17 (m, 2H), 3.97 - 3.90 (m, 1H), 3.70 -3.60 (m, 3H), 2.50 - 2.38 (m, 8H), 2.40 - 2.27 (m, 5H), 2.26 - 2.07 (m, 6H), 2.00 - 1.89 (m, 2H), 1.85 - 1.70 (m, 3H), 1.53 - 1.32 (m, 5H), 1.31 - 1.19 (m, 4H), 0.97 - 0.89 (m, 13H).

[0681] Example 17 (25,45)-4-hydroxy-l-((5)-2-(5-(4-((lr,45)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanamido)-3,3-dimethylbutanoyl)-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0682]

[0683] OH

[0684] The compound was prepared according to the procedures described for Example 14 and obtained as a formate. LCMS (ESI): m / z 883.4 (M+H)+. 'H NMR (400 MHz, DMSO-tfc) d 8.98 (s, 1H), 8.63 (t, J= 6.0 Hz, 1H), 8.58 - 8.51 (m, 1H), 8.21 - 8.17 (m, 1H), 7.85 (d, J= 8.8 Hz, 1H), 7.75 - 7.55 (m, 2H), 7.43 - 7.37 (m, 4H), 6.23 - 6.10 (m, 1H), 5.74 - 5.56 (m, 1H), 4.49 -4.41 (m, 2H), 4.40 - 4.30 (m, 1H), 4.29 - 4.18 (m, 2H), 3.97 - 3.87 (m, 1H), 3.84 - 3.59 (m, 4H), 2.46 - 2.42 (m, 4H), 2.40 - 2.28 (m, 5H), 2.27 - 2.17 (m, 5H), 2.16 - 2.09 (m, 1H), 2.03 - 1.91 (m, 2H), 1.90 - 1.79 (m, 2H), 1.78 - 1.70 (m, 1H), 1.56 - 1.44 (m, 8H), 1.43 - 1.19 (m, 7H), 0.95 (s, 9H).

[0685] Example 18 (25,47?)-l-((5)-2-(3-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy -N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0686]

[0687] Step6

[0688]

[0689] OH Step 1: (3A,55)-l-((5)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate

[0690] To a stirred mixture of tert-butyl ((5)-l-((25,4A)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3, 3 -dimethyl- l-oxobutan-2-yl)carbamate (2.0 g, 3.77 mmol) and 4-dimethylaminopyridine (690.6 mg, 5.65 mmol) in DCM (20 mL) was added AC2O (0.43 mL, 4.52 mmol) at 25 °C. The resulting reaction mixture was stirred at 25°C for 16 h. After that, the reaction was quenched with H2O (15 mL) and extracted with DCM (15 mL x 2). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with 0 - 5% MeOH in DCM to afford the title compound (1.8 g, 83%) as a white solid. LCMS (ESI): m / z 595.1 (M+Na)+.

[0691] Step 2: (3A,55)-l-((5)-2-amino-3,3-dimethylbutanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate

[0692] To a stirred solution of (3A,55)-l-((5)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate (1.8 g, 3.1mmol) in 1,4-dioxane (70 mL) was added HCl / dioxane (4 M, 4.0 mL), which was stirred at 25 °C for 1 h. Then the reaction mixture was concentrated and the residue was purified by column chromatography eluting with 0-10% MeOH in DCM to afford the title compound (1.2 g, 81%) as a white solid.

[0693] Step 3: (3A,55)-l-((S)-2-(3-hydroxypropanamido)-3,3-dimethylbutanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate

[0694] To a stirred mixture of 3-hydroxypropanoic acid (114.36 mg, 1.27 mmol), (3A,55)-1-((5)-2-amino-3,3-dimethylbutanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate (300.0 mg, 0.63 mmol) and T3P (0.38 mL, 1.27 mmol) in DCM (2 mL) was added Et3N (321.2 mg, 3.17 mmol) dropwise at 25°C, then the reaction mixture was stirred at 40 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced and the residue was purified by column chromatography on silica gel eluting with 0 - 5% MeOH in DCM to afford the title compound (110 mg, 32%) as a colorless oil. LCMS (ESI): m / z 545.2 (M+H)+.

[0695] Step 4: (3A,55)-l-((S)-3,3-dimethyl-2-(3-(tosyloxy)propanamido)butanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate

[0696] To a stirred solution of (3A,55)-l-((5)-2-(3-hydroxypropanamido)-3,3-dimethylbutanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate (110.0 mg, 0.2 mmol) in DCM (1 mL) was added Et3N (61.3 mg, 0.6 mmol) at 0 °C. Then p-TsCl (77.0 mg, 0.4 mmol) in DCM (1 mL) was added dropwise to the solution at 0°C. After stirring at 25 °C for 16 h, the reaction mixture was filtrated. The filtrate was concentrated and the residue was purified was purified by column chromatography on silica gel eluting with 0 - 5% MeOH in DCM to afford the title compound (60 mg, 43%) as a colorless oil. LCMS (ESI): m / z 699.3 (M+H)+.

[0697] Step 5: (3A,55)-l-((5)-2-(3-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)propanamido)-3,3-dimethylbutanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate

[0698] A mixture of (3A,55)-l-((5)-3,3-dimethyl-2-(3-(tosyloxy)propanamido)butanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate (30.0 mg, 0.04 mmol), 4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)-A-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)pyrimidin-2-amine (25.0 mg, 0.05 mmol), Nal (12.9 mg, 0.09 mmol) and DIEA (0.01 mL, 0.09 mmol) in acetone (0.50 mL) was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to give the crude product. The crude product was purified by pre-TLC (10% MeOH in DCM, Rf = 0.4) to afford the title compound (40 mg, 92%) as a yellow solid.

[0699] Step 6: (25,4A)-l-((5)-2-(3-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0700] To a stirred solution of (3A,55)-l-((5)-2-(3-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)propanamido)-3,3-dimethylbutanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate (30.0 mg, 0.03 mmol) in THF (1.5 mL) was added LiOH H2O (3.7 mg, 0.09 mmol) in H2O (0.30 mL) at 25 °C. After stirring at 25 °C for 2 h, the reaction mixture was acidified with HC1 (IM) aqueous solution till pH ~ 7. Then the solution was concentrated to give crude product, which was purified by reverse phase chromatography (acetonitrile 60 - 80 / 0.225% FA in water) to afford the title compound (2.8 mg, 9%) as a white solid. LCMS (ESI): m / z 969.5 (M+H)+.1H NMR (400 MHz, DMSO-tL) d 8.89 (s, 1 H), 8.64 -8.50 (m, 2 H), 8.37 (dd, J= 4.8, 2.0 Hz, 1 H), 8.23 (s, 1 H), 8.09 (d, J= 5.2 Hz, 1 H), 7.46 - 7.41 (m, 2 H), 7.39 - 7.34 (m, 2 H), 7.28 - 7.20 (m, 2 H), 7.20 - 7.13 (m, 4 H), 6.93 (d, J= 7.6 Hz, 1 H), 6.67 - 6.53 (m, 1 H), 5.13 (d, J= 3.2 Hz, 1 H), 4.53 (d, J= 9.2 Hz, 1 H), 4.48 - 4.38 (m, 2 H), 4.38 - 4.30 (m, 1 H), 4.21 (dd, J= 16.0, 5.6 Hz, 1 H), 3.70 - 3.55 (m, 4 H), 2.68 - 2.65 (m, 3 H), 2.45 - 2.35 (m, 5 H), 2.34 - 2.29 (m, 5 H), 2.06 - 1.99 (m, 1 H), 1.95 - 1.87 (m, 3 H), 1.85 -1.70 (m, 2 H), 1.39 - 1.09 (m, 6 H), 1.06 - 0.82 (m, 15 H).

[0701] Example 19 (25, 4A)-l-((5)-2-(4-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin- 3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0702]

[0703] Step 1: ethyl 4-(4-((lr, 4r)-4-((4-(2-(l-benzylcyclopropoxy) pyridin-3-yl) pyrimidin-2-yl) amino)cyclohexyl)piperazin-l-yl)butanoate

[0704] To a stirred solution of 4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)-N-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)pyrimidin-2-amine in MeCN (2 mL) were added K2CO3 (85.6 mg, 0.62 mmol), KI (102.8 mg, 0.62 mmol) and ethyl 4-bromobutyrate (0.03 mL, 0.23 mmol) at 25 °C. Then the reaction mixture was stirred at 75 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into ice-water (25 mL), and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (40 mL x 2) and dried with Na2SC>4, concentrated to give crude product, which was purified by column chromatography on silica gel eluting with 0 - 10% MeOH in DCM to afford the title compound (50 mg, 41%) as a white oil. LCMS (ESI): m / z 599.6 (M+H)+.

[0705] Step 2: 4-(4-((lr, 4r)-4-((4-(2-(l -benzyl cycloprop oxy) pyridin-3-yl) pyrimidin-2-yl) amino)cyclohexyl)piperazin-l-yl)butanoic acid

[0706] To a stirred solution of ethyl 4-(4-((lr, 4r)-4-((4-(2-(l -benzylcyclopropoxy) pyridin-3-yl) pyrimidin-2-yl) amino)cyclohexyl)piperazin-l-yl)butanoate (50.0 mg, 0.08 mmol) in THF (2.0 mL) was added LiOH H₂O (10.5 mg, 0.25 mmol) in H2O (0.5 mL) at 25 °C. After stirring at 25 °C for 2 h, the reaction mixture was acidified with HC1 (2.0 M) dropwise till pH ~ 7, and concentrated to afford the title compound (35 mg, 73%) as a white solid. LCMS (ESI): m / z 571.6 (M+H)+.

[0707] Step 3: (25,47?)-l-((5)-2-(4-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0708] To a mixture of 4-(4-((lr,4r)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)butanoic acid (39.7 mg, 0.07 mmol) and T3P (0.03 mL, 0.09 mmol) in DCM (2 mL) was added DIEA (0.04 mL, 0.23mmol) dropwise at 0°C After stirred at 0 °C for 10 min, (25, 47?)-l-((5)-2-amino-3, 3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamidee (20.0 mg, 0.05 mmol) was added to the reaction solution. Then the reaction mixture was then stirred at 25 °C for another 2 h. After that, the reaction mixture was diluted with H2O (5 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (20 mL), dried with anhydrous sodium sulfate and concentrated under vacuum. The resulted residue was purified by reverse phase chromatography (acetonitrile 1- 28% / 0.2% formic acid in water) to afford the Example 19 compound (7.4 mg, 15%) as a white solid. LCMS (ESI): m / z 983.7 (M+H)+. 'H NMR (400 MHz, DMSO-tL) <58.98 (s, 1H), 8.56 (t, J= 6.4 Hz, 1H), 8.39 (dd, J= 2.0, 4.8 Hz, 1H), 8.24 (s, 1H), 8.12 (d, J= 5.2 Hz, 1H), 8.04 (d, J= 9.2 Hz, 1H), 7.45 - 7.35 (m, 4H), 7.25 - 7.13 (m, 7H), 6.63 (s, 1H), 4.56 (d, J= 9.2 Hz, 1H), 4.48 - 4.38 (m, 2H), 4.38 - 4.32 (m, 1H), 4.26 - 4.18 (m, 1H), 3.78 - 3.58 (m, 2H), 3.35 - 3.25 (m, 2H), 3.05 - 2.95 (m, 2H), 2.48 - 2.35 (m, 8H), 2.29 -2.19 (m, 2H), 2.10 - 1.98 (m, 6H), 1.97 - 1.85 (m, 2H), 1.85 - 1.75 (m, 3H), 1.51 - 1.45 (m, 3H), 1.39 - 1.25 (m, 3H), 0.96 - 0.91 (m, 13H).

[0709] Exampl e 20 (25,47?)- 1 -((5)-2-(4-(4-(( 1 r,45)-4-((6-(3 -fluoro-4-((3,3, 3 -trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-J]pyrimidin-2- yl)amino)cyclohexyl)piperazin-l-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0710]

[0711] Step 1: 3,3,3-trifluoro-A-(2-fluoro-4-(8-methyl-2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl)amino)pyrido[3,2-d]pyrimidin-6-yl)phenyl)propane-l -sulfonamide

[0712] To a stirred solution of tert-butyl 4-((lr,4r)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-J]pyrirnidin-2-yl)amino)cyclohexyl)piperazine-l -carboxylate (200.0 mg, 0.29 mmol) in EtOAc (2 mL) was added HC1 (3.0 mL, 4 M in 1,4- dioxane) at 25 °C. After stirring at 25°C for 3 h, the reaction mixture was concentrated under reduced pressure to give the title compound (110 mg, 64%) as a yellow solid. LCMS (ESI): m / z 596.3 (M+H)+.

[0713] Step 2: tert-butyl 4-(4-((lr,4r)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)butanoate

[0714] To a stirred solution of 3,3,3-trifluoro-A-(2-fluoro-4-(8-methyl-2-(((lr,4r)-4-(piperazin-l-yl)cy cl ohexyl)amino)pyrido[3, 2- ]pyrimidin-6-yl)phenyl)propane-l -sulfonamide (80.0 mg, 0.13 mmol) in DMF (5 mL) was added Et3N (0.03 mL, 0.2 mmol) and / <? / 7-butyl4-bromobutanoate (26.97 mg, 0.12 mmol) at 25 °C. Then the reaction mixture was stirred at 25 °C for 3 h. After that, the resulted mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by pre-TLC (10% MeOH in DCM, Rf = 0.4) to afford the title compound (23 mg, 23%) as yellow oil. LCMS (ESI): m / z 738.4 (M+H)+.

[0715] Step 3: 4-(4-((lr,4r)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2- ]pyrimi din-2 -yl)amino)cy cl ohexyl)piperazin-l-yl)butanoic acid

[0716] To a stirred solution of tert-butyl 4-(4-((lr,4r)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)butanoate (23.0 mg, 0.03 mmol) in DCM (1.5 mL) was added TFA (0.5 mL, 6.73 mmol) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under vacuum and the residue was purified by pre-TLC (10% MeOH in DCM, Rf = 0.5) to afford the title compound (15 mg, 71%) as a yellow oil. LCMS (ESI): m / z 682.3 (M+H)+.

[0717] Step 4: (25,4A)-l-((S)-2-(4-(4-((lr,4S)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0718] To a stirred mixture of 4-(4-((lr,4r)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)butanoic acid (15.0 mg, 0.02 mmol) and T3P (0.03 mL, 0.04 mmol) in DMF (1 mL) was added DIEA (0.02 mL, 0.11 mmol) and (25,4A)-l-((5)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (14.2 mg, 0.03 mmol) at 25 °C. Then the reaction mixture was stirred at 40 °C for 2 h. After cooling to room temperature, the reaction mixture was purified by pre-HPLC (acetonitrile 21 - 51 / 0.225% FA in water) to afford the title compound (14.2 mg, 30%) as a white solid. LCMS (ESI): m / z 548.1 (M / 2+H)+. 'HNMR (400 MHz, DMSO-tL) d 9.09 (s, 1H), 8.98 (s, 1H), 8.57 (t, J= 6.0 Hz, 1H), 8.17 (s, 2H), 7.93 (d, J= 12.8 Hz, 1H), 7.90 - 7.83 (m, 2H), 7.56 - 7.48 (m, 1H), 7.46 - 7.35 (m, 5H), 5.14 (s, 1H), 4.54 (d, J= 9.6 Hz, 1H), 4.47 - 4.39 (m, 2H), 4.38 - 4.32 (m, 1H), 4.21 (dd, J= 5.2, 15.6 Hz, 1H), 3.85 - 3.75 (m, 1H), 3.70 - 3.61 (m, 2H), 3.25 - 3.15 (m, 1H), 2.77 - 2.68 (m, 2H), 2.55 - 2.52 (m, 8H), 2.50 - 2.46 (m, 2H), 2.44 (s, 3H), 2.29 - 1.97 (m, 10H), 1.94 - 1.81 (m, 3H), 1.75 - 1.55 (m, 2H), 1.45 - 1.25 (m, 4H), 0.94 (s, 9H).

[0719] Example 21 (2£,4A)-l-((5)-3,3-dimethyl-2-(4-(4-((lr,45)-4-((8-methylpyrido[3,2-t / ]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)butanamido)butanoyl)-4-hydroxy- / ' / -(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0720]

[0721] The compound was prepared according to the procedures described for Example 20. LCMS (ESI): m / z 825.4 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 9.06 (s, 1 H), 8.98 (s, 1 H), 8.58 (t, J= 6.0 Hz, 1 H), 8.42 (d, J= 4.4 Hz, 1 H), 7.86 (d, J= 9.2 Hz, 1 H), 7.52 (d, J= 4.8 Hz, 1 H), 7.44 - 7.36 (m, 4 H), 5.15 (d, J= 3.6 Hz, 1 H), 4.54 (d, J= 9.2 Hz, 1 H), 4.49 - 4.39 (m, 2 H), 4.38 - 4.32 (m, 1 H), 4.21 (dd, J= 15.6, 5.2 Hz, 1 H), 3.85 - 3.75 (m, 1 H), 3.70 - 3.59 (m, 2 H), 3.45 - 3.35 (m, 2 H), 3.34 - 3.18 (m, 3 H), 2.59 - 2.52 (m, 2 H), 2.48 - 2.44 (m, 1 H), 2.44 (s, 3 H), 2.39 - 2.29 (m, 3 H), 2.27 (d, J= 9.2 Hz, 1 H), 2.25 - 2.17 (m, 4 H), 2.16 - 2.12 (m, 1 H), 2.12 - 1.97 (m, 3 H), 1.95 - 1.88 (m, 1 H), 1.88 - 1.81 (m, 2 H), 1.69 - 1.55 (m, 2 H), 1.40 - 1.25 (m, 4 H), 0.94 (s, 9 H).

[0722] Example 22 (25,47?)- 1 -((S)-2-(4-(4 -(( lr,45)-4-((6-(3 -fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0723]

[0724] The compound was prepared according to the procedures described for Example 20. LCMS (ESI): m / z 1138.6 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 8.98 (s, 1 H), 8.67 - 8.54 (m, 2 H), 8.16 (s, 1 H), 7.93 (s, 1 H), 7.88 - 7.83 (m, 1 H), 7.59 (d, J= 12.8 Hz, 1 H), 7.46 - 7.37 (m, 6 H), 5.71 (s, 1 H), 4.53 (d, J= 9.6 Hz, 1 H), 4.48 - 4.39 (m, 2 H), 4.38 - 4.32 (m, 1 H), 4.21 (dd, J= 15.6, 5.2 Hz, 1 H), 3.83 - 3.75 (m, 1 H), 3.70 - 3.60 (m, 4 H), 2.85 - 2.75 (m, 4 H), 2.64 - 2.52 (m, 4 H), 2.50 (s, 3 H), 2.41 - 2.30 (m, 4 H), 2.30 - 2.20 (m, 4 H), 2.20 - 2.10 (m, 2 H), 2.01 (s, 3 H), 1.95 - 1.80 (m, 3 H), 1.70 - 1.60 (m, 2 H), 1.60 - 1.50 (m, 6 H), 1.40 - 1.25 (m, 4 H), 0.94 (s, 9 H). Example 23 (2£,47?)-4-hydroxy-l-((5)-2-(4-(4-((lr,45 -4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)butanamido)-3,3-dimethylbutanoyl)-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0725] HO

[0726]

[0727] The compound was prepared according to the procedures described for Example 20. LCMS (ESI): m / z 869.6 (M+H)+. 'HNMR (400 MHz, DMSO-tfc) d 8.92 (s, 1 H), 8.51 (s, 1 H), 8.23 (s, 1 H), 8.14 (s, 1 H), 7.60 (d, J= 9.2 Hz, 1 H), 7.50, (d, J= 8.4 Hz, 1 H), 7.44 - 7.36 (m, 4 H), 6.16 (d, J= 9.2 Hz, 1 H), 5.70 - 5.60 (m, 1 H), 4.54 (d, J= 8.8 Hz, 1 H), 4.50 - 4.42 (m, 1 H), 4.40 - 4.33 (m, 1 H), 4.32 - 4.21 (m, 1 H), 3.79 - 3.53 (m, 4 H), 3.16 - 3.05 (m, 2 H), 2.73 -2.53 (m, 4 H), 2.47 - 2.43 (m, 5 H), 2.42 - 2.30 (m, 3 H), 2.25 - 2.10 (m, 3 H), 2.10 - 1.85 (m, 6 H), 1.75 - 1.60 (m, 2 H), 1.60 - 1.47 (m, 6 H), 1.45 - 1.21 (m, 4 H), 0.96 (s, 9 H).

[0728] Example 24 (25',47?)-4-hydroxy-l-((5)-2-(2-(3-((4-((lr,4S)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)acetamido)-3,3-dimethylbutanoyl)-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide Step 1

[0729] Step 2 Step 3

[0730]

[0731] Step 1: tert-butyl 5-(4-((lr,4r)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin- 2-yl)amino)cy clohexyl)piperazin- 1 -yl)pentanoate

[0732] To a stirred solution of 4-[2-(l-benzylcyclopropoxy)-3-pyridyl]-7V-(4-piperazin-l-ylcyclohexyl)pyrimidin-2-amine (200 mg, 383 pmol) in DMF (0.50 mL) was added DIEA dropwise (297 mg, 2.30 mmol) at 20 °C. After stirred at 20 °C for 20 min, K2CO3 (265 mg, 1.92 mmol), KI (63.7 mg, 383 pmol) and tert-butyl 5-bromopentanoate (100 mg, 422 pmol) were added to the reaction mixture. Then the reaction mixture was stirred at 20 °C for another 8 h. After that, the reaction mixture was concentrated and the residue was purified by column chromatography eluting with 10% - 20% EtOAc in MeOH to afford the title compound (254 mg, crude) as yellow oil. 'HNMR (400 MHz, DMSO-t / 6) d 8.40 - 8.30 (m, 2H), 8.05 - 7.95 (m, 2H), 7.23 - 7.13 (m, 6H), 6.64 (d, J= 6.4 Hz, 1H), 3.85 - 3.75 (m, 1H), 3.40 - 3.30 (m, 3H), 2.95 -2.76 (m, 3H), 2.75 - 2.57 (m, 3H), 2.55 - 2.45 (m, 3H), 2.32 - 2.25 (m, 2H), 2.25 - 2.15 (m, 2H), 2.10 - 2.00 (m, 2H), 1.70 - 1.52 (m, 4H), 1.51 - 1.42 (m, 12 H), 1.40 - 1.30 (m, 2 H), 1.05 - 0.95 (m, 4 H).

[0733] Step 2: 5-(4-((lr,4r)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)pentanoic acid

[0734] To a stirred solution of tert-butyl 5-(4-((lr,4r)-4-((4-(2-(l-benzylcyclopropoxy)pyridin- 3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanoate (180 mg, 341 pmol) in EtOAc (2.0 mL) and MeOH (0.5 mL) was added HC1 (4 M, 0.1 mL in EtOAc) at 20 °C, then the mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (acetonitrile 5-35 / 0.075% TFAin water) to afford the title product (72.0 mg, 45%) as a white solid. LCMS (ESI): m / z 585.1 (M+H)+Step 3: (25,4A)-l-((5)-2-(5-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0735] To a stirred solution of 5-(4-((lr,4r)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanoic acid (48.6 mg, 83.1 umol) in DMF (1.00 mL) was added DIEA (32.2 mg, 249 umol) and HATU (33.2 mg, 87.3 umol) at 0 °C. After stirring at 0 °C for 0.5 h, (25,4A)-l-[(25)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-A-[(15)-l-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (40.0 mg, 83.1 pmol) in DMF (0.10 mL) was added dropwise to the reaction mixture, which was stirred at 0 °C for another 1 h. After that, the reaction mixture was purified by pre-HPLC (acetonitrile 1-50 / 0.225% FA in water) to afford the title compound (23.5 mg, 28%) as a white solid. LCMS (ESI): m / z 1011.5 (M+H)+. 'HNMR (400 MHz, MeOD) 38.89 (s, 1H), 8.35 - 8.22 (m, 2H), 8.01 (d, J = 5.6 Hz, 1H), 7.47 - 7.40 (m, 4H), 7.27 - 7.13 (m, 6H), 6.64 (d, J= 5.6 Hz, 1H), 5.05 - 5.00 (m, 1H), 4.65 (s, 1H), 4.65 - 4.60 (m, 1H), 4.49 - 4.40 (m, 1H), 3.90 (d, J= 5.6 Hz, 1H), 3.85 - 3.70 (m, 2H), 2.95 - 2.60 (m, 8H), 2.55 - 2.47 (m, 5H), 2.40 - 2.30 (m, 2H), 2.28 - 2.15 (m, 3H), 2.10 - 1.95 (m, 4H), 1.75 - 1.57 (m, 6H), 1.53 (d, J= 3.6 Hz, 2H), 1.50 - 1.30 (m, 5H), 1.06 (s, 9H) 1.02 - 0.93 (m, 4H).

[0736] Exampl e 25 (2A',4 / )-4-hy droxy- 1 -((5)-2-(5 -(4-(( 1 r,45 -4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanamido)-3,3-dimethylbutanoyl)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0737]

[0738] The Example 25 compound was prepared according to the procedures described for Example 24. LCMS (ESI): m / z 897.5 (M+H)+. 'HNMR (400 MHz, MeOD) 38.89 (s, 1H), 8.55 (s, 1H), 7.66 (d, J= 8.8 Hz, 1H), 7.50 - 7.40 (m, 4H), 6.28 (d, J= 8.8, 1H), 5.85 - 5.75 (m, 1H), 5.08 - 5.00 (m, 1H), 4.65 (s, 1H), 4.64 - 4.55 (m, 1H), 4.49 - 4.40 (m, 1H), 3.98 - 3.82 (m, 2H), 3.80 - 3.75 (m, 1H), 2.95 - 2.65 (m, 11H), 2.50 (s, 3H), 2.47 - 2.27 (m, 2H), 2.25 - 2.05 (m, 5H), 2.04 - 1.95 (m, 1H), 1.75 - 1.55 (m, 11H), 1.53 (d, J= 6.8 Hz, 2H), 1.50 - 1.40 (m, 4H), 1.07 (s, 9H).

[0739] Exampl e 26 (2A',4 / )-4-hy droxy- 1 -((5)-2-(5 -(4-(( 1 r,45 -4-((8-i sopropyl-7-oxo-7, 8-dihydropteridin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanamido)-3,3-dimethylbutanoyl)-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0740] CbzHN Step 2

[0741] Step 4 Step 5 Step 3

[0742]

[0743] Step 1: tert-butyl 4-(4-(((benzyloxy)carbonyl)amino)cyclohexyl)piperazine-l-carboxylate

[0744] A mixture of benzyl (4-oxocyclohexyl)carbamate (10.0 g, 40.44 mmol) and tert-butyl piperazine- 1 -carboxylate (7.53 g, 40.44 mmol) in DCM (200 mL) was stirred at 25 °C for 2 h under N2 atmosphere. Then NaBH(OAc)s (2.57 g, 121.32 mmol) andHOAc (0.9 mL, 16.18 mmol) were added to the reaction mixture. The resulting reaction mixture was stirred at 25 °C for 16 h. After that, the reaction was quenched with saturated NH4CI solution (50 mL) and diluted with H2O (100 mL). Then the mixture was extracted with DCM (100 mL x 2). The combined organic layer was concentrated and purified by column chromatography on silica gel eluting with 0 - 60% ethyl acetate in petroleum ether to afford tert-butyl 4-(4- (((benzyloxy)carbonyl)amino)cyclohexyl)piperazine-l-carboxylate (15.0 g) as a mixture of two isomers. It was further separated by SFC (DAICEL CHIRALCEL OD (250 mm*50 mm, 10 urn)); CC>2 / (EtOH + 0.1% NH3 H2O) = 70 / 30; 200 mL / min) to afford the title compound (6.80 g, 40 %, second peak on SFC) as a white solid. LCMS (ESI): m / z 418.3 (M+H)+.

[0745] Step 2: tert-butyl 4-((lr,4r)-4-aminocyclohexyl)piperazine-l -carboxylate

[0746] To a solution of tert-butyl 4-((lr,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)piperazine-l-carboxylate (6.8 g, 16.29 mmol) in MeOH (70 mL) was added 10% Pd / C (1.1 g) at 25 °C under Ar atmosphere. Then the reaction mixture was stirred at 25 °C for 16 h under H2 (15 psi). After that, the reaction mixture was filtered and the filtrate was concentrated to dryness to afford the title compound (4.62 g, 100%) as a yellow solid. 'HNMR (400 MHz, DMSO-d6) <53.25 (s, 4H), 2.46 - 2.41 (m, 1H), 2.41 -2.36 (m, 4H), 2.24 - 2.13 (m, 1H), 1.81 - 1.64 (m, 4H), 1.38 (s, 9H), 1.27 - 1.12 (m, 2H), 1.08 -0.91 (m, 2H).

[0747] Step 3: tert-butyl 4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropteridin-2-yl)amino)cyclohexyl)piperazine-l -carboxylate

[0748] A mixture of 2-chloro-8-isopropylpteridin-7(8H)-one (2.0 g, 8.9 mmol), CsF (1.35 g, 8.9 mmol), DIEA(4.7 mL, 26.71 mmol) and tert-butyl 4-((lr,4r)-4-aminocyclohexyl)piperazine-l-carboxylate (2.5 g, 8.9 mmol) in DMSO (20 mL) was stirred at 60 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with H2O (50 mL), extracted with EtOAc (50 mL x 3). The organic layers were combined, washed by brine solution (50 mL x 3), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with 0 - 10% MeOH in DCM to afford the title compound (1.5 g, 36%) as a yellow solid. LCMS (ESI): m / z 472.2 (M+H)+.

[0749] Step 4: 8-isopropyl-2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl)amino)pteridin-7(8H)-one hydrochloride

[0750] To a solution of tert-butyl 4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropteridin-2-yl)amino)cyclohexyl)piperazine-l -carboxylate (1.5 g, 3.18 mmol) in EtOAc (10 mL) was added HC1 (12.0 mL, 4 M in EtOAc) at 0 °C. Then the reaction mixture was stirred at 25 °C for 3 h. After that, the reaction mixture was concentrated to afford the title compound (1.30 g, 100%) as a white solid. The crude product was directly used in the next step without further purification.

[0751] Step 5: tert-butyl 5-(4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropteridin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)pentanoate

[0752] To a stirred solution of tert-butyl 5-bromopentanoate (436.0 mg, 1.84 mmol) in DMF (5 mL) was added DIEA (0.32 mL, 1.84 mmol), and the mixture was stirred at 25 °C for 0.1 h. Then KI (101.7 mg, 0.61 mmol), K2CO3 (254.1 mg, 1.84 mmol) and 8-isopropyl-2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl)amino)pteridin-7(8H)-one hydrochloride (250.0 mg, 0.61 mmol) were added to the above reaction mixture at 25 °C. The resulting reaction mixture was stirred at 25 °C for another 16 h. After that, the mixture was filtered to remove the undissolved solid and the filtrate was concentrated under vacuum to give the crude product, which was purified by column chromatography on silica gel eluting with 0 - 5% MeOH in DCM to afford the title compound (120 mg, 37%) as a yellow solid. LCMS (ESI): m / z 528.2 (M+H)+.

[0753] Step 6: 5-(4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropteridin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)pentanoic acid

[0754] To a solution of tert-butyl 5-(4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropteridin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanoate (40.0 mg, 0.08 mmol) in DCM (1 mL) was added TFA (0.23 mL, 3.03 mmol) at 0 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated to afford the title compound (35.7 mg, 100%) as a white solid. The crude product was directly used in the next step without further purification.

[0755] Step 7: (25,4A)-4-hy droxy- 1 -((5 -2-(5 -(4-(( 1 r,45)-4-((8-i sopropyl-7-oxo-7, 8-dihydropteridin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanamido)-3,3-dimethylbutanoyl)-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0756] A mixture of 5-(4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropteridin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanoic acid (34.5 mg, 0.07 mmol), HATU (61.8 mg, 0.16 mmol) and DIEA (0.07 mL, 0.41 mmol) in DMF (1.0 mL) was stirred at 25 °C for 0.5 h. Then (25,4A)-l-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (35.0 mg, 0.08 mmol) in DMF (0.3 mL) was added dropwise to the reaction mixture. The resulting reaction mixture was stirred at 25 °C for 2 h. After that, the reaction mixture was purified by pre-HPLC (acetonitrile 20 - 50 / 0.225% FA in water) to afford the Example 26 compound (22.5 mg, 29%) as a white solid. LCMS (ESI): m / z 884.5 (M+H)+. 'H NMR (400 MHz, DMSO-d6) d 8.93 (s, 1H), 8.61 (s, 1H), 8.24 (t, J= 5.6 Hz, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.49 (d, J= 9.2 Hz, 1H), 7.44 - 7.36 (m, 4H), 5.55 - 5.45 (m, 1H), 4.54 (d, J= 9.2 Hz, 1H), 4.50 - 4.36 (m, 3H), 4.29 - 4.22 (m, 1H), 3.72 - 3.65 (m, 3H), 2.65 -2.55 (m, 4H), 2.50 - 2.40 (m, 6H), 2.40 - 2.31 (m, 3H), 2.30 - 2.22 (m, 1H), 2.20 - 2.13 (m, 1H), 2.08 - 1.97 (m, 4H), 1.95 - 1.85 (m, 2H), 1.60 -1.48 (m, 8H), 1.50 - 1.24 (m, 8H), 0.96 (s, 9H).

[0757] Example 27 (25,4A)-4-hydroxy-l-((5)-2-(4-((lA,35)-3-((4-((lr,45)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)-U / -l,2,3-triazol-l-yl)-3-methylbutanoyl)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide step 9

[0758]

[0759] Step 1: tert-butyl (5)-(l-(4-bromophenyl)ethyl)carbamate

[0760] To a stirred solution of (5)-l-(4-bromophenyl)ethan-l-amine (10.0 g, 50.0 mmol) in DCM (200 mL) was added BOC2O (13 g, 60.0 mmol) at 0 °C. Then the reaction mixture was stirred at 25 °C for 16 h. After that, the mixture was concentrated and the residue was triturated with petroleum ether (200 mL) to afford the title compound (13 g, 78%) as a white solid. 'H NMR (400 MHz, CDCl3) 37.44 (d, J= 6.8 Hz, 2H), 7.17 (d, J= 8.0 Hz, 2H), 4.71 - 4.74 (m, 1H), 1.42 - 1.40 (m, 12H).

[0761] Step 2: tert-butyl (S)-(l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate

[0762] To a mixture of tert-butyl (5)-(l-(4-bromophenyl)ethyl)carbamate (13.0 g, 43.31 mmol) and Pd(OAc)2 (97 mg, 0.43 mmol) in DMF (200 mL) were added KOAc (8.5 g, 86.61 mmol) and 4-methylthiazole (4.73 mL, 51.97 mmol) at 25 °C. Then the mixture was stirred at 90 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layer was dried with anhydrous sodium sulphate, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with 0 - 10% ethyl acetate in petroleum ether to afford the title compound (12 g, 87%) as a yellow solid. LCMS (ESI): m / z 319.1 (M+H)+. 'HNMR (400 MHz, DMSO-tL) 38.98 (s, 1H), 7.46 - 7.37 (m, 5H), 4.63 - 4.47 (m, 1H), 2.45 (s, 3H), 1.37 (s, 9H), 1.32 (d, J= 6.8 Hz, 3H).

[0763] Step 3: (S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethan-l-amine hydrochloride

[0764] To a solution of tert-butyl (5)-(l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (12.0 g, 37.68 mmol) in EtOAc (10 mL) was added 4 M HC1 in EtOAc (40 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. After that, the reaction mixture was concentrated under vacuum to give the title compound (9.6 g, 100%) as a white solid. LCMS (ESI): m / z 219.1(M+H)+.

[0765] Step 4: tert-butyl (2A,45)-4-hydroxy-2-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-l -carboxylate

[0766] To a solution of (25,4A)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (10.89 g, 47.1 mmol) in DMF (100 mL) were added HATU (21.5 g, 56.5 mmol), DIEA(16.5 mL, 94.2 mmol) and (5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethan-l-amine hydrochloride (12.0 g, 47.1 mmol) at 0 °C under nitrogen atmosphere. Then the reaction mixture was stirred at 25 °C for 12 h. After that, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was concentrated and purified by column chromatography on silica gel eluting with 0 - 40% (EtOAc: Ehanol = 3: 1) in petroleum ether to afford the title compound (12.0 g, 59%) as a yellow solid. LCMS (ESI): m / z 432.4 (M+H)+.

[0767] Step 5: (25,4A)-4-hydroxy-A-((5)- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride

[0768] To a solution of tert-butyl (2A,45)-4-hydroxy-2-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-l -carboxylate (12.0 g, 27.81mmol) in EtOAc (20 mL) was added 4 M HC1 in EtOAc (40 mL) at 0 °C. After stirring at 25 °C for 2 h, the mixture was concentrated under vacuum to give the title compound (10 g, 100%) as a white solid. LCMS (ESI): m / z 331.9 (M+H)+'

[0769] Step 6: (2S,4R)-l-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0770] To a solution of fS')-2-azido-3 -methylbutanoic acid (950 mg, 6.64 mmol) in DMF (30 mL) were added DIEA(2.31 mL, 13.28 mmol) and HATU (3.78 g, 9.96 mmol) at 0 °C. After stirring at 0 °C for 10 min., (2S, 4A)-4-hydroxy-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (2.43 g, 6.64 mmol) was added to the reaction mixture, which was stirred at 25 °C for 2 h. After that, the reaction mixture was diluted with ethyl acetate (60 mL), washed with water (30 mL x 3). The organic layer was concentrated and the residue was purified by column chromatography on silica gel eluting with 0 - 25 % (EtOAc: Ethanol = 3:1) in petroleum ether) to afford the title compound (1.6 g, 53%) as a white solid. LCMS (ESI): m / z 457.5 (M+H)+. 'HNMR (400 MHz, CHC13) d 8.71 (s, 1H), 7.48 - 7.27 (m, 5H), 5.10 - 5.03 (m, 1H), 4.80 (dd, J = 6.0 Hz, 8.4 Hz, 1H), 4.71 - 4.67 (m, 1H), 3.76 - 3.68 (m, 1H), 3.64 - 3.57 (m, 1H), 3.44 - 3.37 (m, 1H), 2.65 - 2.59 (m, 1H), 2.55 (s, 3H), 2.40 - 2.21 (m, 1H), 2.03 - 2.00 (m, 1H), 1.49 (d, J= 6.8 Hz, 3H), 1.11 (d, J= 6.8 Hz, 3H), 1.01 (d, J= 6.8 Hz, 3H).

[0771] Step 7: 8-isopropyl-2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl)amino)pyrido[2,3-d]pyrimidin-7(87 / )-one hydrochloride

[0772] To a solution of / <? / 7-butyl 4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazine-l -carboxylate (6.5 g, 13.81 mmol) in 1,4-dioxane (20 mL) was added 4M HC1 in 1,4-dioxane (100 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 4 h. Then the reaction mixture was concentrated under vacuum to afford the crude title compound as a yellow solid. The crude product was directly used for the next step without further purification. LCMS (ESI): m / z 371.2 (M+H)+.

[0773] Step 8: 2-((( 1 A,4r)-4-(4-((( lr,3A)-3 -ethynylcyclobutyl)methyl)piperazin- 1 -yl)cyclohexyl)amino)-8-isopropylpyrido[2,3-J]pyrimidin-7(8J7)-one and 2-(((lA,4r)-4-(4-(((l,35)-3-ethynylcyclobutyl)methyl)piperazin-l-yl)cyclohexyl)amino)-8-isopropylpyrido[2,3- ]pyrimidin-7(8J7)-one

[0774] To a mixture of (3-ethynylcyclobutyl)methyl methanesulfonate (297.2 mg, 1.58 mmol) and K2CO3 (671.5 mg, 4.86 mmol) in DMF (1 mL) was added 8-isopropyl-2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl)amino)pyrido[2,3-J]pyrimidin-7(8J7)-one hydrochloride (450.0 mg, 1.11 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 16 h. After that, the reaction mixture was cooled to room temperature. The mixture was purified by pre-HPLC (acetonitrile 7- 37 / 0.225% FA in water) to afford a mixture of two isomers (120 mg) as a yellow solid. It was further purified by SFC (Daicel Chiralcel OJ (250 mm * 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 80 / 20; 70 mL / min) to afford 2-(((lA,4r)-4-(4-(((lr,3A)-3-ethynylcyclobutyl)methyl)piperazin-l-yl)cyclohexyl)amino)-8-isopropylpyrido[2,3-J]pyrimidin-7(8J7)-one (63 mg, 12%, first peak on SFC) as a yellow solid and 2-(((lA,4r)-4-(4-(((l,35)-3-ethynylcyclobutyl)methyl)piperazin-l-yl)cyclohexyl)amino)-8-isopropylpyrido[2,3-J]pyrimidin-7(8J7)-one (50 mg, 10%, second peak on SFC) as a yellow solid. Absolute configuration was arbitrarily assigned to each isomer. LCMS (ESI): m / z 463.2 (M+H)+.

[0775] Step 9: (25',4A)-4-hydroxy-l-((5)-2-(4-((lA,35 -3-((4-((lr,45)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)-U / -l,2,3-triazol-l-yl)-3-methylbutanoyl)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0776] To a solution of 2-(((lA,4r)-4-(4-(((lr,3A)-3-ethynylcyclobutyl)methyl)piperazin-l-yl)cyclohexyl)amino)-8-isopropylpyrido[2,3- ]pyrimidin-7(8J7)-one (25.0 mg, 0.05 mmol) in t-BuOH (1 mL) and water (1 mL) was added sodium L-ascorbate (5.4 mg, 0.03 mmol), CuSO4'5H2O (6.8 mg, 0.03 mmol) and (25,4A)-l-((5)-2-azido-3-methylbutanoyl)-4-hydroxy-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (27.1 mg, 0.06 mmol) at 25 °C. The resulting reaction mixture was stirred at 25 °C for 16 h. Then the mixture was purified by pre-HPLC (acetonitrile 13-43 / 0.225% FA in water) to afford the title compound (27.4 mg, 51%) as a white solid. Absolute configuration was arbitrarily assigned. LCMS (ESI): m / z 919.9 (M+H)+. 'H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.58 - 8.45 (m, 2H), 7.96 (s, 1H), 7.76 - 7.55 (m, 2H), 7.48 - 7.42 (m, 2H), 7.40 - 7.34 (m, 2H), 6.23 - 6.07 (m, 1H), 5.77 -5.52 (m, 1H), 5.20 (d, J= 10.4 Hz, 1H), 4.96 - 4.87 (m, 1H), 4.37 (t, J= 8.0 Hz, 1H), 4.31 (s, 1H), 3.80 - 3.59 (m, 4H), 2.49 - 2.44 (m, 6H), 2.44 - 2.29 (m, 10H), 2.27 - 2.15 (m, 2H), 2.09 -1.95 (m, 3H), 1.94 - 1.73 (m, 6H), 1.55 - 1.46 (m, 6H), 1.38 (d, J= 6.8 Hz, 3H), 1.33 - 1.22 (m, 4H), 1.03 (d, J = 6.4 Hz, 3H), 0.64 (d, J = 6.4 Hz, 3H).

[0777] Example 28 (25',4A)-4-hydroxy-l-((5)-2-(4-((15',3A)-3-((4-((lr,4A)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)-U / -l,2,3-triazol-l-yl)-3-methylbutanoyl)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0778]

[0779] The compound was prepared according to the procedures described for Example 27. Absolute configuration was arbitrarily assigned. LCMS (ESI): m / z 920.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) d 8.98 (s, 1H), 8.58 - 8.48 (m, 2H), 8.02 - 7.95 (m, 1H), 7.74 - 7.57 (m, 2H), 7.49. 7.43 (m, 2H), 7.41 - 7.35 (m, 2H), 6.25 - 6.09 (m, 1H), 5.76 - 5.55 (m, 1H), 5.22 (d, J = 10.4 Hz, 1H), 4.91 (t, J= 7.6 Hz, 1H), 4.38 (t, J= 8.0 Hz, 1H), 4.32 (s, 1H), 3.79 - 3.73 (m, 2H), 3.67 - 3.63 (m, 2H), 2.48 - 2.45 (m, 6H), 2.43 - 2.40 (m, 4H), 2.39 - 2.32 (m, 4H), 2.24 - 2.15 (m, 4H), 2.09 - 2.03 (m, 3H), 1.99 - 1.92 (m, 2H), 1.90 - 1.76 (m, 4H), 1.53 (d, J= 7.2 Hz, 4H), 1.47 (d, J= 6.8 Hz, 2H), 1.38 (d, J= 6.8 Hz, 3H), 1.35 - 1.25 (m, 4H), 1.04 (d, J= 6.4 Hz, 3H), 0.65 (d, J= 6.8 Hz, 3H).

[0780] Example 29 (25',4A)-4-hydroxy-l-((5)-2-(4-((15',3A)-3-((4-((lr,4A)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)-U / -l,2,3-triazol-l-yl)-3-methylbutanoyl)-A-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5J / -benzo[7]annulen-5-yl)pyrrolidine-2-caroxamide

[0781]

[0782] The compound was prepared according to the procedures described for Example 27. Absolute configuration was arbitrarily assigned. LCMS (ESI): m / z 981.5 (M+Na)+. 'H NMR. (400 MHz, DMSO-d6) d 8.97 (s, 1H), 8.61 - 8.50 (m, 2H), 8.02 (s, 1H), 7.76 - 7.56 (m, 2H), 7.30 - 7.24 (m, 2H), 7.20 (d, J= 7.6 Hz, 1H), 6.22 - 6.11 (m, 1H), 5.73 -5.53 (m, 1H), 5.24 - 5.20 (m, 1H), 5.00 - 4.94 (m, 1H), 4.49 (t, J= 8.0 Hz, 1H), 4.39 - 4.35 (m, 1H), 3.77 - 3.70 (m, 4H), 2.89 - 2.86 (m, 2H), 2.48 - 2.45 (m, 6H), 2.44 - 2.40 (m, 4H), 2.39 - 2.31 (m, 5H), 2.24 - 2.17 (m, 4H), 2.11 - 2.06 (m, 2H), 2.00 - 1.81 (m, 10H), 1.63 - 1.57 (m, 1H), 1.54 - 1.45 (m, 6H), 1.34 -1.25 (m, 5H), 1.05 (d, J= 6.4 Hz, 3H), 0.65 (d, J= 6.4 Hz, 3H).

[0783] Example 30 (25,4A)-l-((S)-2-(4-((15,3A)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)-U / -l,2,3-triazol-l-yl)-3-methylbutanoyl)-4-hydroxy-7V-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5J / -benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide

[0784] NH H

[0785] N -N, 0

[0786] T-NN>N:

[0787] NI

[0788]

[0789] The compound was prepared according to the procedures described for Example 27. Absolute configuration was arbitrarily assigned. LCMS (ESI): m / z 1074.0 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 38.97 (s, 1H), 8.56 (d, J= 8.0 Hz, 1H), 8.37 (dd, J= 2.0, 4.8 Hz, 1H), 8.29 - 8.19 (m, 1H), 8.09 (d, J= 5.2 Hz, 1H), 8.02 (s, 1H), 7.28 - 7.23 (m, 3H), 7.22 - 7.13 (m, 6H), 6.98 (d, J= 7.6 Hz, 1H), 6.59 (s, 1H), 5.28 - 5.17 (m, 2H), 5.04 - 4.94 (m, 1H), 4.55 - 4.45 (s, 1H), 4.37 (s, 1H), 3.83 - 3.75 (m, 1H), 3.71 - 3.62 (m, 2H), 3.57 - 3.49 (m, 2H), 2.88 (s, 2H), 2.62 - 2.53 (m, 2H), 2.48 - 2.40 (m, 9H), 2.39 - 2.30 (m, 4H), 2.22 - 2.17 (m, 3H), 2.10 - 2.04 (m, 2H), 1.99 - 1.78 (m, 10H), 1.64 - 1.56 (m, 1H), 1.32 - 1.20 (m, 6H), 1.05 (d, J= 6.4 Hz, 3H), 0.92 (s, 4H), 0.65 (d, J= 6.4 Hz, 3H).

[0790] Example 31 (25,4A)-l-((S)-2-(4-((lA,3S)-3-((4-((lr,4S)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)-U / -l,2,3-triazol-l-yl)-3-methylbutanoyl)-4-hydroxy-7V-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide NH

[0791]

[0792] The compound was prepared according to the procedures described for Example 27. Absolute configuration was arbitrarily assigned. LCMS (ESI): m / z 517.6 (M / 2+H)+. 'H NMR (400 MHz, DMSO-d6) 38.98 (s, 1H), 8.50 (d, J= 7.6 Hz, 1H), 8.37 - 8.25 (m, 1H), 8.24 (s, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.96 (s, 1H), 7.49 - 7.41 (m, 2H), 7.40 - 7.33 (m, 2H), 7.26 - 7.12 (m, 6H), 6.98 (d, J= 7.6 Hz, 1H), 6.59 (s, 1H), 5.20 (d, J= 10.0 Hz, 1H), 5.18 - 5.12 (m, 1H), 4.91 (t, J= 7.2 Hz, 1H), 4.37 (t, J= 8.4 Hz, 1H), 4.31 (s, 1H), 3.75 (d, J= 6.4 Hz, 1H), 3.64 (d, J = 10.0 Hz, 2H), 3.35 - 3.30 (m, 6H), 2.45 (s, 3H), 2.43 - 2.31 (m, 10H), 2.22 (s, 1H), 2.10 - 1.90 (m, 4H), 1.86 - 1.74 (m, 5H), 1.40 - 1.33 (m, 3H), 1.31 - 1.22 (m, 4H), 1.03 (d, J= 6.4 Hz, 3H), 0.92 (s, 4H), 0.64 (d, J= 6.4 Hz, 3H).

[0793] Example 32 (25,4A)-l-((S)-2-(4-((15,3A)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)-U / -l,2,3-triazol-l-yl)-3-methylbutanoyl)-4-hydroxy-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0794]

[0795] The compound was prepared according to the procedures described for Example 27. Absolute configuration was arbitrarily assigned. LCMS (ESI): m / z 1033.7 (M+H)+. 'H NMR (400 MHz, DMSO-tL) <58.98 (s, 1H), 8.50 (d, J= 7.6 Hz, 1H), 8.37 (dd, J= 2.0, 4.8 Hz, 1H), 8.25 (s, 1H), 8.09 (d, J= 5.2 Hz, 1H), 8.03 - 7.95 (m, 1H), 7.47 - 7.41 (m, 2H), 7.41 - 7.34 (m, 2H), 7.25 - 7.12 (m, 6H), 6.98 (d, J= 8.0 Hz, 1H), 6.59 (s, 1H), 5.22 (d, J= 10.4 Hz, 1H), 5.19 - 5.13 (m, 1H), 4.91 (t, J= 7.2 Hz, 1H), 4.38 (t, J= 8.4 Hz, 1H), 4.32 (s, 1H), 3.78 - 3.74 (m, 1H), 3.65 (d, J= 10.8 Hz, 2H), 3.57 - 3.51 (m, 2H), 3.30 (s, 4H), 2.45 (s, 3H), 2.44 - 2.30 (m, 8H), 2.21 (s, 3H), 2.12 - 1.88 (m, 6H), 1.84 - 1.75 (m, 3H), 1.41 - 1.34 (m, 3H), 1.28 - 1.24 (m, 4H), 1.04 (d, J= 6.4 Hz, 3H), 0.92 (s, 4H), 0.65 (d, J= 6.4 Hz, 3H).

[0796] Example 33 rac-(25,47?)-4-hydroxy-7V-methyl-l-[rac-(25)-2-[4-[4-[4-[4-[[4-[2-(l-benzylcyclopropoxy)-3-pyridyl]pyrimidin-2-yl]amino]cyclohexyl]piperazin-l-yl]butyl]triazol-l-yl]-3,3-dimethyl-butanoyl]pyrrolidine-2-carboxamide

[0797]

[0798] The compound was prepared according to the procedures described for Example 27 and obtained as a formate. LCMS (ESI): m / z 848.5 (M+H)+.1H NMR (400 MHz, CDCl3) d 8.42 (s, 1H), 8.37 (dd, J= 4.8, 2.0 Hz, 1H), 8.30 (d, J= 6.8 Hz, 1H), 8.10 (d, J= 5.2 Hz, 1H), 7.88 (s, 1H), 7.27 - 7.18 (m, 5H), 7.08 (dd, J= 7.6, 4.8 Hz, 1H), 6.82 (d, J= 5.2 Hz, 1H), 6.76 (d, J= 5.2 Hz, 1H), 5.40 (s, 1H), 5.07 (s, 1H), 4.60 (t, J= 8.4 Hz, 1H), 4.52 (s, 1H), 3.88 - 3.73 (m, 3H), 3.38 (s, 2H), 2.94 (s, 4H), 2.86 (d, J= 4.8 Hz, 4H), 2.70 (dd, J= 14.4, 6.8 Hz, 6H), 2.35 - 2.18 (m, 6H), 2.07 (d, J= 10.0 Hz, 3H), 1.78 (dd, J= 13.6, 6.0 Hz, 1H), 1.67 (dd, J= 14.0, 6.4 Hz, 1H), 1.61 - 1.46 (m, 4H), 1.34 - 1.20 (m, 2H), 1.11 (s, 9H), 1.04 - 1.00 (m, 2H), 0.95 - 0.90 (m, 2H).

[0799] Example 34 (2S,4R)-4-hydroxy-l-((S)-2-(4-(3-(4-((lr,4S)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)propyl)-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carb oxami de

[0800]

[0801] The compound was prepared according to the procedures described for Example 27. LCMS (ESI): m / z 893.6 (M+H)+. 'HNMR (400 MHz, DMSO-tL) d 8.93 (s, 1H), 8.51 (s, 1H), 8.24 - 8.14 (m, 1H), 7.90 - 7.81 (m, 1H), 7.60 (d, J= 92 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.40 -7.37 (m, 2H), 6.26 - 6.07 (m, 1H), 5.72 - 5.58 (m, 1H), 5.20 (d, J= 10.0 Hz, 1H), 4.96 - 4.93 (m, 1H), 4.48 - 4.38 (m, 1H), 4.36 - 4.31 (m, 1H), 3.86 - 3.78 (m, 1H), 3.76 - 3.69 (m, 1H), 3.61 -3.53 (m, 1H), 2.70 - 2.61 (m, 4H), 2.46 (s, 3H), 2.45 - 2.44 (m, 1H), 2.40 - 2.35 (m, 4H), 2.34 -2.18 (m, 6H), 2.07 - 1.97 (m, 3H), 1.93 - 1.84 (m, 3H), 1.80 - 1.72 (m, 2H), 1.53 (d, J= 6.8 Hz, 6H), 1.42 (d, J= 6.8 Hz, 3H), 1.40 - 1.22 (m, 5H), 1.07 - 0.97 (m, 3H), 0.75 - 0.65 (d, J= 6.8 Hz, 3H).

[0802] Example 35 (25,47?)-l-((S)-2-(4-(3-(4-((lr,4S)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)propyl)-lH-1,2,3 -tri azol- 1 -y l)-3 -methylbutanoyl )-4-hydroxy-7V-((5)- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0803]

[0804] The compound was prepared according to the procedures described for Example 27. LCMS (ESI): m / z 1007.6 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.50 (d, J= 7.6 Hz, 1H), 8.42 - 8.34 (m, 1H), 8.32 - 8.20 (m, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.91 (s, 1H), 7.48 - 7.42 (m, 2H), 7.40 - 7.33 (m, 2H), 7.25 - 7.21 (m, 2H), 7.19 - 7.13 (m, 3H), 6.98 (d, J = 7.6 Hz, 1H), 6.59 (s, 1H), 5.28 - 5.09 (m, 2H), 4.97 - 4.87 (m, 1H), 4.37 (t, J= 8.4 Hz, 1H), 4.35 - 4.25 (s, 1H), 3.77 - 3.74 (m, 1H), 3.62 (d, J= 10.8 Hz, 2H), 3.30 (s, 2H), 2.61 (t, J= 7.6 Hz, 2H), 2.50 - 2.46 (m, 5H), 2.45 - 2.36 (m, 3H), 2.33 (s, 3H), 2.27 - 2.15 (m, 4H), 2.09 - 2.01 (m, 1H), 2.00 - 1.91 (m, 2H), 1.84 - 1.69 (m, 5H), 1.38 (d, J= 7.2 Hz, 3H), 1.26 - 1.23 (m, 5H), 1.03 (d, J= 6.4 Hz, 3H), 0.92 (s, 4H), 0.64 (d, J = 6.4 Hz, 3H).

[0805] Example 36 (25,47?)-4-hydroxy-l-((5)-2-(4-(3-(4-((lr,4S)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)propyl)-U / -l,2,3-triazol-l-yl)-3-methylbutanoyl)-7V-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5JT-benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide

[0806]

[0807] Step 1: tert-butyl (25,4A)-4-hydroxy-2-(((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5J / -benzo[7]annulen-5-yl)carbamoyl)pyrrolidine-l -carboxylate

[0808] A mixture of (2, 4 / )-l -(tert-butoxycarbonyl )-4-hydroxypyrroli di ne-2-carboxylic acid (393.8 mg, 1.7 mmol) in DMF (6 mL) were added HATU (706.36 mg, 1.86 mmol) and DIEA (0.54 mL, 3.1 mmol) at 25 °C. After stirring at 25 °C for 30 min, (5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5J / -benzo[7]annulen-5-amine (400.0 mg, 1.55mmol) was added at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine (50 mL), dried over with Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0-25% (25% ethanol in ethyl acetate) in petroleum ether to afford the title compound (730 mg, 99%) as colorless oil. LCMS (ESI): m / z 472.4 (M+H)+.

[0809] Step 2: (25,4A)-4-hydroxy-A-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-57 / -benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide hydrochloride

[0810] A mixture of tert-butyl (25, 4A)-4-hydroxy-2-(((5)-2-(4-methylthiazol-5-yl)-6, 7,8,9-tetrahydro-5J / -benzo[7]annulen-5-yl)carbamoyl)pyrrolidine-l-carboxylate (730.0 mg, 1.55 mmol) in HC1 (10 mL, 4 M) in EtOAc was stirred at 20 °C for 30 min. Then the reaction mixture was concentrated to afford the title compound (631 mg, 99%) as a white solid and was used directly in the next step without further purification.

[0811] Step 3: (25,4A)-l-((5)-2-azido-3-methylbutanoyl)-4-hydroxy-A-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5J / -benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide To a solution of fS')-2-azido-3 -methylbutanoic acid, prepared in Step 5 (266.78 mg, 1.62 mmol) in DMF (3 mL) were added DIE A (0.81 mL, 4.63 mmol) and HATU (704.61 mg, 1.85 mmol) at 25 °C. After stirring at 25°C for 30 min, (2,4A)-4-hydroxy-A-((5 -2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5J / -benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide hydrochloride (630.0 mg, 1.54 mmol) in DMF (3 mL) was added dropwise to the reaction mixture at 0 °C. Then the resulting reaction mixture was stirred at 0 °C for another 2 h. After that, the reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine (50 mL), dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0-20% (25% ethanol in ethyl acetate) in petroleum ether and then further purified by chiral SFC (Daicel Chiralcel AD (250 mm * 30 mm, 10 um), Supercritical CO2 / (EtOH + 0.1% NH3 H2O) = 60 / 40; 80 mL / min) to afford the title compound (560 mg, 73%) as a white solid. LCMS (ESI): m / z 497.4 (M+H)+. 'H NMR (400 MHz, DMSO ) d 8.97 (s, 1H), 8.55 (d, J= 7.6 Hz, 1H), 7.29 - 7.24 (m, 2H), 7.22 - 7.18 (m, 1H), 5.18 (d, J= 3.6 Hz, 1H), 4.97 (t, J = 8.8 Hz, 1H), 4.59 (t, J= 8.4 Hz, 1H), 4.33 (s, 1H), 3.73 (d, J= 8.4 Hz, 1H), 3.60 - 3.49 (m, 2H), 2.91 - 2.82 (m, 2H), 2.45 (s, 3H), 2.24 - 2.15 (m, 1H), 2.10-2.03 (m, 1H), 1.92 - 1.82 (m, 4H), 1.67 - 1.54 (m, 1H), 1.35- 1.25 (s, 1H), 0.99 (d, J= 6.8 Hz, 3H), 0.96 (d, J= 6.8 Hz, 3H).

[0812] Step 4: (25,4A)-4-hydroxy-l-((, )-2-(4-(3-(4-((lr,45)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)propyl)-U / -l,2,3-triazol- l-yl)-3-methylbutanoyl)-A-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5JT-benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide

[0813] To a solution of (25,4A)-l-((5)-2-azido-3-methylbutanoyl)-4-hydroxy-A-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5J / -benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide (40.95 mg, 0.08 mmol) in water (1 mL) and 2-Methyl-2-propanol (0.5 mL) were added sodium 1-ascorbate (54.45 mg, 0.27 mmol), Q1SO45H2O (22.3 mg, 0.09 mmol) and 8-isopropyl-2-(((lr,4r)-4-(4-(pent-4-yn-l-yl)piperazin-l-yl)cyclohexyl)amino)pyrido[2,3- ]pyrimidin-7(8J7)-one (30.0 mg, 0.07 mmol) at 25 °C. Then the mixture was stirred at 25 °C for 16 h. After that, the reaction mixture was filtered, the filtrate was purified by pre-HPLC (acetonitrile 20-50 / 0.025% HC1 in water) to afford the title compound (14.5 mg, 22%) as a white solid as a HC1 salt. LCMS (ESI): m / z 933.7 (M+H)+. 'H NMR (400MHz, DMSO ) d 9.02 (s, 1H), 8.64 - 8.55 (m, 2H), 8.05 (s, 1H), 7.67 (d, J= 9.6 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.20 (d, J= 7.6 Hz, 1H), 6.27 - 6.14 (m, 1H), 5.75 - 5.60 (m, 1H), 5.26 (d, J= 10.4 Hz, 1H), 5.03 - 4.93 (m, 1H), 4.50 (t, J= 8.4 Hz, 1H), 4.37 (s, 1H), 3.86 - 3.68 (m, 9H), 3.63 - 3.47 (m, 5H), 3.40 - 3.30 (m, 1H), 3.25 - 3.15 (m, 2H), 2.90 - 2.80 (s, 2H), 2.73 (t, J= 7.2 Hz, 2H), 2.47 - 2.45 (m, 3H), 2.26 - 2.03 (m, 8H), 1.99 - 1.79 (m, 4H), 1.75 - 1.60 (m, 3H), 1.55 - 1.45 (m, 3H), 1.45 - 1.25 (m, 3H), 1.42 - 1.26 (m, 3H), 1.06 (d, J= 6.8 Hz, 3H), 0.66 (d, J= 6.8 Hz, 3H).

[0814] Step 5: (5)-2-azido-3 -methylbutanoic acid

[0815] To a mixture of L-valine (500.0 mg, 4.27 mmol) in MeOH (13 mL) was added copper(II) sulfate pentahydrate (10.66 mg, 0.04 mmol) and K2CO3 (1.59 g, 11.52 mmol) at 0 °C. Then 1H-imidazole-1 -sulfonyl azide hydrochloride (939.35 mg, 4.48 mmol) was added into the mixture, the resulting reaction mixture was stirred at 20 °C for 16 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and was acidified with IM HC1 solution until the pH ~ 1, extracted with DCM (35 mL x 4). The combined organic layer was dried over Na2SC>4 and concentrated to afford the title compound (0.61 g, 99%) as a colorless oil. 'H NMR (400MHZ, CDCl3) <53.79 (d, J= 5.6 Hz, 1H), 2.33 - 2.21 (m, 1H), 1.08 (d, J= 6.8 Hz, 3H), 1.03 (d, J= 6.8 Hz, 3H).

[0816] Example 37 (25,47?)-l-((S)-2-(4-(3-(4-((lr,4S)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)propyl)-lH- l,2,3-triazol-l-yl)-3-methylbutanoyl)-4-hydroxy-7V-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide

[0817]

[0818] The compound was prepared according to the procedures described for Example 36. LCMS (ESI): m / z 1047.8 (M+H)+. 'HNMR (400 MHz, DMSO-tL) d 8.97 (s, 1H), 8.56 (d, J= 7.6 Hz, 1H), 8.37 (dd, J = 2.0, 4.8 Hz, 1H), 8.31 - 8.17 (m, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.93 (s, 1H), 7.30 - 7.11 (m, 10H), 6.98 (d, J= 7.6 Hz, 1H), 6.59 (s, 1H), 5.27 - 5.18 (m, 2H), 4.98 (t, J= 8.8 Hz, 1H), 4.49 (t, J= 7.6 Hz, 1H), 4.40 - 4.30 (m, 1H), 3.78 (dd, J= 3.6, 10.8 Hz, 1H), 3.70 - 3.60 (m, 2H), 2.93 - 2.80 (m, 2H), 2.65 - 2.55 (m, 2H), 2.48 - 2.44 (m, 4H), 2.42 - 2.37 (m, 2H), 2.37 - 2.29 (m, 3H), 2.25 (t, J= 6.8 Hz, 3H), 2.21 - 2.12 (m, 2H), 2.01 - 1.86 (m, 6H), 1.90 -1.80 (m, 4H), 1.78 - 1.67 (m, 3H), 1.66 - 1.54 (m, 1H), 1.35 - 1.18 (m, 6H), 1.04 (d, J = 6.4 Hz, 3H), 0.95 - 0.85 (m, 4H), 0.64 (d, J= 6.8 Hz, 1H).

[0819] Example 38 (25',47?)-4-hydroxy-l-((5)-2-(4-((U?,35)-3-((4-((lr,45)-4-((8-isopropyl-7-oxo-7, 8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l- yl)methyl)cyclobutyl)-U / -l,2,3-triazol-l-yl)-3-methylbutanoyl)-7V-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5J / -benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide

[0820]

[0821] The compound was prepared according to the procedures described for Example 36. LCMS (ESI): m / z 959.8 (M+H)+. 'HNMR (400 MHz, DMSO ) d 8.97 (s, 1H), 8.61 - 8.49 (m, 2H), 7.98 (s, 1H), 7.75 - 7.55 (m, 2H), 7.30 - 7.24 (m, 2H), 7.20 (d, J= 7.6 Hz, 1H), 6.23 - 6.11 (m, 1H), 5.77 - 5.54 (m, 1H), 5.22 (d, J= 10.4 Hz, 1H), 5.01 - 4.94 (m, 1H), 4.48 (t, J= 8.0 Hz, 1H), 4.37 (s, 1H), 3.82 - 3.60 (m, 4H), 2.90 - 2.84 (m, 2H), 2.49 - 2.45 (m, 6H), 2.44 - 2.30 (m, 10H), 2.26 - 2.08 (m, 3H), 2.03 - 1.76 (m, 12H), 1.66 - 1.58 (m, 1H), 1.55 - 1.46 (m, 6H), 1.35 - 1.24 (m, 5H), 1.05 (d, J= 6.4 Hz, 3H), 0.65 (d, J= 6.4 Hz, 3H).

[0822] Example 39 (25,47?)-l-((5)-2-(4-((17?,35)-3-((4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)-U / -l,2,3-triazol-l-yl)-3-methylbutanoyl)-4-hydroxy-7V-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5J / -benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide

[0823]

[0824] The compound was prepared according to the procedures described for Example 36. Absolute configuration was arbitrarily assigned. LCMS (ESI): m / z 1073.9 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 38.97 (s, 1H), 8.56 (d, J= 7.6 Hz, 1H), 8.37 (dd, J= 2.0, 4.8 Hz, 1H), 8.31 - 8.19 (m, 1H), 8.10 (d, J= 4.8 Hz, 1H), 7.98 (s, 1H), 7.29 - 7.23 (m, 3H), 7.22 - 7.13 (m, 6H), 7.01 (d, J= 7.6 Hz, 1H), 6.59 (s, 1H), 5.28 - 5.16 (m, 2H), 4.98 (t, J= 8.8 Hz, 1H), 4.48 (t, J= 8.0 Hz, 1H), 4.37 (s, 1H), 3.84 - 3.74 (m, 1H), 3.70 - 3.61 (m, 2H), 3.45 - 3.41 (m, 2H), 2.90 - 2.84 (m, 2H), 2.70 - 2.55 (m, 4H), 2.48 - 2.31 (m, 13H), 2.20 - 2.14 (m, 1H), 2.00 - 1.77 (m, 12H), 1.65 - 1.55 (m, 1H), 1.38 - 1.22 (m, 6H), 1.05 (d, J= 6.4 Hz, 3H), 0.92 (s, 4H), 0.64 (d, J = 6.4 Hz, 3H).

[0825] Example 40 (25,47?)- 1 -((5)-2-(4-((( 17?,35)-3 -((4-(( lr,47?)-4-((6-(3 -fluoro-4-((3,3,3 - trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-J]pyrimidin-2- yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methyl)-lH-l,2,3-triazol-l-yl)-3- methylbutanoyl)-4-hydroxy-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carb oxami de

[0826] OBn OBn

[0827]

[0828] Step 1: tert-butyl 2-(3-((benzyloxy)methyl)cyclobutylidene)acetate

[0829] Amixture of 3-((benzyloxy)methyl)cyclobutan-l-one (20.0 g, 105.1 mmol) and (tert- butoxycarbonylmethylene)triphenylphosphorane (43.5 g, 115.6 mmol) in toluene (300 mL) was stirred at 120 °C for 4 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 0 - 10% ethyl acetate in petroleum ether to afford the title compound (25 g, 83%) as yellow oil. LCMS (ESI): m / z 311.1 (M+Na)+.

[0830] Step 2: tert-butyl 2-(3-(hydroxymethyl)cyclobutyl)acetate

[0831] To a stirred solution of tert-butyl 2-(3 -((benzyloxy )methyl)cy cl obutylidene)acetate (25.0 g, 86.7 mmol) in MeOH (100 mL) and AcOH (25 mL) was added 10% Pd(OH)2 / C (10 g) at 25 °C. Then the reaction mixture was stirred at 25 °C for 16 h under H2 atmosphere (15 psi). After that, the reaction mixture was passed through a pad of celite and then the filtrate was concentrated under reduced pressure. The residue was adjusted to pH = 7 ~ 8 with NaHCCh aqueous solution, and extracted with ethyl acetate (100 mL x 3). The combined organics were washed with brine (100 mL x 2), dried over sodium sulfate, filtered and concentrated to afford the crude title compound (15 g, 86%) as a light oil. LCMS (ESI):

[0832]

[0833] m / z (M+Na)+

[0834] Step 3: tert-butyl 2-((lr,3r)-3-(((ter / -butyldiphenylsilyl)oxy)methyl)cyclobutyl)acetate To a mixture of tert-butyl 2-(3-(hydroxymethyl)cyclobutyl)acetate (15.0 g, 74.9 mmol) and U / -imidazole (10.2 g, 149.8 mmol) in DCM (200 mL) was added tertbutylchlorodiphenylsilane (25.3 mL, 97.4 mmol) at 0 °C. Then the mixture was stirred at 25 °C for 16 h. After that, the reaction mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel eluting with 0 - 10% ethyl acetate in petroleum ether to afford tert-butyl 2-(3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl) acetate (25.0 g). It was further purified by SFC (Daicel Chiralcel OJ (250 mm * 50 mm, 10 um), Supercritical CO2 / (EtOH + 0.1% NH4OH) = 90 / 10; 200 mL / min) to afford the title compound (7.0 g, 28%, first peak on SFC) as a yellow oil. LCMS (ESI): m / z 461.1 (M+Na)+.

[0835] Step 4: 2-((lr,3r)-3-(((tertebutyldiphenylsilyl)oxy)methyl)cyclobutyl)ethan-l-ol To a solution of tert-butyl 2-[3-[[ter / -butyl(diphenyl)silyl]oxymethyl]cyclobutyl]acetate (10.0 g, 22.8 mmol) in THF (25 mL) was added DIBAL-H (45.6 mL, 45.59 mmol) at 0 °C under nitrogen atmosphere. Then the reaction mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. After that, the reaction mixture was poured into ice-water (25 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SC>4, concentrated to give crude product, which was purified by column chromatography on silica gel eluting with 0 - 10% EtOAc in petroleum ether to afford the title compound (5.3 g, 63%) as an off-yellow oil. 'HNMR (400 MHz, DMSO-tL) d 7.62 - 7.60 (m, 4H), 7.49 - 7.40 (m, 6H), 4.27 (t, J= 5.2 Hz, 1H), 3.65 (d, J= 6.8 Hz, 2H), 3.33 - 3.31 (m, 2H), 2.47 - 2.38 (m, 1H), 2.30 - 2.20 (m, 1H), 1.89 - 1.81 (m, 2H), 1.69 - 1.60 (m, 2H), 1.55 (q, J= 6.8 Hz, 2H), 1.00 (s, 9H).

[0836] Step 5: 2-((lr,3r)-3-(((tertebutyldiphenylsilyl)oxy)methyl)cyclobutyl)acetaldehyde To a mixture of 2-[3-[[ / c77-butyl(diphenyl)silyl]oxymethyl]cyclobutyl]ethanol (5.3 g, 14.38 mmol) and SiC>2 (300.0 mg) in DCM (50 mL) was added PCC (6.2 g, 28.76 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (5.2 g, 99%) as a yellow oil. The crude product was directly used in the next step without further purification.

[0837] Step 6: / c77-butyldiphenyl((( l,s,3 / ')-3-(prop-2-yn- l -yl)cyclobutyl)methoxy)silane To a solution of 2-[3-[[ / c77-butyl(diphenyl)silyl]oxymethyl]cyclobutyl]acetaldehyde (5.2 g, 14.19 mmol) in MeOH (50 mL) were added dimethyl(l-diazo-2-oxopropyl)phosphonate (8.18 g, 42.56 mmol) and K2CO3 (3.92 g, 28.37 mmol) at 25 °C. Then the reaction mixture was stirred at 25 °C for 1 h. After that, the reaction mixture was poured into ice-water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (50 mL), dried with Na2SC>4, concentrated to give crude product, which was purified by column chromatography on silica gel (0 - 3% EtOAc in petroleum ether) to afford the title compound (2.3 g, 45%) as an off-yellow oil. 'H NMR (400 MHz, DMSO-tL) d 7.65 - 7.57 (m, 4H), 7.50 -7.39 (m, 6H), 3.65 (d, J= 6.4 Hz, 2H), 2.74 (t, J= 2.4 Hz, 1H), 2.47 - 2.39 (m, 1H), 2.38 - 2.33 (m, 1H), 2.28 - 2.23 (m, 2H), 1.94 - 1.83 (m, 2H), 1.80 - 1.71 (m, 2H), 1.00 (s, 9H).

[0838] Step 7: ((ls,3r)-3-(prop-2-yn-l-yl)cyclobutyl)methanol

[0839] To a solution of terLbutyl-diphenyl-[(3-prop-2-ynylcyclobutyl)methoxy]silane (25 mg, 6.9 mmol) in THF (20 mL) was added IM TBAF in THF (7.58 mL, 7.58 mmol) at 0 °C. Then the reaction mixture was stirred at 20 °C for 0.5 h. After that, the reaction mixture was concentrated to give the crude product, which was purified by column chromatography on silica gel eluting with 0 - 20% EtOAc in petroleum ether to afford the title compound (600 mg, 70%) as an off-yellow oil. 'H NMR (400 MHz, DMSO-tL) d 4.47 (t, J= 5.2 Hz, 1H), 3.44 - 3.36 (m, 2H), 2.73 (t, J= 2.4 Hz, 1H), 2.41 - 2.28 (m, 2H), 2.27 - 2.24 (m, 2H), 1.85 - 1.77 (m, 2H), 1.75 - 1.67 (m, 2H).

[0840] Step 8: ((ls,3r)-3-(prop-2-yn-l-yl)cyclobutyl)methyl methanesulfonate

[0841] To a mixture of (3-prop-2-ynylcyclobutyl)methanol (100.0 mg, 0.81 mmol) and TEA (0.34 mL, 2.42 mmol) in DCM (4 mL) was added MS2O (0.21 g, 1.21 mmol) at 0 °C. Then the reaction mixture was stirred at 25 °C under nitrogen atmosphere for 16 h. After that, the reaction mixture was concentrated to remove the solvent to afford the title compound (0.16 g, 98%) as a colorless oil. The crude product was directly used in the next step without further purification.

[0842] Step 9: 3,3,3-trifluoro-A-(2-fluoro-4-(8-methyl-2-(((lA,4r)-4-(4-(((ls,3A)-3-(prop-2-yn-l-yl)cyclobutyl)methyl)piperazin-l-yl)cyclohexyl)amino)pyrido[3,2-d]pyrimidin-6-yl)phenyl)propane- 1 -sulfonamide To a solution of 3,3,3-trifluoro-A-[2-fluoro-4-[8-methyl-2-[(4-piperazin-l-ylcyclohexyl)amino]pyrido[3,2-d]pyrimidin-6-yl]phenyl]propane-l -sulfonamide (149.0 mg, 0.25 mmol) in DMF (2 mL) was added K2CO3 (138.29 mg, 1 mmol) and (3-prop-2-ynylcyclobutyl)methyl methanesulfonate (0.1 g, 0.5 mmol) at 25 °C. Then the mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated to give crude product, which was purified by pre-TLC (10% MeOH in DCM, Rf = 0.4) to afford the title compound (60 mg, 34%) as a yellow solid. LCMS (ESI): m / z 702.4 (M+H)+.

[0843] Step 10: (25, 4R)- 1 -((S)-2-(4-((( 1 R, 3S)-3 -((4-(( 1 r,4A)-4-((6-(3 -fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methyl)-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl)-4-hydroxy-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carb oxami de

[0844] To a solution of 3,3,3-trifluoro-A-[2-fluoro-4-[8-methyl-2-[[4-[4-[(3-prop-2-ynylcyclobutyl)methyl]piperazin-l-yl]cyclohexyl]amino]pyrido[3,2-d]pyrimidin-6-yl]phenyl]propane-l -sulfonamide (60.0 mg, 0.09 mmol) in water (1 mL) and DMF (0.5 mL) were added sodium ascorbate (34 mg, 0.17 mmol), (25,4A)-l-[(25)-2-azido-3-methyl-butanoyl]-4-hydroxy-7V-[(15)-l-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (74.16 mg, 0.16 mmol) and Q1SO4 5H2O (10.67 mg, 0.04 mmol). Then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was purified by pre-HPLC (acetonitrile 18 - 48 / 0.225% FA in water) to afford the title compound (8.5 mg, 8.2 %) as an off-yellow solid. LCMS (ESI): m / z 1158.6 (M+H)+. 'H NMR (400 MHz, DMSO-tfc) δ 9.11 (s, 1H), 8.92 (s, 1H), 8.22 (d, J= 7.6 Hz, 1H), 8.14 (s, 1H), 8.13 (s, 1H), 7.99 (d, J= 12.4 Hz, 1H), 7.94 (d, J= 8.8 Hz, 1H), 7.82 (s, 1H), 7.52 (t, J= 8.4 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.41 - 7.35 (m, 2H), 7.25 (d, J= 7.6 Hz, 1H), 5.20 (d, J = 10.0 Hz, 1H), 5.00 - 4.85 (m, 2H), 4.44 (t, J= 8.0 Hz, 1H), 4.38 - 4.28 (m, 1H), 3.90 - 3.74 (m, 2H), 3.57 (d, J= 11.2 Hz, 1H), 3.38 - 3.32 (m, 3H), 2.84 - 2.72 (m, 6H), 2.60 - 2.55 (m, 7H), 2.46 (s, 4H), 2.43 - 2.42 (m, 6H), 2.16 - 2.00 (m, 4H), 1.93 - 1.85 (m, 3H), 1.84 - 1.76 (m, 4H), 1.42 (d, J= 6.8 Hz, 3H), 1.38 - 1.37 (d, J= 3.6 Hz, 3H), 1.04 (d, J= 6.4 Hz, 3H), 0.68 (d, J = 6.4 Hz, 3H).

[0845] Example 41 (25,4A)-l-((5)-3,3-dimethyl-2-(2-(4-(4-((lr,45)-4-((7-oxo-8-(tetrahydro-2J / -pyran-4-yl)-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)piperidin-l-yl)acetamido)butanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0846]

[0847] Step 1: methyl 3 -(methoxymethylene)cyclobutane-l -carboxylate

[0848] To a stirred solution of (methoxymethyl)triphenylphosphonium bromide (145 g, 374.62 mmol) in THF (300 mL) was added Z-BuOK (42 g, 374.62 mmol) under nitrogen atmosphere at 0 °C. Then the reaction mixture was stirred at 25 °C for 1 h. After that, a solution of methyl 3- oxocyclobutane- 1 -carboxylate (24 g, 187.31 mmol) in THF (30 mL) was added dropwise at 0 °C and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was extracted with EtOAc (700 mL x 3) and washed by brine (1.5 L x 2). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with 0-2% ethyl acetate in petroleum ether to afford the title compound (8.3 g, 29%) as a colorless oil. 'H NMR (400 MHz, CDCh) δ 5.85 - 5.80 (m, 1H), 3.70 (s, 3H), 3.56 (s, 3H), 3.22 - 3.12 (m, 1H), 3.01 - 2.95 (m, 2H), 2.94 - 2.90 (m, 1H), 2.89 - 2.81 (m, 1H).

[0849] Step 2: methyl 3 -formylcyclobutane- 1 -carboxylate

[0850] To a solution of the methyl 3 -(methoxymethylene)cyclobutane-l -carboxylate (8.3 g, 53.14 mmol) in DCM (120 mL) was added TFA (7.9 mL, 106.29 mmol) and water (20 mL) at 25 °C. Then the resulting reaction mixture was stirred at 25 °C for 3 h. The phases were separated and the aqueous layer was extracted with DCM (20 mL x 3). The organic layers were combined and concentrated to afford the crude title compound (7.6 g) as a yellow oil. The crude product was directly used in the next step without further purification.

[0851] Step 3: methyl (ls,3s)-3-ethynylcyclobutane-l-carboxylate and methyl (lr,3r)-3-ethynylcyclobutane- 1 -carboxylate

[0852] To a mixture of methyl 3 -formylcyclobutane- 1 -carboxylate (7.6 g, 53.46 mmol), K2CO3 (14.8 g, 106.93 mmol) in MeOH (120 mL) was added dimethyl (l-diazo-2-oxopropyl)phosphonate (15.4 g, 80.2 mmol) at 0 °C. Then the reaction mixture was stirred at 25 °C for 4 h under nitrogen. The solvent of the reaction solution was steamed away and the residue was purified by column chromatography on silica gel eluting with 0-3% ethyl acetate in petroleum ether to afford methyl ( I. s,3.s)-3-ethynylcyclobutane- l -carboxylate (peak 1, 16 g) as a colorless oil and methyl (lr,3r)-3-ethynylcyclobutane-l-carboxylate (peak 2, 7 g) as a colorless oil. The absolute configuration of the tetrahydric ring is uncertain, and the structure is tentatively assigned.

[0853] Methyl (ls,3s)-3-ethynylcyclobutane-l-carboxylate: 'HNMR (400 MHz, CDCI3) δ 3.71 (s, 3H), 3.32 - 3.23 (m, 1H), 3.21 - 3.13 (m, 1H), 2.64 - 2.56 (m, 2H), 2.42 - 2.34 (m, 2H), 2.22 (d, J = 2.4 Hz, 1H).

[0854] Methyl (lr,3r)-3-ethynylcyclobutane-l-carboxylate: 'HNMR (400 MHz, CDCI3) δ 3.69 (s, 3H), 3.10 - 3.01 (m, 1H), 2.99 - 2.90 (m, 1H), 2.56 - 2.50 (m, 2H), 2.48 - 2.39 (m, 2H), 2.18 (d, J = 2.4 Hz, 1H).

[0855] Step 4: ((l,3 )-3-ethynylcyclobutyl)methanol

[0856] To a solution of methyl (ls,3s)-3-ethynylcyclobutane-l-carboxylate (16 g, crude) in THF (10 mL) was added LiAlH4 (8.7 mL, 2.5 M in THF) at 0 °C, the resulting reaction mixture was stirred at 0 °C for 2 h under N2 atmosphere. After that, the reaction was quenched with Na₂SO₄·10H₂O until solid formation occurred at 0 °C, the solid was removed by filtration. The filtrate was concentrated under vacuum to give the title compound (360 mg, 23%) as a colorless oil. 'HNMR (400 MHz, CDCI3) d 3.66 (d, J= 6.8 Hz, 2H), 3.11 - 2.99 (m, 1H), 2.69 - 2.57 (m, 1H), 2.30 - 2.22 (m, 2H), 2.21 (d, J= 2.4 Hz, 1H), 2.18 - 2.09 (m, 2H).

[0857] Step 5: ((l,3 )-3-ethynylcyclobutyl)methyl methanesulfonate

[0858] To a solution of ((l,3 )-3-ethynylcyclobutyl)methanol (100 mg, 0.91 mmol) and Et3N (0.38 mL, 2.72 mmol) in DCM (5 mL) at 0 °C was added MS2O (237 mg, 1.36 mmol). The reaction mixture was stirred at 25 °C under nitrogen atmosphere for 16 h. Then the reaction mixture was extracted with DCM (10 mL x 3) and washed by brine (15 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (120 mg, 70%) as a yellow oil. The crude product was directly used in the next step without further purification.

[0859] Step 6: 3,3,3-trifluoro-A-(2-fluoro-4-(8-methyl-2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl)amino)pyrido[3,2-d]pyrimidin-6-yl)phenyl)propane-l -sulfonamide

[0860] To a solution of / <? / 7-butyl 4-((lr,4r)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl) sulfonamido)phenyl)-8-methylpyrido[3,2-d]pyrimidin-2-yl)amino)cyclohexyl)piperazine-l-carboxylate (800 mg, 1.15 mmol) in 1,4-di oxane (4 mL) was added HC1 (10 mL, 2M in 1,4-dioxane), the reaction mixture was stirred at 25 °C for 2 h. After that, the reaction mixture was concentrated under vacuum to dryness to afford the title compound (650 mg, 89%). The crude product was directly used in the next step without further purification. LCMS (ESI): m / z 596.4 (M+H)+.

[0861] Step 7: A-(4-(2-(((lA,4r)-4-(4-(((ls,35)-3-ethynylcyclobutyl)methyl)piperazin-l-yl)cyclohexyl)amino)-8-methylpyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3,3,3-tri fluoropropane- 1 -sulfonamide

[0862] To a mixture of ((l,3 )-3-ethynylcyclobutyl)methyl methanesulfonate (116 mg, 0.62 mmol), 3,3,3-trifluoro-A-(2-fluoro-4-(8-methyl-2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl) amino)pyrido[3,2-J]pyrimidin-6-yl)phenyl)propane-l -sulfonamide (300 mg, 0.47 mmol) and K2CO3 (131 mg, 0.95 mmol) in DMF (2 mL) at 25 °C. The reaction mixture was stirred at 80 °C for 16 h. Then the reaction mixture was cooled to room temperature, extracted with EtOAc (10 mL x 3) and washed by brine (15 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with 2% MeOH in DCM to afford the title compound (40 mg, 12%) as a yellow solid. LCMS (ESI): m / z 688.4 (M+H)+. Step 8: (25,47?)- 1 -((5)-2-(4-(( 1 S,3R)-3 -((4-(( 1 r,47?)-4-((6-(3 -fluoro-4-((3,3, 3 -trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)methyl)cy clobutyl)- 1H- 1,2,3 -tri azol- 1 -y l)-3 -methylbutanoyl)-4-hydroxy-A-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-57T-benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide

[0863] To a mixture of (25, 47?)-A-((5)-2-((Z)-2-amino-l -mercaptoprop- l-en-l-yl)-6, 7,8,9-tetrahydro-57 / -benzo[7]annulen-5-yl)-l-((5)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (32 mg, 0.06 mmol), A-(4-(2-(((17?,4r)-4-(4-(((ls,35)-3-ethynylcyclobutyl)methyl)piperazin-l-yl)cyclohexyl)amino)-8-methylpyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3,3,3-trifluoropropane-l-sulfonamide (40 mg, 0.06 mmol) and sodium 1-ascorbate (5.8 mg, 0.03 mmol) in water (1 mL) and / -BuOH (1 mL) was added, Q1SO45H2O (7.3 mg, 0.03 mmol) at 25 °C. Then the reaction mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the mixture was purified by pre-HPLC (acetonitrile 30 -60 / 0.075% TFA in water) to afford the title compound (18.2 mg, 26 %) as a TFA salt as a yellow solid. The absolute configuration of the tetrahydric ring is uncertain, and the structure is tentatively assigned. LCMS (ESI): m / z 1184.9 (M+H)+. 'HNMR (400 MHz, DMSO ) d 10.16 (s, 1H), 9.26 - 9.12 (m, 1H), 8.98 (s, 1H), 8.55 (d, J= 7.2 Hz, 1H), 8.27 (s, 1H), 8.13 - 8.07 (m, 2H), 8.04 (d, J = 6.8 Hz, 1H), 7.78 - 7.75 (m, 1H), 7.56 (t, J= 8.4 Hz, 1H), 7.30 - 7.25 (m, 2H), 7.20 (d, J= 7.6 Hz, 1H), 5.27 (d, J= 10.0 Hz, 1H), 5.04 - 4.91 (m, 2H), 4.48 (t, J= 8.0 Hz, 1H), 4.38 (s, 1H), 3.87 - 3.84 (m, 2H), 3.83 - 3.81 (m, 1H), 3.47 - 3.41 (m, 1H), 3.25 - 3.20 (m, 2H), 2.92 - 2.76 (m, 7H), 2.58 (s, 6H), 2.47 - 2.44 (m, 5H), 2.42 - 2.40 (m, 1H), 2.34 - 2.31 (m, 2H), 2.28 - 2.18 (m, 5H), 2.12 - 2.02 (m, 3H), 2.00 - 1.72 (m, 7H), 1.65 - 1.56 (m, 3H), 1.50 - 1.35 (m, 3H), 1.34 - 1.28 (m, 1H), 1.07 ( d, J = 6.4 Hz, 3H), 0.67 (d, J= 6.4 Hz, 3H).

[0864] Example 42 (25,47?)-l-((5)-2-(4-((17?,35)-3-((4-((lr,45)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)methyl)cy clobutyl)- 1H- 1,2,3 -tri azol- 1 -y l)-3 -methylbutanoyl)-4-hydroxy-A-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-57T-benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide

[0865]

[0866] The compound was prepared according to the procedures described for Example 41. (3-ethynylcyclobutyl)methyl methanesulfonate was used for the N-alkylation step. LCMS (ESI): m / z 1229.0 (M+H)+. 'HNMR (400 MHz, DMSO-d6) d 8.92 (s, 1H), 8.61 (s, 1H), 8.28 (d, J= 8.0 Hz, 1H), 7.95 - 7.85 (m, 2H), 7.63 (dd, J= 2.0, 12.4 Hz, 1H), 7.57 - 7.48 (m, 2H), 7.45 -7.40 (m, 1H), 7.28 - 7.21 (m, 3H), 5.80 - 5.71 (m, 1H), 5.28 - 5.19 (m, 1H), 5.08 - 4.98 (m, 2H), 4.61 - 4.51 (m, 1H), 4.39 (s, 1H), 3.85 - 3.73 (m, 2H), 3.65 - 3.54 (m, 2H), 3.43 - 3.35 (m, 4H), 2.92 - 2.87 (m, 3H), 2.86 - 2.75 (m, 4H), 2.71 - 2.64 (m, 4H), 2.58 - 2.54 (m, 3H), 2.48 - 2.46 (m, 4H), 2.30 - 2.23 (m, 1H), 2.20 - 2.00 (m, 5H), 1.98 - 1.79 (m, 8H), 1.73 - 1.66 (m, 1H), 1.58 (d, J= 6.4 Hz, 6H), 1.44 - 1.34 (m, 5H), 1.10 - 1.03 (m, 3H), 0.73 - 0.68 (m, 3H).

[0867] Example 43 (25,47?)-l-((5)-2-(4-((17?,35)-3-((4-((lr,45)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)methyl)cy clobutyl)- 1H- 1,2,3 -tri azol- 1 -y l)-3 -methylbutanoyl)-4-hydroxy-7V-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5JT-benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide

[0868]

[0869] The compound was prepared according to the procedures described for Example 41 and obtained as a formate. The absolute configuration of the tetrahydric ring is uncertain and the structure is tentatively assigned. LCMS (ESI): m / z 1228.9 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 38.97 (s, 1H), 8.65 - 8.59 (m, 1H), 8.56 (d, J= 7.6 Hz, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.90 - 7.81 (m, 2H), 7.53 (d, J= 13.2 Hz, 1H), 7.41 - 7.35 (m, 2H), 7.29 - 7.24 (m, 2H), 7.20 (d, J= 8.0 Hz, 1H), 5.81 - 5.66 (m, 1H), 5.22 (d, J= 10.4 Hz, 2H), 5.01 - 4.95 (m, 1H), 4.48 (t, J= 8.4 Hz, 1H), 4.37 (s, 1H), 3.83 - 3.72 (m, 2H), 3.70 - 3.64 (m, 2H), 3.47 - 3.42 (m, 4H), 3.25 - 3.16 (m, 7H), 2.91 - 2.82 (m, 2H), 2.77 - 2.69 (m, 2H), 2.52 - 2.51 (m, 3H), 2.47 -2.43 (m, 4H), 2.41 - 2.31 (m, 7H), 2.22 - 2.18 (m, 1H), 2.05 - 1.98 (m, 2H), 1.87 - 1.79 (m, 5H), 1.58 (d, J= 6.8 Hz, 4H), 1.52 (d, J= 6.8 Hz, 2H), 1.36 - 1.28 (m, 5H), 1.05 (d, J= 6.4 Hz, 3H), 0.65 (d, = 6.4 Hz, 3H).

[0870] Example 44 (25,47?)-l-((S)-2-(4-((U?,3S)-3-((4-((lr,4S)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)methyl)cy clobutyl)- 1H- 1,2,3 -tri azol- 1 -y l)-3 -methylbutanoyl)-4-hydroxy-7V-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5J / -benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide

[0871] NH H

[0872] N. N,

[0873] NA W I N—

[0874] N

[0875]

[0876] The compound was prepared according to the procedures described for Example 41. (3-ethynylcyclobutyl)methyl methanesulfonate was used for the N-alkylation step. LCMS (ESI): m / z 1184.8 (M+H)+.1HNMR(400 MHz, DMSO-t / 6) d 9.25 - 9.08 (m, 1H), 8.97 (s, 1H), 8.55 (d, J= 7.6 Hz, 1H), 8.23 (s, 1H), 8.07 - 8.04 (m, 1H), 8.02 - 7.97 (m, 2H), 7.71 - 7.61 (m, 1H), 7.57 - 7.51 (m, 1H), 7.29 - 7.24 (m, 2H), 7.22 - 7.18 (m, 1H), 5.29 - 5.19 (m, 2H), 5.02 - 4.94 (m, 1H), 4.54 - 4.45 (m, 1H), 4.39 - 4.33 (m, 1H), 3.83 - 3.74 (m, 2H), 3.71 - 3.65 (m, 1H), 3.59 - 3.53 (m, 1H), 2.91 - 2.85 (m, 2H), 2.84 - 2.70 (m, 7H), 2.67 - 2.62 (m, 2H), 2.59 - 2.55 (m, 6H), 2.47 - 2.44 (m, 5H), 2.43 - 2.39 (m, 1H), 2.26 - 2.08 (m, 5H), 1.98 - 1.78 (m, 10H), 1.66 -1.58 (m, 1H), 1.45 - 1.28 (m, 6H), 1.09 - 1.03 (m, 3H), 0.68 - 0.64 (m, 3H).

[0877] Example 45 (25,47?)-l-((S)-2-(4-((U?,3S)-3-((4-((lr,4S)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)methyl)cy clobutyl)- 1H- 1,2,3 -tri azol- 1 -y l)-3 -methylbutanoyl)-4-hydroxy-7V-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5J / -benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide

[0878]

[0879] The compound was prepared according to the procedures described for Example 41 and obtained as a formate. The absolute configuration of the tetrahydric ring is uncertain and the structure is tentatively assigned. LCMS (ESI): m / z 1184.7 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.97 (s, 1H), 8.56 (d, J= 7.2 Hz, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 8.03 - 7.97 (m, 2H), 7.93 (d, J= 10.4 Hz, 1H), 7.59 (s, 1H), 7.52 - 7.47 (m, 1H), 7.29 - 7.24 (m, 2H), 7.20 (d, J= 8.0 Hz, 1H), 5.23 (d, J= 10.4 Hz, 2H), 4.98 (t, J= 8.8 Hz, 1H), 4.49 (t, J= 8.0 Hz, 1H), 4.37 (s, 1H), 3.81 - 3.75 (m, 2H), 3.70 - 3.65 (m, 1H), 3.31 - 3.27 (m, 1H), 2.88 (s, 2H), 2.82 - 2.67 (m, 4H), 2.66 - 2.58 (m, 5H), 2.57 - 2.51 (m, 6H), 2.48 - 2.44 (m, 5H), 2.42 - 2.41 (m, 1H), 2.27 - 2.00 (m, 5H), 1.96 - 1.80 (m, 10H), 1.66 - 1.57 (m, 1H), 1.40 - 1.28 (m, 6H), 1.05 (d, J= 6.4 Hz, 3H), 0.65 (d, J= 6.4 Hz, 3H).

[0880] Example 46 (25,47?)-l-((5)-2-(4-((15,37?)-3-((4-((lr,47?)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)methyl)cy clobutyl)- 1H- 1,2,3 -tri azol- 1 -y l)-3 -methylbutanoyl)-4-hydroxy-7V-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5JT-benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide

[0881]

[0882] The compound was prepared according to the procedures described for Example 41. The absolute configuration of the tetrahydric ring is uncertain and the structure is tentatively assigned. LCMS (ESI): m / z 1228.8 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.78 (s, 1H), 8.93 (s, 1H), 8.63 (s, 1H), 8.26 (d, J= 7.6 Hz, 1H)), 8.01 - 7.94 (m, 2H), 7.64 (d, J= 12.4 Hz, 2H), 7.54 - 7.50 (m, 1H), 7.46 - 7.42 (m, 1H), 7.27 - 7.23 (m, 3H), 5.80 - 5.74 (m, 1H), 5.25 (d, J= 9.6 Hz, 1H), 5.14 - 4.92 (m, 2H), 4.55 (t, J= 8.0 Hz, 1H), 4.40 (s, 1H), 3.89 - 3.78 (m, 4H), 3.68 - 3.63 (m, 4H), 3.04 - 3.00 (m, 3H), 2.95 - 2.88 (m, 4H), 2.85 - 2.79 (m, 4H), 2.57 - 2.53 (m, 3H), 2.48 - 2.45 (m, 4H), 2.35 - 2.30 (m, 2H), 2.28 - 2.21 (m, 2H), 2.14 - 2.06 (m, 5H), 1.98 - 1.83 (m, 5H), 1.72 - 1.69 (m, 1H), 1.59 (d, J= 6.8 Hz, 6H), 1.52 - 1.41 (m, 5H), 1.08 (d, J = 6.4 Hz, 3H), 0.72 (d, J= 6.4 Hz, 3H).

[0883] Example 47 (25,47?)-l-((5)-2-(5-(4-((lr,45)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0884]

[0885] Step 1: (3A,55)-l-((5)-3,3-dimethyl-2-(5-oxopentanamido)butanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate

[0886] To a solution of (3R, 55)-l-((5)-2-(5-hydroxypentanamido)-3,3-dimethylbutanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate (100.0 mg, 0.17 mmol) in DCM (3.0 mL) was added DMP (88.87 mg, 0.21 mmol) at 25 °C. Then the reaction mixture was stirred at 40 °C for 3 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to afford the title compound (90 mg, 90%) as a white oil. LCMS (ESI): m / z 571.1 (M+H)+.

[0887] Step 2: (3A,5S)-l-((S)-2-(5-(4-((lr,4S)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-J]pyrimidin-2- yl)amino)cyclohexyl)piperazin-l-yl)pentanamido)-3,3-dimethylbutanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate

[0888] A mixture of (3A,55)-l-((5)-3,3-dimethyl-2-(5-oxopentanamido)butanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate (89.38 mg, 0.16 mmol) and 3,3,3-trifluoro-N-(2-fluoro-4-(8-methyl-2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl)amino)pyrido[3,2-d]pyrimidin-6-yl)phenyl)propane-l -sulfonamide (55.0 mg, 0.09 mmol) in DCM (2 mL) was stirred at 25 °C for 1 h. Then NaBH(OAc)3 (27.66 mg, 0.13 mmol) was added to the reaction mixture, which was stirred at 25 °C for 3 h under N2 atmosphere. After that, the mixture was diluted with water (5 mL), extracted with EtOAc (5 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by pre-TLC (10% MeOH in DCM, Rf = 0.7) to afford the title compound (28 mg, 28%) as a yellow solid. LCMS (ESI): m / z 1150.5 (M+H)+.

[0889] Step 3: (25,4A)-l-((S)-2-(5-(4-((lr,4S)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0890] To a stirred solution of [(3A,55)-l-((5)-2-(5-(4-((lr,45)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanamido)-3,3-dimethylbutanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl acetate (28.0 mg, 0.02 mmol) in H2O (1 mL) and THF (3 mL) was added LiOH H2O (1.46 mg, 0.06 mmol) at 25 °C, then the reaction mixture was stirred at 25 °C for 3 h. After that, the reaction mixture was concentrated under reduced pressure to give crude product, which was purified by pre-HPLC (acetonitrile 58 -88 / 0.225% FA in water) to afford the title compound (25 mg, 87%) as a yellow solid. LCMS (ESI): m / z 1108.5 (M+H)+.1HNMR(400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.98 (s, 1H), 8.57 (t, J= 6.0 Hz, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 8.00 (d, J= 13.2 Hz, 1H), 7.94 (d, J= 8.8 Hz, 1H), 7.87 (d, J= 9.2 Hz, 1H), 7.59 (s, 1H), 7.54 - 7.48 (m, 1H), 7.45 - 7.35 (m, 4H), 5.15 (s, 1H), 4.55 (d, J= 9.2 Hz, 1H), 4.48 - 4.39 (m, 2H), 4.40 - 4.32 (m, 1H), 4.28 - 4.20 (m, 1H), 3.85 -3.70 (m, 4H), 3.67 - 3.62 (m, 1H), 2.83 - 2.71 (m, 3H), 2.67 - 2.62 (m, 3H), 2.65 - 2.57 (m, 2H), 2.54 (s, 3H), 2.48 - 2.43 (m, 4H), 2.30 - 2.20 (m, 2H), 2.20 - 2.01 (m, 5H), 1.96 - 1.81 (m, 3H), 1.56 - 1.45 (m, 3H), 1.55 - 1.35 (m, 7H), 1.06 - 0.87 (m, 9H).

[0891] Example 48 (2£,4A)-l-((5)-3,3-dimethyl-2-(5-(4-((lr,45)-4-((8-methylpyrido[3,2-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanamido)butanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide The compound was prepared according to the procedures described for Example 47. LCMS (ESI): m / z 839.5 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.99 (s, 1H), 8.58 (t, J= 6.0 Hz, 1H), 8.42 (d, J= 4.4 Hz, 1H), 8.20 (s, 1H), 7.87 (d, J= 9.2 Hz, 1H), 7.60 -7.52 (m, 2H), 7.45 - 7.35 (m, 4H), 4.55 (d, J= 9.2 Hz, 1H), 4.48 - 4.41 (m, 2H), 4.38 - 4.33 (m, 1H), 4.22 (dd, J= 16.0, 5.6 Hz, 1H), 3.85 - 3.73 (m, 2H), 3.72 - 3.62 (m, 2H), 2.56 - 2.53 (m, 2H), 2.47 - 2.43 (m, 4H), 2.42 - 2.32 (m, 4H), 2.37 - 2.20 (m, 5H), 2.20 - 2.08 (m, 3H), 2.07 -1.99 (m, 2H), 1.96 -1.91 (m, 1H), 1.90 - 1.72 (m, 3H), 1.52 - 1.45 (m, 2H), 1.43 - 1.38 (m, 2H), 1.37 - 1.22 (m, 5H), 1.00 - 0.91 (m, 9H).

[0892] Example 49 (2S,4R)-l-((S)-2-(5-(4-((lr,4S)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0893]

[0894] The compound was prepared according to the procedures described for Example 47. LCMS (ESI): m / z 1152.6 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.68 - 8.54 (m, 2H), 7.94 (s, 1H), 7.87-7.82 (m, 2H), 7.61-7.58 (m, 1H), 7.49 - 7.34 (m, 6H), 5.85 - 5.70 (m, 1H), 5.15 (s, 1H), 4.54 (d, J= 9.2 Hz, 1H), 4.50 - 4.40 (m, 2H), 4.40 - 4.32 (m, 1H), 4.22 (dd, J = 15.6, 5.2 Hz, 1H), 3.84 - 3.72 (m, 2H), 3.70 - 3.62 (m, 3H), 2.85 - 2.70 (m, 3H), 2.60 - 2.52 (m, 5H), 2.42 - 2.37 (m, 3H), 2.33 - 2.20 (m, 5H), 2.20 - 2.09 (m, 2H), 2.08 - 1.80 (m, 7H), 1.65 - 1.55 (m, 4H), 1.55 - 1.45 (m, 4H), 1.44 - 1.20 (m, 6H), 0.94 (s, 9H).

[0895] Example 50 (2S,4R)-4-hydroxy-l-((S)-2-(5-(4-((lr,4S)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)pentanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0896]

[0897] The compound was prepared according to the procedures described for Example 47. LCMS (ESI): m / z 883.4 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.60 - 8.51 (m, 2H), 8.19 (s, 1H), 7.86 (d, J= 9.2 Hz, 1H), 7.73 (d, J= 7.6 Hz, 1H), 7.66 - 7.54 (m, 2H), 7.45 - 7.32 (m, 4H), 6.21 - 6.11 (m, 1H), 5.75 - 5.60 (m, 1H), 4.54 (d, J= 9.2 Hz, 1H), 4.47 - 4.39 (m, 2H), 4.37 - 4.32 (m, 1H), 4.21 (dd, J= 5.2, 16.0 Hz, 1H), 3.75 - 3.60 (m, 3H), 2.55 - 2.51 (m, 2H), 2.48 - 2.40 (m, 4H), 2.40 - 2.28 (m, 3H), 2.28 - 2.18 (m, 4H), 2.17 - 1.95 (m, 5H), 1.90 -1.75 (m, 4H), 1.60 - 1.43 (m, 8H), 1.42 - 1.33 (m, 3H), 1.35 - 1.20 (m, 3H), 0.93 (s, 9H).

[0898] Exampl e 51 (25,4 / ?)- 1 -((5)-2-(7-(4-(( 1 r,4r)-4-((6-(3 -fluoro-4-((3,3, 3 -trifluoropropyl)sulfonamido)phenyl)-8-methylpyrido[3,2-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0899]

[0900] The compound was prepared according to the procedures described for Example 47. LCMS (ESI): m / z 1136.6 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.98 (s, 1H), 8.61 - 8.54 (m, 1H), 8.20 (s, 1H), 7.99 (d, J=13.6 Hz, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.87 (d, J = 9.6 Hz, 1H), 7.61 (s, 1H), 7.49 (t, J= 8.8 Hz, 1H), 7.44 - 7.37 (m, 4H), 5.15 (s, 1H), 4.54 (d, J = 9.2 Hz, 1H), 4.49 - 4.39 (m, 2H), 4.37 - 4.30 (m, 1H), 4.21 (dd, J= 5.6, 16.0 Hz, 1H), 3.85 -3.75 (m, 1H), 3.68 - 3.62 (m, 2H), 2.80 - 2.70 (m, 2H), 2.65 - 2.55 (m, 4H), 2.58 - 2.50 (m, 3H), 2.44 (s, 3H), 2.28 - 2.18 (m, 3H), 2.18 - 2.05 (m, 4H), 2.04 - 1.95 (m, 3H), 1.94 - 1.79 (m, 4H), 1.44 - 1.33 (m, 7H), 1.33 - 1.20 (m, 9H), 0.93 (s, 9H).

[0901] Example 52 (25,4 / ?)-l-((5)-3,3-dimethyl-2-(7-(4-((lr,4r)-4-((8-methylpyrido[3,2-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)heptanamido)butanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0902]

[0903] The compound was prepared according to the procedures described for Example 47. LCMS (ESI): m / z 867.5 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.99 (s, 1H), 8.57 (t, J= 6.0 Hz, 1H), 8.43 (d, J= 4.4 Hz, 1H), 7.86 (d, J= 10.0 Hz, 1H), 7.60 - 7.50 (m, 1H), 7.45 - 7.30 (m, 5H), 5.13 (d, J= 3.6 Hz, 1H), 4.55 (d, J= 9.2 Hz, 1H), 4.48 - 4.40 (m, 2H), 4.38 - 4.30 (m, 1H), 4.22 (dd, J= 5.6, 16.0 Hz, 1H), 3.85 - 3.73 (m, 1H), 3.71 - 3.62 (m, 2H), 2.45 (s, 3H), 2.27 - 2.15 (m, 8H), 2.17 - 1.99 (m, 6H), 1.95 - 1.70 (m, 4H), 1.55 - 1.40 (m, 2H), 1.40 -1.20 (s, 14H), 0.94 (s, 9H).

[0904] Example 53 (25,47?)-l-((S)-2-(7-(4-((lr,4r)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0905]

[0906] The compound was prepared according to the procedures described for Example 47. LCMS (ESI): m / z 1180.8 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.68 - 8.54 (m, 2H), 7.93 (s, 1H), 7.90 - 7.80 (m, 1H), 7.58 (d, J= 12.8 Hz, 1H), 7.47 - 7.37 (m, 7H), 5.85 -5.65 (m, 1H), 5.15 (s, 1H), 4.55 (d, J= 9.2 Hz, 1H), 4.48 - 4.41 (m, 2H), 4.38 - 4.30 (m, 1H), 4.22 (dd, J= 5.6, 16.0 Hz, 1H), 3.73 - 3.60 (m, 3H), 2.85 - 2.70 (m, 2H), 2.45 (s, 3H), 2.40 -2.36 (m, 2H), 2.32 - 2.20 (m, 4H), 2.15 - 1.78 (m, 8H), 1.64 - 1.51 (m, 8H), 1.50 - 1.16 (m, 18H), 0.94 (s, 9H).

[0907] Example 54 (25,47?)-4-hydroxy-l-((5)-2-(7-(4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)heptanamido)-3,3-dimethylbutanoyl)-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0908]

[0909] The compound was prepared according to the procedures described for Example 47. LCMS (ESI): m / z 911.6 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.62 - 8.56 (m, 1H), 8.53 (s, 1H), 7.87 (d, J= 9.2 Hz, 1H), 7.74 (d, J= 7.6 Hz, 1H), 7.64 (d, J= 9.2 Hz, 1H), 7.44. 7.38 (m, 4H), 6.24 - 6.11 (m, 1H), 5.75 - 5.55 (m, 1H), 5.15 (d, J= 3.2 Hz, 1H), 4.55 (d, J = 9.2 Hz, 1H), 4.49 - 4.40 (m, 2H), 4.38 - 4.30 (m, 1H), 4.27 - 4.17 (m, 1H), 3.70 - 3.60 (m, 2H), 2.45 (s, 3H), 2.31 - 2.16 (m, 7H), 2.15 - 2.05 (m, 2H), 2.05 - 1.97 (m, 3H), 1.95 - 1.81 (m, 4H), 1.58 - 1.43 (m, 10H), 1.41 - 1.20 (m, 12H), 0.94 (s, 9H). Example 55 and Example 56 (2£,47?)-4-hydroxy-l-((5)-2-(2-((17?,35)-3-(4-((lr,4S)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0910] H

[0911]

[0912]

[0913] Step 1: methyl 3-((4-((lr,4r)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutanecarboxylate

[0914] To a solution of 4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)-7V-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)pyrimidin-2-amine hydrochloride (200 mg, 383 umol) in MeOH (3.00 mL) and THF (3.00 mL) was added Et₃N dropwise till pH ~ 7, then HO Ac was added dropwise to the mixture till pH ~ 5. Then methyl 3 -formylcyclobutanecarboxylate (81.8 mg, 575 umol) was added to the reaction mixture. After stirring at 20 °C for 0.5 h, 2-MePyBH3 (61.5 mg, 575 umol) was added to the reaction mixture. The resulting reaction mixture was stirred at 40 °C for 10 h under N2 atmosphere. After that, the reaction was quenched by addition of aqueous NH4CI solution (5 mL) and diluted with water (5 mL). The resulting mixture was extracted with EtOAc (10 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give crude product, which was purified by column chromatography on silica gel eluting with 0 ~ 10% MeOH in DCM to afford the title compound (204 mg, 87 %) as yellow oil. LCMS (ESI): m / z 611.3 (M+H)+.

[0915] Step 2: (lA,3r)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutanecarboxylic acid & (15,35)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)methyl)cy clobutanecarboxylic acid

[0916] To a solution of methyl 3-((4-((lr,4r)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutanecarboxylate (154 mg, 252 pmol) in MeOH (3.0 mL) and H2O (3.00 mL) was added LiOH H2O (21.2 mg, 504 umol) at 25 °C. Then the mixture was stirred at 40 °C for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by pre- HPLC (acetonitrile 10 - 50 / 0.225% TFA in water) to give a mixture of the two isomers (130 mg) as a white solid, which was further separated by SFC to afford the trans isomer (30.0 mg, 20%, second peak on SFC) as a white solid and the cis isomer (80.0 mg, 53%, first peak on SFC) as a white solid. LCMS (ESI): m / z 597.3 (M+H)+.

[0917] Step 3: (2£,4A)-l-((5)-2-((lA,35)-3-((4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide To a solution of (lA,3r)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutanecarboxylic acid (22.0 mg, 36.8 umol) in DMF (1.0 mL) were added DIE A (23.8 mg, 184 umol) and HATU (14.7 mg, 38.7 umol) at 0 °C. After stirring at this temperature for 30 min, (25,4A)-l-((5)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (17.2 mg, 36.8 umol) in DMF (1.00 mL) was added dropwise to the reaction mixture at 0 °C. The resulting reaction mixture was stirred at 0 °C for another 1 h. After that, the reaction mixture was concentrated and purified by pre-HPLC (acetonitrile 15 - 45 / 0.225% TFA in water) to afford the title compound (18.4 mg, 47%) as a TFA salt as a white solid. LCMS (ESI): m / z 1009.7 (M+H)+. 'H NMR (400 MHz, MeOD) d 8.95 (s, 1H), 8.66 (t, J= 6.0 Hz, 1H), 8.47 (dd, J= 6.8, 2.0 Hz, 1H), 8.42 - 8.38 (m, 1H), 8.05 (d, J= 6.0 Hz, 1H), 7.65 - 7.67 (m, 1H), 7.50 - 7.48 (m, 2H), 7.45 - 7.43 (m, 2H), 7.23 - 7.16 (m, 6H), 6.87 (d, J= 6.0 Hz, 1H), 4.68 (d, J= 9.2 Hz, 1H), 4.60 - 4.59 (m, 1H), 4.58 - 4.54 (m, 2H), 4.42 - 4.39 (m, 1H), 3.95 - 3.90 (m, 2H), 3.85 - 3.80 (m, 1H), 3.36 (s, 4H), 3.28 - 3.18 (m, 5H), 3.15 - 3.05 (m, 4H), 2.88 - 2.78 (m, 1H), 2.50 (s, 3H), 2.48 - 2.38 (m, 2H), 2.30 - 2.00 (m, 9H), 1.74 - 1.61 (m, 2H), 1.57 - 1.46 (m, 2H), 1.08 - 1.01 (m, 13H).

[0918] Step 4: (25,4A)-l-((S)-2-((15,3A)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0919] To a solution of (15,35)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutanecarboxylic acid (40.0 mg, 67.0 umol) in DMF (1.00 mL) was added DIE A (43.3 mg, 335 umol) and HATU (26.7 mg, 70.4 umol) at 0 °C. After stirring at this temperature for 30 min, (25,4A)-l-((5)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (31.3 mg, 67.0 umol) in DMF (1.00 mL) was added dropwise to the reaction mixture at 0 °C, which was stirred at 0 °C for another 1 h. After that, the reaction mixture was concentrated and purified by pre-HPLC (acetonitrile 15 - 45 / 0.225% TFA in water) to afford the title compound (24.5 mg, 35 %) as a TFA salt as a white solid. LCMS (ESI): m / z 1009.7 (M+H)+. 'H NMR (400 MHz, MeOD) d 8.90 (s, 1H), 8.48 - 8.45 (m, 1H), 8.43 - 8.38 (m, 1H), 8.05 (d, J= 6.4 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.54 - 7.48 (m, 2H), 7.47 - 7.45 (m, 2H), 7.31 - 7.15 (m, 6H), 6.86 (d, J = 6.0 Hz, 1H), 4.69 - 4.64 (m, 1H), 4.62 - 4.59 (m, 1H), 4.56 - 4.51 (m, 2H), 4.42 - 4.36 (m, 1H), 3.98 - 3.90 (m, 1H), 3.88 - 3.82 (m, 1H), 3.40 - 3.30 (m, 4H), 3.28 -3.15 (m, 5H), 3.14 - 2.99 (m, 4H), 2.70 - 2.62 (m, 1H), 2.50 (s, 3H), 2.46 - 1.96 (m, 12H), 1.70 - 1.60 (m, 2H), 1.58 - 1.43 (m, 2H), 1.09 - 1.00 (m, 13H).

[0920] Example 57 (25,4A)-l-((5)-2-(6-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)spiro[3.3]heptane-2-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0921]

[0922] Step 1: (25,4A)-l-((S)-2-((15,3A)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0923] To a solution of 2-oxospiro[3.3]heptane-6-carboxylic acid (66.0 mg, 428 pmol) in DMF (1.00 mL) was added DIEA (166.0 mg, 1.28 mmol) and HATU (170 mg, 449 pmol) at 0°C. After stirring at 0 °C for 0.5 h, a solution of (25,4A)-l-[(25)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl] pyrrolidine-2-carboxamide (200 mg, 428 pmol) in DMF (0.50 mL) was added dropwise to the reaction the mixture. The resulting reaction mixture was stirred at 0 °C for another 2 h. After that, H2O (1.50 mL) was added to the mixture, which was extracted with EtOAc (2.0 mL x 6). The combined organic layer was washed with brine (10 mL), dried with Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel eluting with 0 ~ 5% MeOH in ethyl acetate to afford the title compound (163 mg, 44%) as a yellow solid. LCMS (ESI): m / z 567.2 (M+H)+.

[0924] Step 2: (25,4A)-l-((5)-2-(6-(4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)spiro[3.3]heptane-2-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide To a solution of 4-[2-(l-benzylcyclopropoxy)-3-pyridyl]-N-(4-piperazin-l-ylcyclohexyl)pyrimidin-2-amine (64.3 mg, 123 umol) in THF (0.50 mL) and MeOH (0.50 mL) was added Et3N dropwise until pH ~ 8, then acidified by HOAc until pH reached 4. (25,4A)-1-[(25)-3,3-dimethyl-2-[(2-oxospiro[3.3]heptane-6-carbonyl)amino] butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (70.0 mg, 123 pmol) was added to the above mixture and the reaction mixture was stirred at 60 °C for 2 h. After cooling to room temperature, borane;2-methylpyridine (26.4 mg, 247 pmol) was added to the reaction mixture in one portion. The resulting reaction mixture was stirred at 60 °C for another 8 h. After cooling to room temperature, the mixture was concentrated and the residue was purified by pre-HPLC (acetonitrile 20 - 50 / 0.225% TFAin water) to afford the title compound (55.8 mg, 43%) as a TFA salt as a white solid. LCMS (ESI): m / z 518.4 (M / 2+H)+. 'H NMR (400 MHz, MeOD) d 8.93 (s, 1H), 8.49 - 8.42 (m, 1H), 8.40 - 8.33 (m, 1H), 8.03 - 7.97 (m, 1H), 7.50 - 7.42 (m, 2H), 7.41 - 7.37 (m, 2H), 7.23 - 7.10 (m, 6H), 6.86 - 6.78 (m, 1H), 4.62 - 4.56 (m, 1H), 4.55 - 4.45 (m, 3H), 4.38 - 4.28 (m, 1H), 4.04 - 3.73 (m, 3H), 3.43 - 3.31 (m, 5H), 3.28 - 3.02 (m, 6H), 2.55 - 2.42 (m, 4H), 2.39 - 2.01 (m, 14H), 1.71 - 1.56 (m, 2H), 1.55 - 1.42 (m, 2H), 1.08 - 0.95 (m, 14H).

[0925] Example 58 (25',4A)-4-hydroxy-l-((5)-2-(6-(4-((lr,4A)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)spiro[3.3]heptane-2-carboxamido)-3,3-dimethylbutanoyl)-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carb oxami de

[0926] The compound was prepared according to the procedures described for Example 57 and obtained as a TFA salt. LCMS (ESI): m / z 921.6 (M+H)+. 'H NMR (400 MHz, MeOD) 38.94 (s, 1H), 8.54 (s, 1H), 7.68 (d, J= 9.2 Hz, 1H), 7.50 - 7.42 (m, 4H), 6.35 - 6.25 (m, 1H), 5.87 - 5.75 (m, 1H), 4.65 - 4.50 (m, 4H), 4.40 - 4.32 (m, 1H), 3.97 - 3.76 (m, 3H), 3.30 - 3.25 (m, 2H), 3.24 - 3.00 (m, 5H), 2.56 - 2.45 (m, 4H), 2.40 - 1.98 (m, 15H), 1.74 - 1.42 (m, 11H), 1.09 - 0.97 (m, 10H).

[0927] Example 59 (2S,4R)-4-hydroxy-l-((S)-2-(3-((4-((lr,4S)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l- yl)methyl)cyclobutanecarboxamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0928] The compound was prepared according to the procedures described for Example 57. LCMS (ESI): m / z 895.2 (M+H)+. 'HNMR (400 MHz, MeOD) 38.84 (s, 1H), 8.48 (s, 1H), 7.64 (d, J= 9.6 Hz, 1H), 7.50 - 7.40 (m, 4H), 6.26 (d, J= 8.4 Hz, 1H), 5.85 -5.80 (m, 1H), 4.68 - 4.48 (m, 4H), 4.35 (d, J= 15.6 Hz, 1H), 3.95 - 3.80 (m, 3H), 3.15 - 3.05 (m, 1H), 2.75 - 2.60 (m, 4H), 2.57 - 2.40 (m, 9H), 2.38 - 2.30 (m, 2H), 2.30 - 2.01 (m, 8H), 2.00 - 1.85 (m, 2H), 1.70 - 1.50 (m, 6H), 1.48 - 1.33 (m, 4H), 1.06 - 0.97 (m, 9H).

[0929] Example 60 (25',47?)-4-hydroxy-l-((5)-2-(2-((U?,35)-3-((4-((lr,45)-4-((8-isopropyl-7-oxo-7, 8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0930] Step 2

[0931]

[0932]

[0933] Step 4

[0934]

[0935] Step 5

[0936]

[0937] Step 6

[0938] Step 7

[0939]

[0940] Step 1: tert-butyl 2-(3-((benzyloxy)methyl)cyclobutylidene)acetate

[0941] To a stirred solution of 3-((benzyloxy)methyl)cyclobutan-l-one (21 g, 100.39 mmol) in toluene (140 mL) was added tert-butyl 2-(triphenyl-15-phosphaneylidene)acetate (41.5 g, 100.39 mmol) at 25 °C. Then the reaction mixture was stirred at 120 °C for 2 h under N2 atmosphere. After that, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography eluting with 0 - 10% EtOAc in petroleum ether to afford the title compound (25 g, 78%) as yellow oil. 'H NMR (400 MHz, CDCI3) d 7.48 - 7.23 (m, 5H), 5.56 (s, 1H), 4.56 (s, 2H), 3.63 - 3.43 (m, 2H), 3.28 - 3.17 (m, 1H), 2.95 - 2.57 (m, 4H), 1.49 (s, 9H).

[0942] Step 2: tert-butyl 2-(3-(hydroxymethyl)cyclobutyl)acetate

[0943] To a stirred solution of tert-butyl 2-(3 -((benzyloxy )methyl)cy cl obutylidene)acetate (25 g, 87 mmol) in MeOH (500 mL) and HO Ac (25 mL) was added Pd(OH)2 / C (20% load on C, 10 g). Then the mixture was stirred at 25 °C for 16 h under H2 atmosphere (15 psi). The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (100 ml x 3). The filtrate was concentrated to give the title compound (15.9 g, 89%) as yellow oil. 'H NMR (400 MHz, CDCI3) 33.67 (d, J= 7.2 Hz, 1H), 3.55 (d, J= 6.4 Hz, 1H), 2.69 - 2.49 (m, 1H), 2.40 - 2.35 (m, 1H), 2.29 - 2.28 (m, 1H), 2.25 - 2.16 (m, 1H), 2.00 - 1.89 (m, 1H), 1.88 -1.79 (m, 1H), 1.51 - 1.37 (m, 11H).

[0944] Step 3: tert-butyl 2-(3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)acetate

[0945] To a stirred solution of tert-butyl 2-(3-(hydroxymethyl)cyclobutyl)acetate (15.9 g, 79.4 mmol) and imidazole (10.8 g, 79.4 mmol) in DCM (600 mL) was added TBDPSC1 (32.7 g, 119.1 mmol) at 25 °C. Then the reaction mixture was stirred at 25 °C for 16 h. After that, the reaction mixture was concentrated and the residue was purified by column chromatography eluting with 0 - 10% EtOAc in petroleum ether to afford the title compound (20 g, 68%) as a colorless oil. 'H NMR (400 MHz, DMSO - d6) 37.66 - 7.54 (m, 4H), 7.50 - 7.36 (m, 6H), 3.65 (d, J= 6.4 Hz, 1H), 3.54 (d, J= 5.2 Hz, 1H), 3.28 - 3.27 (m, 1H), 2.45 - 2.28 (m, 2H), 2.24 -2.17 (m, 1H), 2.12 - 1.88 (m, 2H), 1.79 - 1.69 (m, 1H), 1.57 - 1.47 (m, 1H), 1.24 (s, 9H), 0.99 (s, 9H).

[0946] Step 4: tert-butyl 2-((lr,3r)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)acetate tert-butyl 2-(3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)acetate (20 g, 45.6 mmol) was purified by SFC (Daicel Chiralcel OJ (250 mm * 50 mm, 10 um), Supercritical CO2 / (EtOH + 0.1% NH4OH) = 90 / 10; 200 mL / min) to give the title compound (8.1 g, 40.5%, first peak on SFC) as a colorless oil.XHNMR (400 MHz, DMSO-tL) 37.65 - 7.56 (m, 4H), 7.50 -7.37 (m, 6H), 3.65 (d, J= 6.4 Hz, 2H), 3.32 (s, 1H), 2.44 (d, J= 5.6 Hz, 1H), 2.32 (d, J= 7.2 Hz, 2H), 1.97 - 1.86 (m, 2H), 1.77 - 1.66 (m, 2H), 1.37 (s, 9H), 1.00 (s, 9H).

[0947] Step 5: tert-butyl 2-((lr,3r)-3-(hydroxymethyl)cyclobutyl)acetate

[0948] To a stirred solution of tert-butyl 2-((lr, 3r)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)acetate (2 g, 4.6 mmol) in THF (10 mL) was added TBAF (10 mL, 1 M in THF) at 0 °C. Then the reaction mixture was stirred at 25 °C for 2 h. After that, the reaction mixture was concentrated and the residue was purified by column chromatography eluting with 0 - 30% EtOAc in petroleum ether to afford the title compound (0.91 g, 99%) as a colorless oil. 'HNMR (400 MHz, CDCl3) 33.67 (d, J= 7.2 Hz, 2H), 2.71 -2.59 (m, 1H), 2.51 - 2.34 (m, 3H), 2.00 - 1.90 (m, 2H), 1.87 - 1.76 (m, 2H), 1.43 (s, 9H).

[0949] Step 6: tert-butyl 2-((lr,3r)-3-formylcyclobutyl)acetate

[0950] To a stirred solution of tert-butyl 2-((lr, 3r)-3-(hydroxymethyl)cyclobutyl)acetate (0.3 g, 1.5 mmol) and SiC>2 (0.3 g) in DCM (6 mL) was added PCC (0.65 g, 3 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2h. After that, the reaction mixture was filtered and the filtrate was used into next step directly without further purification.

[0951] Step 7: 8-isopropyl-2-(((lr, 4r)-4-(piperazin-l-yl)cyclohexyl)amino)pyrido[2,3-d]pyrimidin-7(8J7)-one

[0952] To a mixture of tert-butyl 4-[4-[(8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]cyclohexyl]piperazine-l -carboxylate (200 mg, 0.42 mmol) in EtOAc (2.0 mL) was added HClZEtOAc (2 mL, 4 M) at 25 °C. After stirring at 25 °C for another 2 h, the reaction mixture was concentrated and used for next step directly without further purification. LCMS (ESI): m / z 371.1 (M+H)+.

[0953] Step 8: tert-butyl 2-((1R,3r)-3-((4-((lr,4A)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetate

[0954] To a solution of 8-isopropyl-2-(((lr, 4r)-4-(piperazin-l-yl)cyclohexyl)amino)pyrido[2,3-t / ]pyrimidin-7(8J7)-one (170 mg, 0.42 mmol) in THF (3 mL) and MeOH (3 mL) was added TEA till pH = 7, then HO Ac was added dropwise to the solution till pH = 5. Then tert-butyl 2-(3-formylcyclobutyl)acetate (95 mg, 0.48 mmol) was added to the solution. After stirred at 25°C for 0.5 h, 2-MePyBH3 (67 mg, 0.63 mmol) was added to the reaction mixture and stirred at 40 °C for another 16 h under N2 atmosphere. After cooling to room temperature, the reaction was quenched with H2O (10 mL), extracted with EtOAc (20 mL x 2). The combined organic layer was washed by brine (30 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum to give title compound (230 mg, 99%) as a yellow solid. LCMS (ESI): m / z 553.3 (M+H)+.

[0955] Step 9: 2-((lR,3r)-3-((4-((lr,4R)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)methyl)cyclobutyl)acetic acid

[0956] To a stirred solution of tert-butyl 2-((1R,3r)-3-((4-((lr,4A)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl) acetate (230 mg, 0.42 mmol) in EtOAc (2.0 mL) was added 4 M HC1 in EtOAc (1 mL) at 25°C. After stirring at 25 °C for 2 h, the solution was concentrated and the residue was purified by pre- HPLC (acetonitrile 3 - 33 / 0.225% FA in water) to afford the title compound (120 mg, 58%) as a white solid. LCMS (ESI): m / z 497.2 (M+H)+.

[0957] Step 10: (25,4A)-4-hy droxy- 1 -((S)-2-(2-(( 1 R, 3S)-3 -((4-(( 1 r,45)-4-((8 -i sopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0958] To a stirred solution of 2-[3-[[4-[4-[(8-isopropyl-7-oxo-pyrido[2,3-J]pyrimidin-2-yl)amino]cyclohexyl]piperazin-l-yl]methyl]cyclobutyl]acetic acid (60 mg, 0.12 mmol) and HATU (50 mg, 0.13 mmol) in DMF (2 mL)was added DIEA (0.11 mL, 0.6 mmol) dropwise at 0 °C. After stirred at 0 °C for 30 min, (25,4A)-l-[(25)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (57 mg, 0.13 mmol) was added to the reaction mixture, which was stirred at 25 °C for 2 hours. After that, the solution was purified by pre-HPLC (acetonitrile 18 - 48 / 0.225% FA in water) to afford the title compound (12.2 mg, 11%) as a white solid. LCMS (ESI): m / z 909.6 (M+H)+.1H NMR (400 MHz, DMSO-d6) 68.99 (s, 1H), 8.63 - 8.50 (m, 2H), 8.17 (s, 1H), 7.90 - 7.76 (m, 1H), 7.66 - 7.58 (m, 1H), 7.45 - 7.33 (m, 4H), 6.23 - 6.09 (m, 1H), 5.62 (s, 1H), 5.17 (s, 1H), 4.55 - 4.50 (m, 1H), 4.46 -4.40 (m, 2H), 4.36 - 4.32 (m, 1H), 4.26 - 4.17 (m, 1H), 3.84 - 3.41 (m, 6H), 2.46 - 2.23 (m, 13H), 2.13 - 1.81 (m, 7H), 1.80 - 1.71 (m, 4H), 1.61 - 1.39 (m, 7H), 1.37 - 1.20 (m, 4H), 0.96 -0.88 (m, 9H).

[0959] Example 61 (25,4A)-l-((S)-2-(2-(3-((4-((lr,4S)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0960] H

[0961] N. O

[0962] N

[0963] O.

[0964]

[0965] N OH

[0966] The compound was prepared according to the procedures described for Example 60 and obtained as a TFA salt. LCMS (ESI): m / z 1023.1(M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.56 (d, J= 6.0, 1H), 8.44 - 8.40 (m, 1H), 8.25 (s, 1H), 8.14 (d, J= 5.2, 1H), 7.95 -7.80 (m, 1H), 7.45 - 7.38 (m, 4H), 7.33 (s, 1H), 7.25 - 7.10 (m, 6H), 6.65 (s, 1H), 4.57 - 4.50 (m, 1H), 4.48 - 4.31 (m, 3H), 4.26 - 4.17 (m, 1H), 3.84 - 3.41 (m, 7H), 3.30 - 3.00 (m, 7H), 2.75 - 2.55 (m, 4H), 2.45 (s, 3H), 2.43 - 2.15 (m, 3H), 2.13 - 1.98 (m, 5H), 1.95 - 1.85 (m, 3H), 1.65 -1.45 (m, 3H), 1.43 - 1.30 (m, 2H), 1.00 - 0.88 (m, 13H).

[0967] Example 62 (2£,4R)-4-hydroxy-l-((5)-2-(2-(3-((4-((lr,45)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0968]

[0969] The compound was prepared according to the procedures described for Example 60 and obtained as a formate. LCMS (ESI): m / z 909.2 (M+H)+. 'HNMR (400 MHz, DMSO-tfc) d 9.00 (s, 1H), 8.60 - 8.52 (m, 2H), 7.94 - 7.66 (m, 3H), 7.45 - 7.38 (m, 4H), 6.25 - 6.15 (m, 1H), 5.75 -5.65 (m, 1H), 4.57 - 4.50 (m, 1H), 4.48 - 4.31 (m, 3H), 4.26 - 4.17 (m, 1H), 3.84 - 3.41 (m, 7H), 3.40 - 3.10 (m, 7H), 2.75 - 2.55 (m, 2H), 2.45 (s, 3H), 2.43 - 2.25 (m, 1H), 2.25 - 1.98 (m, 7H), 1.97 - 1.85 (m, 3H), 1.65 - 1.35 (m, 12H), 1.00 - 0.88 (m, 9H).

[0970] Example 63 and Example 64 (2S,4R)-l-((S)-2-(2-((lR,3S)-3-((4-((lr,4S)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0971] and

[0972] (2S,4R)-l-((R)-2-(2-((lR,3R)-3-((4-((lr,4R)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carb oxami de Step 3

[0973]

[0974] Step 1: tert-butyl 2-((1R,3r)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetate

[0975] To a stirred solution of 4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)-7V-((lr,4r)-4- (piperazin-l-yl)cyclohexyl)pyrimidin-2-amine hydrochloride (300 mg, 0.58 mmol) in THF (3 mL) and MeOH (3 mL) was added TEA till pH = 7, then HO Ac was added dropwise to the solution till pH around 5. Then tert-butyl 2-((lr,3r)-3-formylcyclobutyl)acetate (132 mg, 0.66 mmol) was added to the reaction mixture under N2 atmosphere. After stirred at 25°C for 0.5 h, 2-MePy BH3 (92 mg, 0.86 mmol) was added to the reaction mixture, and then the reaction mixture was stirred at 40 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was quenched with H2O(10 mL), extracted with EtOAc (20 mLx 2 ). The combined organic layer was washed by brine (30 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum to give title compound (380 mg, 99%) as a yellow solid. LCMS (ESI): m / z 667.4 (M+H)+.

[0976] Step 2: 2-((1R,3r)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)methyl)cyclobutyl)acetic acid

[0977] To a stirred solution of tert-butyl 2-((1R,3r)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetate (380 mg, 0.42 mmol) in EtOAc (2.0 mL) was added 4M HC1 in EtOAc (2 mL), then the mixture was stirred at 25 °C for 2 h. The reaction solution was concentrated and the residue was purified by pre-HPLC (acetonitrile 20 - 50 / 0.225% FA in water) to afford the title compound (150 mg, 43%) as a white solid. LCMS (ESI): m / z 611.3 (M+H)+.

[0978] Step 3: (2S,4R)-l-((S)-2-(2-((lR,3S)-3-((4-((lr,4S)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0979] and

[0980] (2S,4R)-l-((R)-2-(2-((lR,3R)-3-((4-((lr,4R)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carb oxami de

[0981]

[0982] To a stirred mixture of 2-((1R,3r)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetic acid (60 mg, 0.10 mmol), EDCI (23 mg, 0.11 mmol), HOBT (16 mg, 0.11 mmol) and Et3N (0.04 mL, 0.29 mmol) in DMF (2 mL) was added (25,4A)-l-[(25)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-7V-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (42.3 mg, 0.10 mmol) at 0°C. Then the mixture was stirred at 25 °C for 16 h under N2 atmosphere. The mixture was purified by pre-HPLC (acetonitrile 14 - 44 / 0.225% FA in water) and SFC (Daicel Chiralcel AD (250 mm * 30 mm, 10 um), Supercritical CO2 / (z-PrOH + 0.1% NH4OH) = 55 / 45; 90 mL / min) to afford (25,4A)-1-((5)-2-(2-((lA,35)-3-((4-((lr,45)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (13 mg, 20%, first peak on SFC) and (25,4A)-l-((A)-2-(2-((lA,3A)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(8.4 mg, 13%, second peak on SFC) as a white solid. Absolute configuration was arbitrarily assigned to each isomer.

[0983] Example 63 (first peak on SFC): LCMS (ESI): m / z 1038.0 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 38.98 (s, 1H), 8.41 - 8.35 (m, 2H), 8.25 (s, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.39 - 7.35 (m, 2H), 7.25 - 7.14 (m, 6H), 6.98 (d, J= 7.6 Hz, 1H), 6.59 (s, 1H), 5.10 (s, 1H), 4.93 - 4.84 (m, 1H), 4.49 (d, = 9.2 Hz, 1H), 4.43 - 4.36 (m, 1H), 4.27 (s, 1H), 3.66 - 3.57 (m, 2H), 3.30 (s, 6H), 2.45 (s, 3H), 2.41 - 2.25 (m, 10H), 2.10 -2.06 (m, 4H), 1.97 (s, 2H), 1.85 - 1.73 (m, 3H), 1.37 (d, J= 7.2 Hz, 3H), 1.24 (d, J= 9.6 Hz, 7H), 0.92 (s, 13H).

[0984] Example 64 (second peak on SFC): LCMS (ESI): m / z 1037.7 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 38.98 (s, 1H), 8.42 - 8.35 (m, 2H), 8.30 - 8.20 (m, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.78 (d, J= 9.2 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.40 - 7.34 (m, 2H), 7.25 - 7.13 (m, 6H), 6.98 (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 5.20 - 5.05 (m, 1H), 4.95 - 4.85 (m, 1H), 4.50 (d, J= 9.2 Hz, 1H), 4.42 (t, J= 8.0 Hz, 1H), 4.27 (s, 1H), 3.70 - 3.53 (m, 2H), 3.31 - 3.28 (m, 6H), 2.48 - 2.40 (m, 8H), 2.38 - 2.15 (m, 9H), 2.02 - 1.96 (m, 2H), 1.81 - 1.73 (m, 5H), 1.37 (d, J= 7.0 Hz, 3H), 1.30 - 1.22 (m, 5H), 0.92 (s, 13H).

[0985] Example 65 (25,4A)-l-((S)-2-((1R,3S)-3-((4-((lr,4S)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0986]

[0987] To a stirred solution of 2-[3-[[4-[4-[[4-[2-(l-benzylcyclopropoxy)-3-pyridyl]pyrimidin-2-yl]amino]cyclohexyl]piperazin-l-yl]methyl]cyclobutyl]acetic acid (100.0 mg, 0.16 mmol) and HATU (93.38 mg, 0.25 mmol) in DMF (4 mL) was added DIEA (0.14 mL, 0.82 mmol) dropwise at 0 °C. After stirred at 0 °C for 0.5 h, (25,4A)-l-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-A-[(15)-l-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide;hydrochloride(118.14 mg, 0.25 mmol) in DMF (1 mL) was added dropwise to the reaction mixture. Then the mixture was stirred at 25 °C for 15 h under N2 atmosphere. The reaction mixture was purified by pre-HPLC (acetonitrile 20-50 / 0.225% FA in water) to afford the title compound (42.5 mg, 24.5%) as a white solid. LCMS (ESI): m / z 1023.5 (M+H)+.XH NMR (400 MHz, DMSO-tfc) 38.98 (s, 1H), 8.57 (s, 1H), 8.41 - 8.33 (m, 1H), 8.25 (s, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.86 - 7.72 (m, 1H), 7.44 - 7.35 (m, 4H), 7.27 - 7.19 (m, 3H), 7.15 (t, J= 8.4 Hz, 3H), 6.97 (d, J= 7.6 Hz, 1H), 6.59 (s, 1H), 5.13 (s, 1H), 4.52 (d, J =7.2 Hz, 1H), 4.47 - 4.39 (m, 2H), 4.34 (s, 1H), 4.21 (dd, J= 5.2, 16.0 Hz, 1H), 3.64 (d, J= 11.6 Hz, 3H), 3.35 - 3.30 (m, 7H), 2.44 (s, 3H), 2.30 (d, J= 6.4 Hz, 5H), 2.28 - 2.24 (m, 2H), 2.19 - 2.00 (m, 4H), 1.98 - 1.86 (m, 3H), 1.84 - 1.66 (m, 4H), 1.39 - 1.17 (m, 6H), 0.95 - 0.90 (m, 13H).

[0988] Example 66 (25,4A)-l-((S)-2-((1R,3S)-3-(4-((lr,4S)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0989]

[0990] Step 1: 3-(2-diazoacetyl)cyclobutan-l-one

[0991] To a stirred solution of 3 -oxocyclobutane- 1 -carboxylic acid (10.0 g, 87.6 mmol) in DCM (100 mL) was added SOCh (19.1 mL, 262.9 mmol) at 0 °C under N2 atmosphere. After stirring at 20 °C for 2 h, the reaction mixture was concentrated under vacuum, and the residue was dissolved in CH3CN (50 mL) and THF (50 mL). Then TMSCHN2 (83 mL, 166.0 mmol) was added into the reaction mixture, which was stirred at 20 °C for 16 h. After that, the reaction was quenched by addition of HO Ac (10 mL). Then the reaction mixture was diluted with water (200 mL), extracted with EtOAc (200 mL x 2) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with 0 ~ 50% ethyl acetate in petroleum ether to afford the title compound (4.5 g, 39%) as a yellow oil.1H NMR (400 MHz, CDCI3) d 5.39 (s, 1H), 3.52 - 3.44 (m, 2H), 3.19 - 3.15 (m, 3H).

[0992] Step 2: 2-(3-oxocyclobutyl)acetic acid

[0993] To a stirred solution of 3-(2-diazoacetyl)cyclobutan-l-one (2.0 g, 14.48 mmol) in THF (50 mL) and H2O (25 mL) was added AgNCh (2.9 g, 17.38 mmol) at 20 °C, and then the reaction mixture was stirred at 20 °C for 16 h. After that, the reaction mixture was diluted with water (200 mL), extracted with EtOAc (50 mL x 2) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (1.0 g, 45%) as a colorless oil. 'H NMR (400 MHz, CDCl3) <53.36 - 3.24 (m, 2H), 2.92 - 2.80 (m, 3H), 2.74 - 2.69 (m, 2H).

[0994] Step 3: tert-butyl 2-(3-oxocyclobutyl)acetate

[0995] A mixture of 2-(3-oxocyclobutyl)acetic acid (1.0 g, 7.8 mmol), DMAP (476.0 mg, 3.9 mmol) and (Boc)2O (2.5 g, 11.71 mmol) in / -BuOH (20 mL) was stirred at 20 °C for 16 h. After that, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with 0 ~ 10% ethyl acetate in petroleum ether to afford the title compound (600.0 mg, 42%) as a colorless oil. 'H NMR (400 MHz, CDCI3) <53.31 - 3.19 (m, 2H), 2.87 - 2.71 (m, 3H), 2.56 (d, J= 7.2 Hz, 2H), 1.46 (s, 9H).

[0996] Step 4: tert-butyl 2-((1R,3r)-3-(4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)cyclobutyl)acetate

[0997] A mixture of 4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)-A-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)pyrimidin-2-amine hydrochloride (400.0 mg, 0.77 mmol) and tert-butyl 2-(3-oxocyclobutyl)acetate (424.0 mg, 2.3 mmol) in MeOH (4 mL) was stirred at 20 °C for Ih. Then NaBH₃CNCN (241.0 mg, 3.84 mmol) was added into the reaction mixture, and the mixture was stirred at 20 °C for 16 h under N2 atmosphere. After that, the reaction was quenched by aqueous NH4CI (5 mL) and diluted with water (30 mL). The resulting solution was extracted with EtOAc (30 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give crude product, which was purified by column chromatography on silica gel eluting with 0 ~ 10% MeOH in DCM to afford tert-butyl 2-(3-(4-((lr,4r)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)cyclobutyl)acetate (300.0 mg, 60%) as a white solid. It was further purification by SFC (DAICEL CHIRALPAK IE (250 mm * 30 mm, 10 um); Heptane / (EtOH+ 0.1% NH3 H2O) = 90 / 10; 80 mL / min) to afford the title compound (45.0 mg, 15%, second peak on SFC) as a white solid. LCMS (ESI): m / z 653.3 (M+H)+.

[0998] Step 5: 2-((1R,3r)-3-(4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)cyclobutyl)acetic acid

[0999] To a solution of tert-butyl 2-((1R,3r)-3-(4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)cyclobutyl)acetate (45.0 mg, 0.07mmol) in DCM (2 mL) was added HC1 (8 mL, 4 M in 1,4-dioxane), then the mixture was stirred at 20 °C for 1 h. After that, the organic layer was concentrated under vacuum to afford the title compound (41.0 mg, 99%) as a colorless oil. The crude compound was directly used in the next step without further purification. Step 6: (25,4A)-l-((S)-2-((1R,3S)-3-(4-((lr,4S)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1000] To a stirred mixture of2-((1R,3r)-3-(4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)cyclobutyl)acetic acid (45.0 mg, 0.08 mmol), (25,4A)-l-((5)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (39.0 mg, 0.09 mmol) and DIPEA (0.07 mL, 0.38 mmol) in DMF (4 mL) was added HATU (34.0 mg, 0.09 mmol) at 0 °C, then the mixture was stirred at 20 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was purified by pre-HPLC (acetonitrile 33-63 / 0.225% FA in water) to afford the title compound (9.5 mg, 12%) as a formate as a white solid. LCMS (ESI): m / z 1009.6 (M+H)+. 'HNMR (400 MHz, DMSO-d6) d 8.99 (s, 1H), 8.56 (t, J= 6.0 Hz, 1H), 8.37 (dd, J= 2.0, 4.8 Hz, 1H), 8.27 - 8.24 (m, 1H), 8.14 (s, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.89 (d, J = 9.6 Hz, 1H), 7.45 - 7.35 (m, 4H), 7.26 - 7.21 (m, 2H), 7.20 - 7.13 (m, 4H), 7.00 (d, J= 8.0 Hz, 1H), 6.62 - 6.58 (m, 1H), 5.12 (d, J= 2.8 Hz, 1H), 4.53 (d, J= 9.6 Hz, 1H), 4.47 - 4.39 (m, 2H), 4.36 - 4.32 (m, 1H), 4.21 (dd, J= 5.2, 16.0 Hz, 1H), 3.70 - 3.58 (m, 3H), 2.87 - 2.85 (m, 1H), 2.63 - 2.54 (m, 5H), 2.44 (s, 3H), 2.42 - 2.23 (m, 8H), 2.07 - 1.88 (m, 8H), 1.83 - 1.81 (m, 3H), 1.78 - 1.74 (m, 2H), 1.34 - 1.22 (m, 5H), 0.93 (s, 9H).

[1001] Example 67 (25,4A)-4-hydroxy-l-((5)-2-(2-((lA,35)-3-(4-((lr,4S)-4-((8-isopropyl-7-oxo-7, 8-dihydropyrido[2, 3- ]pyrimidin-2 -yl)amino)cyclohexyl)piperazin-l-yl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1002]

[1003] The compound was prepared according to the procedures described for Example 66. LCMS (ESI): m / z 895.4 (M+H)+ 1HNMR (400 MHz, DMSO ) d 8.93 (s, 1H), 8.51 (s, 1H), 8.27 (s, 1H), 7.61 (d, J= 9.2 Hz, 1H), 7.58 - 7.50 (m, 1H), 7.44 - 7.35 (m, 5H), 6.16 (d, J= 9.2 Hz, 1H), 5.72 - 5.59 (m, 1H), 4.92 - 4.90 (m, 1H), 4.53 (d, J= 9.2 Hz, 1H), 4.49 - 4.35 (m, 3H), 4.29 - 4.22 (m, 1H), 3.70 - 3.68 (m, 2H), 3.65 - 3.59 (m, 1H), 2.92 - 2.80 (m, 1H), 2.59 - 2.56 (m, 4H), 2.47 - 2.46 (m, 1H), 2.45 (s, 3H), 2.44 - 2.42 (m, 1H), 2.32 -2.30 (m, 6H), 2.07 - 1.95 (m, 6H), 1.92 - 1.90 (m, 2H), 1.79 - 1.76 (m, 2H), 1.53 (d, J= 6.8 Hz, 6H), 1.39 - 1.28 (m, 4H), 0.95 (s, 9H).

[1004] Example 68 (25,47?)-4-hydroxy-l-((5)-2-(2-((17?,35)-3-((4-((lr,45)-4-((8-isopropyl-7-oxo-7,8-dihydropteridin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1005] H

[1006] N. o

[1007] Il H

[1008] N N N N

[1009] O

[1010]

[1011] O OH

[1012] The compound was prepared according to the procedures described for Example 66 and obtained as a formate. LCMS (ESI): m / z 910.6 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 8.93 (s, 1H), 8.61 (s, 1H), 8.13 (s, 1H), 7.72 (s, 1H), 7.70 - 7.55 (m, 1H), 7.50 - 7.42 (m, 1H), 7.40 - 7.35(m, 4H), 7.37 (s, 1H), 5.58 - 5.45 (m, 1H), 4.52 (d, J= 9.2 Hz, 1H), 4.49 - 4.35 (m, 3H), 4.30 - 4.22 (m, 1H), 3.69 (dd, J= 4.4, 10.4 Hz, 2H), 3.65 - 3.60 (m, 1H), 2.57 - 2.52 (m, 4H), 2.45 (s, 3H), 2.44 - 2.34 (m, 6H), 2.34 - 2.25 (m, 4H), 2.23 - 2.08 (m, 3H), 2.07 - 1.94 (m, 4H), 1.92 - 1.82 (m, 2H), 1.82 - 1.76 (m, 1H), 1.54 (d, J= 6.8 Hz, 6H), 1.43 - 1.23 (m, 6H), 0.94 (s, 9H).

[1013] Example 69 (25',47?)-4-hydroxy-l-((5)-2-(2-(3-((4-((lr,4S)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)acetamido)-3,3-dimethylbutanoyl)-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carb oxami de

[1014]

[1015] Step 1: tert-butyl 3-((4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-t / ]pyri mi di n-2-yl )ami no)cycl ohexyl )pi perazi n- 1 -yl)methyl)azetidine- 1 -carboxylate

[1016] To a stirred solution of 8-isopropyl-2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl)amino)pyrido[2,3-J]pyrimidin-7(8J7)-one (150 mg, 368 umol) in THF (2.0 mL) and MeOH (2.0 mL) was added Et₃N dropwise until pH reached 7 ~ 8, then AcOH was added the reaction mixture until pH reached 4 ~ 5. tert-butyl 3 -formylazetidine- 1 -carboxylate (136 mg, 737 umol) was added to the reaction mixture at 20 °C. After stirring at 20 °C for 0.5 h, (2,6-dimethylpyridin-l-ium-l-yl)boranuide (66.9 mg, 553 umol) was added to the reaction mixture and stirred at 40 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (8.0 mL) and extracted with DCM (10 mL x 3). The combined organic layer was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 0 ~ 15% MeOH in DCM to give title compound (150 mg, 71 %) as a white solid. LCMS (ESI): m / z 540.3 (M+H)+.

[1017] Step 2: 2-(((lr,4r)-4-(4-(azetidin-3-ylmethyl)piperazin-l-yl)cyclohexyl)amino)-8-isopropylpyrido[2,3- ]pyrimidin-7(8J7)-one

[1018] To a stirred solution of tert-butyl 3-((4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)azetidine-l-carboxylate (150 mg, 278 umol) in EtOAc (3.0 mL) was added HC1 / EtOAc (5.0 mL, 4.0 M) at room temperature. After stirring at 25 °C for 2 h, the reaction mixture was concentrated under reduced pressure to give the title compound (149 mg, crude) as a white solid. LCMS (ESI): m / z 440.3 (M+H)+.

[1019] Step 3: (2S,4R)-4-hydroxy-l-((S)-2-(2-(3-((4-((lr,4S)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carb oxami de

[1020] To a stirred solution of 2-(((lr,4r)-4-(4-(azetidin-3-ylmethyl)piperazin-l-yl)cyclohexyl)amino)-8-isopropylpyrido[2,3-J]pyrimidin-7(8J7)-one (100 mg, 210 umol) in DMF (1.00 mL) was added DIEA (163 mg, 1.26 mmol) at 25 °C. After stirring at 25 °C for 0.5 h, K2CO3 (145 mg, 1.05 mmol) and 2-(((lr,4r)-4-(4-(azetidin-3-ylmethyl)piperazin-l-yl)cyclohexyl)amino)-8-isopropylpyrido[2,3-J]pyrimidin-7(8J7)-one (138 mg, 231 umol) were added to the reaction mixture. The resulting reaction mixture was stirred at 25 °C for 12 h. After that, the reaction mixture was filtered and the filtrate was purified by pre-HPLC (acetonitrile 20-50 / 0.225% NH4HCO3 in water) to afford the title compound (26.7 mg, 13%) as a white solid. LCMS (ESI): m / z 910.6 (M+H)+. 'HNMR (400 MHz, MeOD) δ 8.88 (s, 1H), 8.48 (s, 1H), 7.64 (d, J= 9.2 Hz, 1H), 7.50 - 7.35 (m, 4H), 6.26 (d, J= 9.2 Hz 1H), 5.81- 5.77 (m, 1H), 4.63 - 4.50 (m, 5H), 4.39 - 4.35 (m, 1H), 3.90 - 3.78 (m, 3H), 3.65 - 3.54 (m, 2H), 3.17 (s, 2H), 3.05 - 2.98 (m, 2H), 2.64 - 2.75 (m, 1H), 2.70 - 2.58 (m, 5H). 2.55 - 2.49 (m, 6H), 2.40 - 2.19 (m, 8H) 1.65 - 1.50 (m, 6H), 1.49 - 1.35 (m, 4H), 1.15 - 0.95 (m, 9H).

[1021] Example 70 (25,4A)-4-hydroxy-l-((5)-2-(2-(3-(4-((lr,45)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)azetidin-l-yl)acetamido)-3,3-dimethylbutanoyl)-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1022]

[1023] The compound was prepared according to the procedures described for Example 69. LCMS (ESI): m / z 896.5 (M+H)+. 'HNMR (400 MHz, MeOD) δ 8.88 (s, 1H), 8.51 (s, 1H), 8.38 (s, 1H), 7.65 (d, J= 9.2 Hz, 1H), 7.50 - 7.40 (m, 4H), 6.27 (d, J= 9.2 Hz, 1H), 5.80 (s, 1H), 4.67 - 4.62 (m, 1H), 4.59 - 4.42 (m, 4H), 4.41 - 4.32 (m, 1H), 3.93 - 3.60 (m, 6H), 3.41 - 3.35 (m, 2H), 3.29 - 3.17 (m, 5H), 3.93 - 2.03 (m, 1H), 2.70 - 2.52 (m, 4H), 2.50 - 2.47 (m, 3H), 2.29 -2.15 (m, 5H), 2.12 - 2.05 (m, 1H), 1.67 - 1.53 (m, 9H), 1.51 - 1.46 (m, 2H), 1.04 (s, 9H).

[1024] Example 71 (25',4 / ?)-4-hydroxy-l-((5)-2-(2-(4-(4-((lr,45)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3 - J]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)piperidin- 1 -yl)acetamido)-3,3-dimethylbutanoyl)-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carb oxami de

[1025]

[1026] The compound was prepared according to the procedures described for Example 69. LCMS (ESI): m / z 924.6 (M+H)+. 'HNMR (400 MHz, MeOD) δ 8.83 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 7.59 (d, J= 9.2, 1H), 7.43 - 7.36 (m, 4H), 6.22 (d, J= 9.2, 1H), 5.75 (s, 1H), 4.59 (s, 1H), 4.53 - 4.44 (m, 3H), 4.38 - 4.29 (m, 1H), 3.85 - 3.68 (m, 3H), 3.11 - 2.81 (m, 12H), 2.61 -2.53 (m, 1H), 2.43 (s, 3H), 2.28 - 2.08 (m, 8H), 1.96 - 1.88 (m, 2H), 1.70 - 1.46 (m, 13H), 0.99 (s, 9H).

[1027] Example 72 (25',47?)-4-hydroxy-l-((5)-2-(2-(4-((4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3 - J]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)acetamido)-3,3-dimethylbutanoyl)-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carb oxami de

[1028]

[1029] The compound was prepared according to the procedures described for Example 69. LCMS (ESI): m / z 938.6 (M+H)+. 'HNMR (400 MHz, MeOD) δ 8.91 (s, 1H), 8.54 (s, 1H), 8.44 (s, 1H), 7.68 (d, J= 9.2 Hz, 1H), 7.53 - 7.42 (m, 4H), 6.30 ( d, J= 9.2 Hz, 1H), 5.84 (s, 1H), 4.67 (s, 1H), 4.65 - 4.50 (m, 3H), 4.45 - 4.37 (m, 1H), 3.96 - 3.88 (m, 2H), 3.86 - 3.80 (m, 1H), 3.61 - 3.71 (m, 1H), 3.25 - 3.10 (m, 5H), 3.10 - 2.95 (m, 4H), 2.53 - 2.49 (m, 3H), 2.52 (s, 3H), 2.42 (d, = 7.2 Hz, 2H), 2.37 - 2.18 (m, 7H), 2.16 - 2.07 (m, 1H), 1.94 - 1.77 (m, 2H), 1.72 - 1.58 (m, 9H), 1.56 - 1.46 (m, 2H), 1.44 - 1.30 (m, 2H), 1.11 - 1.03 (m, 9H).

[1030] Example 73 (25,4 / ?)-l-((S)-2-(2-(3-(4-((lr,4S)-4-((4-(2-(l-benzylcy cl opropoxy)pyri din-3 -yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)azetidin- 1 -yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1031]

[1032] The compound was prepared according to the procedures described for Example 69. LCMS (ESI): m / z 505.9 (M / 2+H)+. 'HNMR (400 MHz, MeOD) δ 8.87 (s, 1H), 8.35 - 8.25 (m, 2H), 7.98 (d, J= 5.2 Hz, 1H), 7.50 - 7.40 (m, 4H), 7.25 - 7.08 (m, 6H), 6.61 (d, J= 5.2 Hz, 1H), 4.65 - 4.45 (m, 4H), 4.41 - 4.31 (m, 1H), 3.89 - 3.82 (m, 1 H), 3.81 - 3.71 (m, 2H), 3.64 - 3.57 (m, 2H), 3.22 (d, J= 4.8 Hz, 2H), 3.15 - 3.08 (m, 3H), 2.73 - 2.60 (m, 4H), 2.47 (s, 3H), 2.45 -2.30 (m, 4H), 2.26 - 2.18 (m, 1H), 2.15 - 1.95 (m, 6H), 1.49 - 1.25 (m, 5H), 1.06 - 0.93 (m, 14H).

[1033] Example 74 (25,4 / ?)-l-((S)-2-(2-(3-((4-((lr,4S)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)azetidin-l-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1034]

[1035] The compound was prepared according to the procedures described for Example 69. LCMS (ESI): m / z 512.9 (M / 2+H)+. 'HNMR (400 MHz, DMSO-d6) δ 10.20 - 10.05 (m, 1H), 8.99 (s, 1H), 8.70 - 8.62 (m, 1H), 8.60 - 8.51 (m, 1H), 8.40 - 8.35 (m, 1H), 8.27 - 8.16 (m, 1H), 8.12 - 8.06 (m, 1H), 7.45 - 7.33 (m, 4H), 7.25 - 7.08 (m, 6H), 6.62 (s, 1H), 5.38 - 4.95 (m, 1H), 4.60 - 4.50 (m, 1H), 4.49 - 4.31 (m, 4H), 4.25 - 4.10 (m, 4H), 4.08 - 3.95 (m, 3H), 3.93 - 3.82 (m, 2H), 3.45 - 3.33 (m, 3H), 3.31 - 3.25 (m, 2H), 3.23 - 3.08 (m, 2H), 3.05 - 2.82 (m, 6H), 2.78 - 2.66 (m, 1H), 2.45 - 2.43 (m, 3H), 2.10 - 1.97 (m, 4H), 1.95 - 1.82 (m, 2H), 1.60 - 1.45 (m, 2H), 1.39 - 1.26 (m, 2H), 1.05 - 0.92 (m, 9H), 0.90 - 0.83 (m, 4H).

[1036] Example 75 (25,4 / ?)-l-((S)-2-(2-(4-(4-((lr,4S)-4-((4-(2-(l-benzylcy cl opropoxy)pyri din-3 -yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)piperidin- 1 -yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1037]

[1038] The compound was prepared according to the procedures described for Example 69. LCMS (ESI): m / z 1038.7 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.65 - 8.58 (m, 1H), 8.43 - 8.38 (m, 1H), 8.36 - 8.20 (m, 2H), 8.10 (d, J= 5.2, 1H), 7.86 - 7.77 (m, 1H), 7.48 - 7.38 (m, 4H), 7.28 - 7.13 (m, 6H), 6.99 - 6.94 (m, 1H), 6.68 - 6.55 (m, 1H), 4.53 - 4.48 (m, 1H), 4.47 - 4.42 (m, 1H), 4.41 - 4.34 (m, 2H), 4.32 - 4.24 (m, 1H), 3.70 - 3.60 (m, 3H), 3.09 - 2.82 (m, 5H), 2.48 - 2.40 (m, 10H), 2.20 - 2.08 (m, 6H), 2.06 - 1.86 (m, 4H), 1.84 - 1.74 (m, 4H), 1.48 - 1.36 (m, 2H), 1.32 - 1.21 (m, 4H), 0.98 - 0.90 (m, 13H).

[1039] Example 76 (25,47?)-l-((5)-2-(2-(4-((4-((lr,4r)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)piperidin-l-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1040]

[1041] The compound was prepared according to the procedures described for Example 69. LCMS (ESI): m / z 526.9 (M / 2+H)+. 'HNMR (400 MHz, MeOD) δ 8.91 (s, 1H), 8.52 (s, 1H), 8.40 - 8.28 (m, 2H), 8.04 (d, J= 5.6 Hz, 1H), 7.54 - 7.42 (m, 4H), 7.30 - 7.11 (m, 6H), 6.67 (d, J = 5.2 Hz, 1H), 4.67 (s, 1H), 4.62 - 4.51 (m, 3H), 4.49 - 4.35 (m, 1H), 3.97 - 3.77 (m, 3H), 3.37 - 3.35 (m, 3H), 3.22 - 3.03 (m, 6H), 3.00 - 2.90 (m, 3 H), 2.85 - 2.63 (m, 3H), 2.51 (s, 3H), 2.45 -2.07 (m, 11H), 1.93 - 1.76 (m, 2H), 1.70 - 1.54 (m, 3H), 1.50 - 1.27 (m, 4H), 1.11 - 1.03 (m, 9H), 1.02 - 0.97 (m, 4H).

[1042] Example 77 (25,47?)-l-((5)-3,3-dimethyl-2-(2-(4-(4-((lr,45)-4-((7-oxo-8-(tetrahydro-2 -pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)piperidin-l-yl)acetamido)butanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1043]

[1044] step 8 step 9

[1045]

[1046] Step 1: (25',47?)-l-((5)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1047] To a stirred solution of tert-butyl ((5)-l-((25,47?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3, 3 -dimethyl- l-oxobutan-2-yl)carbamate (2 g, 3.77 mmol) in 1,4-di oxane (5 mL) was added HC1 (20 mL, 2M in 1,4-di oxane) at 20 °C. The resulting reaction mixture was stirred at 20 °C for 1 h. Then the reaction mixture was diluted with water (30 mL), basified to pH = 8 with NaHCCh solution, extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with brine solution (30 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (1 g, 62%) as a yellow solid. LCMS (ESI): m / z 431.1 (M+H)+.

[1048] Step 2: (2£,4A)-l-((5)-2-(2-bromoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide To a stirred solution of (2£,4R)-l-((5)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (500 mg, 0.87 mmol) in DCM (5 mL) was added Et3N (0.61 mL, 4.37 mmol) at 0 °C, then 2-bromoacetyl bromide (0.11 mL, 1.31 mmol) was added. The resulting reaction mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. Then the reaction mixture was purified by column chromatography on silica gel eluting with 0 - 2% MeOH in ethyl acetate to afford the title compound (500 mg, 80%) as a yellow solid. LCMS (ESI): m / z 552.9 (M+H)+.

[1049] Step 3: (2£,4. R)-4-hydroxy-l-((5 -2-(2-iodoacetamido)-3,3-dimethylbutanoyl)-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1050] To a stirred solution of (25,4A)-l-((5)-2-(2-bromoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (400 mg, 0.73 mmol) in acetone (4 mL) was added Nal (163 mg, 1.09 mmol) at 25 °C. The reaction mixture was stirred at 60 °C for 2 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (400 mg, 46%) as a yellow solid. The crude product would be directly used in the next step without purification. LCMS (ESI): m / z 599.0 (M+H)+.

[1051] Step 4: ethyl 2-(methylthio)-4-((tetrahydro-2J / -pyran-4-yl)amino)pyrimidine-5-carboxylate

[1052] To a stirred solution of ethyl 4-(iodo-2-methyl)-2-(methylthio)pyrimidine-5-carboxylate (20 g, 85.95 mmol) and Et₃N (35.94 mL, 257.85 mmol) in THF (270 mL) was added tetrahydro-2J / -pyran-4-amine (26.7 mL, 257.85 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 3 h. Then the reaction mixture was extracted with EtOAc (300 mL x 3) and washed by brine (400 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (25.4 g, 99 %) as a yellow oil. The crude product was be directly used in the next step without further purification. LCMS (ESI): m / z 297.9 (M+H)+.

[1053] Step 5: (2-(methylthio)-4-((tetrahydro-2J / -pyran-4-yl)amino)pyrimidin-5-yl)methanol To a stirred solution of ethyl 2-(methylthio)-4-((tetrahydro-27 / -pyran-4-yl)amino)pyrimidine-5-carboxylate (25.4 g, 99.48 mmol) in THF (190 mL) was added LiAlH4 (80 mL, 2.5 M in THF) dropwise at 0 °C. After that, the reaction mixture was stirred at 0 °C for 5 h under N2 atmosphere. Then the reaction was quenched with Na₂SO₄·10H₂O solid until solid formation was observed. The reaction mixture was filtered and the filter cake was dried under vacuum to give the title compound (19 g, 75%) as a white solid. The crude product would be directly used in the next step without purification. LCMS (ESI): m / z 256.0 (M+H)+.

[1054] Step 6: 2-(methylthio)-4-((tetrahydro-2J / -pyran-4-yl)amino)pyrimidine-5-carbaldehyde To a stirred solution of (2-(methylthio)-4-((tetrahydro-2J / -pyran-4-yl)amino)pyrimidin-5-yl)methanol (19 g, 74.41 mmol) in DCM (300 mL) was added MnCh (64.7 g, 744.11 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. Then the reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with 0-15% ethyl acetate in petroleum ether to afford the title compound (13.5 g, 72%) as a yellow solid. LCMS (ESI): m / z 254.0 (M+H)+.

[1055] Step 7: ethyl (£)-3-(2-(methylthio)-4-((tetrahydro-2J / -pyran-4-yl)amino)pyrimidin-5-yl)acrylate

[1056] To a solution of 2-(methylthio)-4-((tetrahydro-2J / -pyran-4-yl)amino)pyrimidine-5-carbaldehyde (13.5 g, 53.29 mmol) in THF (150 mL) was added ethyl 2-(triphenyl-15-phosphaneylidene)acetate (22.3 g, 63.95 mmol) at 25 °C. Then reaction mixture was stirred at 65 °C for 1 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated and purified by column chromatography on silica gel eluting with 0 - 35% ethyl acetate in petroleum ether to afford the title compound (13.1 g, 76%) as a yellow solid. LCMS (ESI): m / z 324.0 (M+H)+.

[1057] Step 8: 2-(methylthio)-8-(tetrahydro-2J / -pyran-4-yl)pyrido[2,3- ]pyrimidin-7(8J7)-one To a solution of ethyl (£)-3-(2-(methylthio)-4-((tetrahydro-2J / -pyran-4-yl)amino) pyrimidin-5-yl)acrylate (13.1 g, 40.51 mmol) in DBU (18.2 mL, 121.52 mmol) was added DIEA (21.2 mL, 121.52 mmol) dropwise, the resulting reaction mixture was heated at 130 °C for 16 h and then cooled to room temperature. After that, the reaction mixture was extracted with EtOAc (100 mL x 3). The organic layer was combined, washed by brine (300 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with 0 - 70% ethyl acetate in petroleum ether to afford the title compound (6.9 g, 61%) as a yellow solid. LCMS (ESI): m / z 277.9 (M+H)+.

[1058] Step 9: 2-(methylsulfonyl)-8-(tetrahydro-27 / -pyran-4-yl)pyrido[2,3-t / ]pyrimidin-7(87 / )-one

[1059] To a solution of 2-(methylthio)-8-(tetrahydro-2J / -pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8J7)-one (2 g, 7.21 mmol) in DCM (20 mL) was added m-CPBA (3.66 g, 18.03 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0 - 40 % (75% EtOAc in EtOH) in petroleum ether to afford the title compound (1.42 g, 64%) as a yellow solid. LCMS (ESI): m / z 331.9 (M+Na)+. Step 10: tert-butyl 4-((lr,4r)-4-((7-oxo-8-(tetrahydro-2J / -pyran-4-yl)-7,8-di hydropyri do[2, 3 -t / ]pyri mi di n-2-yl)amino)cyclohexyl)piperazine- l -carboxyl ate

[1060] To a mixture of tert-butyl 4-((lr,4r)-4-aminocyclohexyl)piperazine-l-carboxylate (504 mg, 1.78 mmol), DIEA(0.84 mL, 4.85 mmol) and 2-(methyl sulfonyl )-8-(tetrahydro-27 / -pyran-4-yl)pyrido[2,3- ]pyrimidin-7(8J7)-one (500 mg, 1.62 mmol) in DMSO (5 mL) was stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature, extracted with EtOAc (15 mL x 3) and washed with brine (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with 0-60% (75% EtOAC in EtOH) in petroleum ether to afford the title compound (420 mg, 51%) as a yellow solid. LCMS (ESI): m / z 513.2 (M+H)+.

[1061] Step 11: 2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl)amino)-8-(tetrahydro-2J / -pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8J7)-one

[1062] To a solution of tert-butyl 4-((lr,4r)-4-((7-oxo-8-(tetrahydro-2J / -pyran-4-yl)-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazine-l -carboxylate (420 mg, 0.82 mmol) in 1,4-di oxane (5 mL) was added HC1 (10 mL, 2 M in 1,4-di oxane) and the resulting reaction mixture was stirred at 25 °C for 2 h. After that, the reaction mixture was concentrated to dryness and afford the crude title compound (330 mg, 98%) as a white solid. The crude product was directly used in the next step without further purification. LCMS (ESI): m / z 413.1 (M+H)+.

[1063] Step 12: tert-butyl 4-(4-((lr,4r)-4-((7-oxo-8-(tetrahydro-2J / -pyran-4-yl)-7,8-dihydropyrido[2,3 - J]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)piperidine- 1 -carboxylate To a solution of 2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl)amino)-8-(tetrahydro-2JT-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8J7)-one (280 mg, 0.68 mmol) in DMSO (3 mL) was added Et3N (0.09 mL, 0.68 mmol) at 25 °C. The resulting reaction mixture was stirred at 25 °C for 10 min and then tert-butyl 4-oxopiperidine-l -carboxylate (270 mg, 1.36 mmol) in DCM (3 mL) was added. After stirring at 25 °C for 0.5 h, NaBH(OAc)3 (431 mg, 2.04 mmol) and HO Ac (0.05 mL, 0.81 mmol) were added. After that, the mixture reaction was stirred at 25 °C for 16 h. Then the reaction mixture was diluted with water (10 mL), washed with EtOAc (15 mL x 3). The turbid aqueous solution was filtered, and the filter cake was dried under vacuum to afford the title compound (420 mg, crude) as a white solid. LCMS (ESI): m / z 596.3 (M+H)+.

[1064] Step 13: 2-(((lr,4r)-4-(4-(piperidin-4-yl)piperazin-l-yl)cyclohexyl)amino)-8-(tetrahydro-2J / -pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8J7)-one

[1065] To a solution of tert-butyl 4-(4-((lr,4r)-4-((7-oxo-8-(tetrahydro-2J / -pyran-4-yl)-7,8-dihydropyrido[2,3 - J]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)piperidine- 1 -carboxylate (420 mg, 0.7 mmol) in 1,4-dioxane (3 mL) was added HC1 (10 mL, 2 M in 1,4-dioxane) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. Then the reaction mixture was concentrated to afford the title compound (340 mg, 76%) as a white solid. LCMS (ESI): m / z 496.2 (M+H)+.

[1066] Step 14: (26', 4 / ?)- 1 -((5)-3, 3 -dimethyl-2-(2-(4-(4-(( 1 r,45)-4-((7 -oxo-8-(tetrahydro-27 / -pyran-4-yl)-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)piperidin-l-yl)acetamido)butanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1067] To a mixture of (25,47?)-4-hydroxy-l-((5)-2-(2-iodoacetamido)-3,3-dimethylbutanoyl)-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (300 mg, 0.5 mmol) and 2-(((lr,4r)-4-(4-(piperidin-4-yl)piperazin-l-yl)cyclohexyl)amino)-8-(tetrahydro-2J / -pyran-4-yl)pyrido[2,3-t / ]pyrimidin-7(8J7)-one (150 mg, 0.25 mmol) in DMF (3 mL) were added DIEA (0.26 mL, 1.51 mmol) and K2CO3 (104 mg, 0.75 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h under N2 atmosphere. Then the reaction mixture was purified by pre-HPLC (acetonitrile 7-37 / 0.225% FA in water) to afford the title compound (13 mg, 5.4%) as a white solid. LCMS (ESI): m / z 966.5 (M+H)+. 'HNMR (400 MHz, DMSO-d6) d 8.92 (s, 1H), 8.52 (s, 1H), 8.35 -8.28 (m, 1H), 7.70 (d, J= 10.0 Hz, 1H), 7.63 (d, J= 9.2 Hz, 1H), 7.45 - 7.37 (m, 4H), 6.18 (d, J = 9.2 Hz, 1H), 5.58 - 5.47 (m, 1H), 5.34 (t, J= 5.2 Hz, 1H), 4.52 - 4.47 (m, 2H), 4.42 - 4.36 (m, 2H), 4.31 - 4.25 (m, 1H), 4.00 (dd, J= 3.6, 10.8 Hz, 2H), 3.71 - 3.68 (m, 1H), 3.65 - 3.57 (m, 1H), 3.43 - 3.37 (m, 2H), 2.99 - 2.91 (m, 4H), 2.90 - 2.80 (m, 2H), 2.47 (s, 4H), 2.45 (s, 3H), 2.19 - 2.11 (m, 4H), 2.06 - 1.99 (m, 6H), 1.90 - 1.84 (m, 2H), 1.83 - 1.71 (m, 3H), 1.53 - 1.42 (m, 6H), 1.39 - 1.31 (m, 4H), 0.96 (s, 9H).

[1068] Example 78 (25,4A)-4-hydroxy-l-((5)-2-(2-(4-(4-((lr,45)-4-((8-isopropyl-7-oxo-7,8-dihydropteridin-2-yl)amino)cyclohexyl)piperazin-l-yl)piperidin-l-yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1069] H

[1070]

[1071] The compound was prepared according to the procedures described for Example 77 and obtained as a formate. LCMS (ESI): m / z 463.6 (M / 2+H)+. 'HNMR (400 MHz, DMSO-tL) d 8.93 (s, 1H), 8.61 (s, 1H), 8.32 (t, J= 6.0 Hz, 1H), 8.18 (s, 1H), 7.75 - 7.67 (m, 2H), 7.63 (s, 1H), 7.45 - 7.37 (m, 4H), 5.56 - 5.44 (m, 1H), 4.53 - 4.45 (m, 2H), 4.44 - 4.35 (m, 2H), 4.32 - 4.24 (m, 1H), 3.70 (dd, J= 4.4, 4.0 Hz, 2H), 3.64 - 3.58 (m, 1H), 2.94 (d, J= 7.2 Hz, 2H), 2.91 -2.82 (m, 4H), 2.48 - 2.47 (m, 3H), 2.46 (s, 3H), 2.23 - 1.93 (m, 10H), 1.90 - 1.71 (m, 4H), 1.54 (d, J= 6.8 Hz, 6H), 1.48 - 1.26 (m, 8H), 0.96 (s, 9H).

[1072] Example 79 (25',47?)-l-((5)-3,3-dimethyl-2-(2-(4-(4-((U?,45)-4-((7-oxo-8-((7?)-tetrahydrofuran-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)piperidin-l-yl)acetamido)butanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1073] H

[1074]

[1075] The compound was prepared according to the procedures described for Example 77. LCMS (ESI): m / z 952.7 (M+H)+. 'HNMR (400 MHz, DMSO ) d 8.92 (s, 1H), 8.54 (s, 1H), 8.33 (t, J= 6.0 Hz, 1H), 7.71 (d, J= 9.2 Hz, 1H), 7.65 (d, J= 9.2 Hz, 1H), 7.44 - 7.38 (m, 4H), 6.20 (d, J= 9.2 Hz, 1H), 6.11 - 6.03 (m, 1H), 4.94 (s, 1H), 4.53 - 4.45 (m, 2H), 4.44 - 4.35 (m, 2H), 4.31 - 4.24 (m, 1H), 4.22 - 4.14 (m, 1H), 4.07 (s, 1H), 3.92 - 3.76 (m, 3H), 3.73 - 3.66 (m, 1H), 3.64 - 3.58 (m, 1H), 2.97 - 2.79 (m, 5H), 2.50 - 2.40 (m, 10H), 2.21 - 1.71 (m, 14H), 1.50 -1.25 (m, 7H), 0.96 (s, 9H).

[1076] Example 80 (2£,47?)-l-((5)-3,3-dimethyl-2-(2-(4-(4-((l£,45)-4-((7-oxo-8-((5')-tetrahydrofuran-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)piperidin-l-yl)acetamido)butanoyl)-4-hydroxy-7V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1077] H

[1078]

[1079] The compound was prepared according to the procedures described for Example 77. LCMS (ESI): m / z 952.7 (M+H)+. 'HNMR (400 MHz, DMSO-t / ) 88.92 (s, 1H), 8.54 (s, 1H), 8.33 (t, J= 6.0 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.65 (d, J= 9.2 Hz, 1H), 7.44 - 7.36 (m, 4H), 6.20 (d, J= 9.2 Hz, 1H), 6.13 - 6.01 (m, 1H), 4.53 - 4.45 (m, 2H), 4.44 - 4.35 (m, 2H), 4.31 -4.25 (m, 1H), 4.21 - 4.14 (m, 1H), 4.07 (s, 1H), 3.91 - 3.78 (m, 3H), 3.73 - 3.66 (m, 1H), 3.64 -3.59 (m, 1H), 3.55 - 3.41 (m, 1H), 2.94 (d, J= 6.4 Hz, 2H), 2.91 - 2.79 (m, 3H), 2.50 - 2.40 (m, 10H), 2.22 - 1.70 (m, 14H), 1.49 - 1.24 (m, 7H), 0.96 (s, 9H).

[1080] Example 81 (25,4A)-l-((5)-3,3-dimethyl-2-(2-(4-(4-((lr,45)-4-((8-(oxetan-3-yl)-7-oxo-7, 8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)piperidin-l-yl)acetamido)butanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carb oxami de

[1081] step 2 step 3

[1082] H

[1083] H

[1084]

[1085] Step 1: 2-(methylthio)-8-(oxetan-3-yl)pyrido[2,3-t / ]pyrimidin-7(87 / )-one

[1086] To a stirred solution of 2-methylsulfanyl-8J / -pyrido[2,3-J]pyrimidin-7-one (5.0 g, 25.9 mmol) in DMF (80 mL) was added NaH (931.5 mg, 38.8mmol, 60% purity in mineral oil) at 0 °C. After stirring at 0 °C for 0.5 h under N2 atmosphere, 3-iodooxetane (7.14 g, 38.81mmol) was added into the reaction mixture. The resulting reaction mixture was stirred at 100 °C for 16 h. After cooling to room temperature, the reaction was quenched by addition of water (200 mL) dropwise and extracted with EtOAc (50 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with 0 -50% ethyl acetate in petroleum ether to afford the title compound (1.0 g, 16%) as a white solid.XH NMR (400 MHz, DMSO-t / 6) d 8.85 (s, 1H), 7.91 (d, J= 9.2 Hz, 1H), 6.57 (d, J= 9.2 Hz, 1H), 5.37 (m, 1H), 4.94 - 4.74 (m, 4H), 2.53 (s, 3H).

[1087] Step 2: 2-(methylsulfonyl)-8-(oxetan-3-yl)pyrido[2,3-t / ]pyrimidin-7(8 / 7)-one

[1088] To a stirred solution of 2-methylsulfanyl-8-(oxetan-3-yl)pyrido[2,3-J]pyrimidin-7-one(1.2 g, 4.8 mmol) in DCM (10 mL) was added m-CPBA (2.65 g, 15.4mmol) in portions at 0°C. After stirring at 0 °C for 3 h, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0 - 50% ethyl acetate in petroleum ether to afford the title compound (1.2 g, 89%) as white solid.1!! NMR (400 MHz, DMSO-tfc) 39.30 (s, 1H), 8.12 (d, J= 9.6 Hz, 1H), 6.89 (d, J= 9.6 Hz, 1H), 5.50 - 5.39 (m, 1H), 4.94 - 4.82 (m, 4H), 3.43 (s, 3H).

[1089] The subsequent procedure for synthesizing Example 81 is similar to that of Example 77. LCMS (ESI): m / z 938.7 (M+H)+. 'HNMR (400 MHz, CDCl3) 38.71 (s, 1H), 8.62 (s, 1H), 8.60 - 7.40 (m, 1H), 7.80 - 7.75 (m, 1H), 7.64 (d, J= 9.2 Hz, 1H), 7.43 - 7.36 (m, 4H), 6.46 (d, J = 9.2 Hz, 1H), 5.95 - 5.85 (m, 1H), 5.15 - 5.05 (m, 1H), 4.78 (t, J= 8.0 Hz, 1H), 4.63 - 4.51 (m, 3H), 4.43 - 4.35 (m, 2H), 4.25 - 4.17 (m, 2H), 4.15 - 4.05 (m, 1H), 3.97- 3.90 (m, 1H), 3.63 -3.55 (m, 1H), 3.00 (s, 2H), 2.97 (s, 2H), 2.89 - 2.76 (m, 8H), 2.65 - 2.56 (m, 2H), 2.55 (s, 3H), 2.38 - 2.31 (m, 2H), 2.24 - 2.16 (m, 2H), 2.08 - 1.98 (m, 7H), 1.65 - 1.40 (m, 7H), 0.96 (s, 9H).

[1090] Example 82 (25,4A)-l-((5)-2-(2-(4-(4-((lr,45)-4-((6-cyclopropyl-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)piperidin-l-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1091]

[1092]

[1093] Step 1: ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate

[1094] To a stirred solution of ethyl 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylate (100.0 g, 429.76 mmol) in anhydrous THF (3.0 L) were added Et3N (179.7 mL, 1.29 mol) and z-PrNEh (109.81 mL, 1.29 mol) under nitrogen atmosphere at 25 °C. After stirring at 25 °C for 3 h, the reaction mixture was poured into ice-water (1.5 L) and extracted with EtOAc (1.0 L - 3). The combined organic layer was washed with brine (2.0 L), dried with Na2SC>4, concentrated to give crude product, which was purified by column chromatography on silica gel eluting with 0 - 3% EtOAc in petroleum ether to afford the title compound (105 g, 96%) as a white oil.XH NMR (400 MHz, DMSO-tL) d 8.54 (s, 1H), 8.08 (d, J= 7.6 Hz, 1H), 4.36 - 4.29 (m, 1H), 4.28 - 4.24 (m, 2H), 2.47 (s, 3H), 1.29 (t, J= 6.8 Hz, 3H), 1.23 (d, J= 6.8 Hz, 6H).

[1095] Step 2: (4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)methanol

[1096] To a stirred solution of ethyl 4-(isopropylamino)-2-methylsulfanyl-pyrimidine-5-carboxylate (205.0 g, 802.85 mmol) in THF (1.4 L) was added LiAlH4(0.8 L, 2.5M in THF) dropwise at 0 °C under N2 atmosphere. Then the reaction mixture was stirred at 25 °C for 3 h. After that, the reaction was quenched by addition of Na2SO4 IOH2O in portions till no gas produced. Then the reaction mixture was filtered and the filtrate was concentrated to give the crude title compound (152 g, 89%) as a yellow solid. The crude product was directly used in the next step without further purification.

[1097] Step 3: 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carbaldehyde

[1098] To a stirred solution of [4-(isopropylamino)-2-methylsulfanyl-pyrimidin-5-yl]methanol (76.0 g, 356.31 mol) in DCM (1.5 L) was added MnC>2 (247.82 g, 2.85 mol) in portions at 20 °C. Then the reaction mixture was stirred at 40 °C for 48 h. After cooling to room temperature, the reaction mixture was filtered to remove undissolved solid and the filtrate was concentrated to give the crude title compound (75 g, 99%) as a brown oil. The crude product would be directly used in the next step without further purification. Step 4: ethyl (£ -3-(4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)acrylate

[1099] To a stirred solution of 4-(isopropylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde (93.0 g, 440.17 mmol) in THF (1.2 L) was added Ph3P=CCO2Et (184.01 g, 528.21 mmol) at 20 °C. Then the reaction mixture was stirred at 65 °C for 1 h under N2atmosphere. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by column chromatography on silica gel eluting with 0 - 35% EtOH in petroleum ether to afford the title compound (111 g, 90%) as a yellow solid.XH NMR (400 MHz, DMSO-tL) <58.36 (s, 1H), 7.77 (d, J= 15.6 Hz, 1H), 7.49 (d, J= 7.6 Hz, 1H), 6.49 (d, J= 15.6 Hz, 1H), 4.41 - 4.29 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 2.44 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H), 1.19 (d, J = 6.8 Hz, 6H).

[1100] Step 5: 8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[1101] A mixture of ethyl (E)-3-[4-(isopropylamino)-2-methylsulfanyl-pyrimidin-5-yl]prop-2-enoate (110.0 g, 390.94 mmol), DIEA (204.28 mL, 1.17 mol) and DBU (175.39 mL, 1.17 mol) was stirred at 130 °C for 12 h under N2atmosphere. After cooling to room temperature, the reaction mixture was poured into ice-water (200 mL) and extracted with EtOAc (150 mL x 3). The combined organic layer was washed with brine (300 mL), dried with Na2SC>4, concentrated to give crude product, which was purified by column chromatography on silica gel eluting with 0 - 70% EtOAc in petroleum ether to afford the title compound (53 g, 58%) as a yellow solid.

[1102] Step 6: 6-bromo-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8J7)-one

[1103] To a stirred solution of 8-isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 4.25 mmol) in DMF (15 mL) was added l-bromo-2,5-pyrrolidinedione (832.0 mg, 4.67 mmol) at 25 °C, then the mixture was stirred at 25 °C for 16 h. After that, the reaction mixture was poured into ice-water (15 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (30 mL x 3), dried with Na2SO4, concentrated to give crude product, which was purified by column chromatography on silica gel eluting with 0-20% EtOAc in petroleum ether to afford the title compound (750 mg, 56 %) as an off-yellow solid.1H NMR (400 MHz, DMSO-tL) 38.84 (s, 1H), 8.48 (s, 1H), 5.80 - 5.70 (m, 1H), 2.60 (s, 3H), 1.54 (d, J = 6.8 Hz, 6H).

[1104] Step 7: 6-cyclopropyl-8-isopropyl-2-(methylthio)pyrido[2,3-J]pyrimidin-7(8J7)-one A mixture of 6-bromo-8-isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (2.0 g, 6.4 mmol), K2CO3(2.6 g, 19.1 mmol), Pd(PPh3)2Cl2(446.8 mg, 0.64 mmol) and cyclopropylboronicacid (656.14 mg, 7.64 mmol) in 1,4-dioxane (18 mL) and water (6 mL) was stirred at 100 °C for 16 h under N2atmosphere. After cooling to room temperature, the reaction mixture was poured into ice-water (25 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (50 mL), dried with Na2SO4, concentrated to give crude product, which was purified by column chromatography on silica gel eluting with 0 - 20% EtOAc in petroleum ether to afford the title compound (0.8 g, 46%) as an off-yellow solid. 'HNMR (400 MHz, DMSO-tL) 38.74 (s, 1H), 7.43 (s, 1H), 5.80 - 5.68 (m, 1H), 2.58 (s, 3H), 2.14 - 2.07 (m, 1H), 1.56 (d, J= 6.8 Hz, 6H), 0.98 - 0.89 (m, 2H), 0.76 - 0.67 (m, 2H).

[1105] Step 8: 6-cyclopropyl-8-isopropyl-2-(methylsulfonyl)pyrido[2,3-J]pyrimidin-7(8J7)-one To a stirred solution of 6-cyclopropyl-8-isopropyl-2-methylsulfanyl-pyrido[2,3- t / ]pyrimidin-7-one (800 mg, 2.91 mmol) in DCM (15 mL) was added m-CPBA (1.5 g, 8.71 mmol) in portions at 0 °C. Then the reaction mixture was stirred at 0 °C for 1.5 h. After that, the reaction mixture was poured into ice-water (15 mL) and extracted with DCM (15 mL x 3). The combined organic layer was washed with brine (30 mL), dried with Na2SO4, concentrated to give crude product, which was purified by column chromatography on silica gel eluting with 0 - 15% EtOAc in petroleum ether to afford the title compound (700 mg, 78%) as a white solid. 'H NMR (400 MHz, DMSO-tL) δ 9.11 (s, 1H), 7.61 (s, 1H), 5.77 - 5.66 (m, 1H), 3.44 (s, 3H), 2.23 - 2.16 (m, 1H), 1.58 (d, J= 7.2 Hz, 6H), 1.07 - 1.02 (m, 2H), 0.84 - 0.79 (m, 2H).

[1106] The subsequent procedure for synthesizing Example 82 is similar to that of Example 77. LCMS (ESI): m / z 964.8 (M+H)+. 'HNMR (400 MHz, DMSO-tL) 38.93 (s, 1H), 8.43 (s, 1H), 8.37 - 8.27 (m, 1H), 7.71 (d, J= 9.6 Hz, 1H), 7.47 - 7.35 (m, 4H), 7.22 - 7.12 (m, 2H), 5.76 - 5.65 (m, 1H), 5.14 - 4.72 (m, 1H), 4.54 - 4.46 (m, 2H), 4.45 - 4.35 (m, 2H), 4.32 - 4.24 (m, 1H), 3.76 - 3.67 (m, 2H), 3.64 - 3.58 (m, 1H), 2.94 (d, J= 7.2 Hz, 2H), 2.91 - 2.81 (m, 3H), 2.50 - 2.45 (m, 6H), 2.46 (s, 3H), 2.22 - 2.09 (m, 4H), 2.07 - 1.93 (m, 5H), 1.92 - 1.75 (m, 4H), 1.55 (d, J= 6.8 Hz, 6H), 1.50 - 1.21 (m, 7H), 0.96 (s, 9H), 0.90 - 0.80 (m, 2H), 0.65 - 0.55 (m, 2H).

[1107] Example 83 (2£,4A)-4-hydroxy-l-((5)-2-(2-(4-(4-((lr,45)-4-((8-isopropyl-6-methoxy- 7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)piperidin-l- yl)acetamido)-3,3-dimethylbutanoyl)-A-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carb oxami de

[1108]

[1109] Step 7

[1110] H

[1111]

[1112] Step 1: ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate

[1113] To a stirred solution of ethyl 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylate (12.5 g, 53.7 mmol) in anhydrous THF (400 mL) was added Et3N (22.5 mL, 161.2mmol) and z-PrNEh (13.7 mL, 161.2 mmol) at 25 °C under N2 atmosphere. Then the resulting mixture was stirred at 25 °C for 3 h. After that, the reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (100 mL x 3). The filtrate was concentrated and purified by column chromatography on silica gel eluting with 0-25% EtOAc in petroleum ether to afford the title compound (12.5 g, 91%) as a white solid.XH NMR (400 MHz, CDCh-t / ,) d 8.60 (s, 1H), 8.11 (s, 1H), 4.47 - 4.37 (m, 1H), 4.35 - 4.28 (m, 2H), 2.52 (s, 3H), 1.36 (t, J= 7.2 Hz, 3H), 1.26 (d, J= 6.8 Hz, 6H).

[1114] Step 2: (4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)methanol

[1115] To a stirred solution of ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 19.6 mmol) in THF (90 mL) was added 2.5 M LiAlHHn THF (15.7 mL, 39.25 mmol) dropwise at 0 °C under N2 atmosphere and stirred at 0 °C for another 4 h. After that, the reaction was quenched by addition of Na2SO4' IOH2O in portions till no gas produced at 0°C. Then the reaction mixture was filtered and the filtrate was concentrated to give the crude title compound (4.1 g, 69%) as a white solid. The crude product was directly used in the next step without further purification.

[1116] Step 3: 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carbaldehyde

[1117] To a stirred solution of (4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)methanol (15.2 g, 49.9 mmol) in DCM (500 mL) was added MnC>2 (30.36 g, 349.2 mmol) in portions at 0 °C, and then the reaction mixture was stirred at 25 °C for 16 h. After that, the reaction mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc (200 mL x 3) and the filtrate was concentrated to give crude product, which was purified by column chorography on silica gel eluting with 0 - 25% ethyl acetate in petroleum ether to afford the title compound (10.4 g, 99%) as yellow solid. 'H NMR (400 MHz, CDCh-tZ) d 9.66 (s, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 4.52 - 4.30 (m, 1H), 2.53 (s, 3H), 1.28 (d, J= 6.8 Hz, 6H).

[1118] Step 4: 8-isopropyl-6-methoxy-2-(methylthio)pyrido[2,3-J]pyrimidin-7(8J7)-one

[1119] To a stirred solution of ethyl methoxyacetate (2.2 mL, 18.5 mmol) in THF (30 mL) was added 1.0 M LiHMDS in THF (17.5 mL, 17.5 mmol) dropwise at -78 °C under N2 atmosphere. After stirring at -78 °C for 30 min, 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (2.6 g, 12.3 mmol) in THF (5.0 mL) was added dropwise. The resulting reaction mixture was stirred at 25 °C for 16 h. After that, the reaction was quenched with ice-water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (100 mL x 2), dried with Na2SC>4 and concentrated to give crude product, which was purified by column chorography on silica gel eluting with 0 ~ 50% ethyl acetate in petroleum ether to afford the title compound (1.6 g, 49%) as a white solid.

[1120] The subsequent procedures for synthesizing Example 83 is similar to that of Example 82. LCMS (ESI): m / z 976.6 (M+Na)+. 'H NMR (400 MHz, DMSO-tL) d 8.97 (s, 1H), 8.64 - 8.57 (m, 1H), 8.52 - 8.45 (m, 1H), 7.81 (d, J= 9.2 Hz, 1H), 7.50 - 7.30 (m, 4H), 7.31 - 7.21 (m, 1H), 7.04 (s, 1H), 5.80 - 5.65 (m, 1H), 5.14 - 5.10 (m, 1H), 4.51 - 4.31 (m, 4H), 4.30 - 4.20 (m, 1H), 3.73 (s, 3H), 3.68 - 3.57 (m, 3H), 3.05 - 2.87 (m, 4H), 2.85 - 2.70 (m, 2H), 2.48 - 2.32 (m, 9H), 2.25 - 2.05 (m, 5H), 2.02 - 1.98 (m, 3H), 1.90 - 1.70 (m, 4H), 1.60 - 1.35 (m, 8H), 1.35 - 1.19 (m, 4H), 0.94 (s, 9H).

[1121] Example 84 (25,4A)-4-hydroxy-l-((5)-2-(4-((4-(4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3 - J]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)piperidin- 1 -yl)methyl)-1H- 1,2,3-triazol- 1 -y l)-3 -methylbutanoyl )-N-(fS')- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide HCI

[1122] step 1 step 2

[1123] HH

[1124]

[1125] Step 1: 8-isopropyl-2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl)amino)pyrido[2,3-t / ]pyrimidin-7(8 / 7)-one hydrochloride

[1126] A mixture of tert-butyl 4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-t / ]pyrimidin-2-yl)amino)cyclohexyl)piperazine-l -carboxylate (1.0 g, 2.12 mmol) in HC1 in dioxane (10 mL, 4 M) was stirred at 25 °C for 4 h. After that, the reaction mixture was concentrated under vacuum to afford the crude title compound (860 mg, 99.5%) as a yellow solid. LCMS (ESI): m / z 371.2 (M+H)+.

[1127] Step 2: tert-butyl 4-(4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)piperidine- 1 -carboxylate

[1128] To a solution of 8-isopropyl-2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl)amino)pyrido[2,3-t / ]pyrimidin-7(8J7)-one hydrochloride (760.0 mg, 1.87 mmol) in DCM (20 mL) was added Et3N until pH = 7.0, Then the reaction mixture was adjusted to pH = 5~6 with AcOH. Then tert-butyl 4-oxopiperidine-l -carboxylate (744 mg, 3.74 mmol) was added to the reaction mixture. After stirring at 25 °C for 1 h, NaBH(OAc)s (1.19 g, 5.6 mmol) was added. The resulting reaction mixture was stirred at 25 °C for another 16 h under N2 atmosphere. After that, the reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with 0 -10% methanol in DCM to afford the title compound (1 g, 97%) as a yellow solid. LCMS (ESI): m / z 554.3 (M+H)+. Step 3: 8-isopropyl-2-(((lr,4r)-4-(4-(piperidin-4-yl)piperazin-l-yl)cyclohexyl)amino)pyrido[2,3-t / ]pyrimidin-7(8 / 7)-one

[1129] To a solution of tert-butyl 4-(4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)piperidine-l -carboxylate (1.0 g, 1.81 mmol) in DCM (3 mL) was added HC1 (1.0 mL, 4.0 M in dioxane) at 25 °C. Then the mixture was stirred at 25 °C for 2 h. After that, the organic layer was concentrated under vacuum to afford the crude title compound (1 g, 98%) as a yellow solid. LCMS (ESI): m / z 454.2 (M+H)+.

[1130] Step 4: 8-isopropyl-2-((( lr,4r)-4-(4-( 1 -(prop-2 -yn- 1 -yl)piperidin-4-yl)piperazin- 1 -yl)cyclohexyl)amino)pyrido[2,3-J]pyrimidin-7(8J7)-one

[1131] To a solution of 8-isopropyl-2-(((lr,4r)-4-(4-(piperidin-4-yl)piperazin-l-yl)cyclohexyl)amino)pyrido[2,3- ]pyrimidin-7(8J7)-one (200.0 mg, 0.35 mmol) in DMF (2 mL) were added K2CO3 (146.09 mg, 1.05 mmol) and propargyl bromide (0.03 mL, 0.28 mmol) at 25 °C. Then the reaction mixture was stirred at 25 °C for 1 h. After that, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried over sodium sulfate, filtered and concentrated to afford the crude title compound (150 mg, 87%) as a yellow solid. LCMS (ESI): m / z 492.4 (M+H)+.

[1132] Step 5: (25',4A)-4-hydroxy-l-((5 -2-(4-((4-(4-((lr,4r)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3 - J]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)piperidin- 1 -yl)methyl)-1 H- 1,2,3-triazol- 1 -y l)-3 -methylbutanoyl )-M(fS')- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1133] To a solution of (2S, 4A)-l-((5)-2-azi do-3 -methyl butanoyl )-4-hydroxy-A-((5)-l -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (111 mg, 0.24 mmol) in water (1 mL), / -BuOH (1 mL) and DMF (1 mL) were added (8-isopropyl-2-(((lr,4r)-4-(4-(l-(prop-2-yn-l-yl)piperidin-4-yl)piperazin-l-yl)cyclohexyl)amino)pyrido[2,3-J]pyrimidin-7(8J7)-one (100.0 mg, 0.2 mmol), Q1SO4 5H2O (25.4 mg, 0.1 mmol) and sodium ascorbate (20.2 mg, 0.1 mmol) at 25 °C. After stirring at 40 °C for 16 h, the reaction mixture was cooled to room temperature and filtered. The filtrate was purified by reverse phase chromatography (acetonitrile 40-70 / 0.1 % (NH3 H2O + NH4HCO3) in water) to afford the title compound (16.0 mg, 8.3%) as a yellow solid. LCMS (ESI): m / z 948.3 (M+H)+. 'H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.52 -8.51 (m, 2H), 8.01 (s, 1H), 7.73 (d, J= 7.2 Hz, 1H), 7.63 (d, J= 9.2 Hz, 1H), 7.48 - 7.30 (m, 4H), 6.19 - 6.13 (m, 1H), 5.75 - 5.55 (m, 1H), 5.26 (d, J= 10.4 Hz, 1H), 5.18 (d, J= 3.6 Hz, 1H), 4.95 - 4.90 (m, 1H), 4.39 (t, J= 8.0 Hz, 1H), 4.31 (s, 1H), 3.76 - 3.63 (m, 4H), 3.52 (s, 2H), 2.90 - 2.80 (m, 2H), 2.55 - 2.45 (m, 7H), 2.25 - 2.15 (m, 1H), 2.05 - 1.68 (m, 14H), 1.53 - 1.46 (m, 6H), 1.39 - 1.27 (m, 10H), 1.04 (d, J= 6.4 Hz, 3H), 0.65 (d, J= 6.4 Hz, 3H). Example 85 (25,47?)-l-((S)-2-(4-((4-(4-((lr,4r)-4-((4-(2-(l-benzylcy cl opropoxy)pyri din-3 -yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)piperidin- 1 -yl)methyl)- 1H- 1,2,3 -tri azol- 1 -y l)-3 -methylbutanoyl)-4-hydroxy-7V-((5)- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1134]

[1135] /

[1136] The compound was prepared according to the procedures described for Example 84 and obtained as a formate. LCMS (ESI): m / z 531.8 (M / 2+H)+.1H NMR (400 MHz, DMSO-tfc) d 8.99 (s, 1H), 8.50 (d, J= 7.6 Hz, 1H), 8.37 (dd, J= 2.0, 4.8 Hz, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 8.09 (d, J= 5.2 Hz, 1H), 8.02 (s, 1H), 7.45 - 7.43 (m, 2H), 7.37 - 7.35 (m, 2H), 7.25 - 7.13 (m, 6H), 6.99 (d, J= 8.0 Hz, 1H), 6.59 (s, 1H), 5.26 (d, J= 10.0 Hz, 1H), 4.95 - 4.88 (m, 1H), 4.39 (t, J= 8.0 Hz, 1H), 4.31 (s, 1H), 3.77 - 3.73 (m, 2H), 3.65 (d, J= 10.4 Hz, 2H), 3.55 (s, 2H), 2.86 (d, J= 8.8 Hz, 2H), 2.64 - 2.53 (m, 6H), 2.47-2.44 (m, 4H), 2.35 - 2.05 (m, 4H), 1.97 - 1.95 (m, 5H), 1.82 - 1.71 (m, 6H), 1.39 - 1.21 (m, 10H), 1.04 (d, J= 6.4 Hz, 3H), 0.92 (s, 4H), 0.65 (d, J = 6.4 Hz, 3H).

[1137] Example 86 (25,47?)-l-((5)-2-(4-(((17?,35)-3-((4-((lr,47?)-4-((6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methyl)-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl)-4-hydroxy-7V-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carb oxami de step 1 step 2

[1138]

[1139] Step 1: (15,3r)-3-(prop-2-yn-l-yl)cyclobutane-l-carbaldehyde

[1140] To a mixture of ((ls,3r)-3-(prop-2-yn-l-yl)cyclobutyl)methanol (50.0 mg, 0.4 mmol) and SiC>2 (50.0 mg) in DCM (3 mL) was added PCC (0.17 g, 0.81 mmol) at 25 °C. Then the reaction mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. After that, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (49 mg, 99%) as a yellow oil. The crude product was directly used in the next step without further purification.

[1141] Step 2: 3,3,3-trifluoro-A-(2-fluoro-4-(8-isopropyl-7-oxo-2-(((lA,4r)-4-(4-(((ls,3A)-3-(prop-2-yn-l-yl)cyclobutyl)methyl)piperazin-l-yl)cyclohexyl)amino)-7,8-dihydropyrido[2,3-J]pyrimidin-6-yl)phenyl)propane- 1 -sulfonamide

[1142] To a stirred mixture of 3,3,3-trifluoro-N-(2-fluoro-4-(8-isopropyl-7-oxo-2-(((lr,4r)-4-(piperazin-l-yl)cyclohexyl)amino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)propane -1-sulfonamide (172.0 mg, 0.27 mmol) and 3-prop-2-ynylcyclobutanecarbaldehyde (49.0 mg, 0.4 mmol) in DCM (2 mL) and MeOH (2 mL) was added NaBJLCN (50.4 mg, 0.8 mmol) and AcOH (0.02 mL, 0.4 mmol) at 25 °C. Then the reaction mixture was stirred at 25 °C for 16 h under N2 atmosphere. After that, the reaction mixture was poured into ice-water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layer was washed with brine (20 mL), dried with Na2SC>4, and concentrated to afford the crude product, which was purified by column chromatography on silica gel eluting with 0 - 2% MeOH in DCM to afford the title compound (0.11 g, 37%) as a light green solid. LCMS (ESI): m / z 746.4 (M+H)+.

[1143] Step 3: (25,47?)- 1 -((S)-2-(4-((( 1R, 3S)-3 -((4-(( 1 r,47?)-4-((6-(3 -fluoro-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methyl)-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl)-4-hydroxy-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carb oxami de

[1144] To a solution of 3,3,3-trifluoro-A-(2-fluoro-4-(8-isopropyl-7-oxo-2-(((17?,4r)-4-(4-(((ls,37?)-3-(prop-2-yn-l-yl)cyclobutyl)methyl)piperazin-l-yl)cyclohexyl)amino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)propane-l-sulfonamide(40.0 mg, 0.05 mmol) in water (1 mL) and DMF (0.50 mL) were added sodium ascorbate (21 mg, 0.11 mmol), (25,47?)-l-[(25)-2-azido-3-methyl-butanoyl]-4-hydroxy-A-[(15)-l-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (46.52 mg, 0.1 mmol) and CuSCE SEEO (6.7 mg, 0.03 mmol) at 25 °C. Then the reaction mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was purified by pre-HPLC (acetonitrile 30 - 50 / 0.225% FA in water) to afford the title compound (21 mg, 31%) as a white solid. LCMS (ESI): m / z 1202.9 (M+H)+. 'HNMR (400 MHz, DMSO-tL) d 8.93 (s, 1H), 8.60 (s, 1H), 8.51 (d, J= 7.6 Hz, 1H), 7.95 (s, 1H), 7.91 - 7.82 (m, 1H), 7.63 - 7.60 (m, 1H), 7.55 - 7.35 (m, 8H), 5.80 - 5.70 (m, 1H), 5.21 (d, J= 10.4 Hz, 1H), 5.02 - 4.90 (m, 2H), 4.37 (t, J= 8.0 Hz, 1H), 4.31 (s, 1H), 3.85 - 3.70 (m, 2H), 3.62 - 3.52 (m, 1H), 3.42 - 3.35 (m, 2H), 2.84 - 2.73 (m, 3H), 2.67 - 2.65 (m, 2H), 2.63 - 2.55 (m, 3H), 2.50 - 2.44 (m, 9H), 2.42 - 2.25 (m, 3H), 2.20 -2.10 (m, 2H), 2.08 - 2.01 (m, 3H), 1.92 - 1.80 (m, 4H), 1.58 - 1.49 (m, 6H), 1.45 - 1.25 (m, 9H), 1.03 (d, J= 6.8 Hz, 3H), 0.63 (d, J= 6.4 Hz, 3H).

[1145] Example 87 (25,47?)-l-((5)-2-(4-(((17?,35)-3-((4-((lr,47?)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methyl)-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl)-4-hydroxy-A-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide

[1146]

[1147] The compound was prepared according to the procedures described for Example 86. LCMS (ESI): m / z 544.6 (M / 2+H)+. 'H NMR (400 MHz, DMSO-tL) d 8.96 (s, 1H), 8.57 (d, J= 7.2 Hz, 1H), 8.36 (dd, J = 2.0, 4.8 Hz, 1H), 8.30 - 8.19 (m, 1H), 8.08 (d, J= 4.8 Hz, 1H), 7.92 -7.85 (m, 1H), 7.30 - 7.10 (m, 10H), 6.97 (d, J= 7.6 Hz, 1H), 6.58 (s, 1H), 5.26 - 5.17 (m, 2H), 4.98 (t, J= 8.8 Hz, 1H), 4.49 (t, J= 8.0 Hz, 1H), 4.36 (s, 1H), 3.83 - 3.72 (m, 1H), 3.70 - 3.57 (m, 2H), 2.92 - 2.82 (m, 2H), 2.76 (d, J= 7.6 Hz, 1H), 2.65 (d, J= 7.6 Hz, 2H), 2.46 - 2.45 (m, 3H), 2.40 - 2.05 (m, 14H), 2.01 - 1.70 (m, 11H), 1.66 - 1.54 (m, 1H), 1.39 - 1.16 (m, 8H), 1.04 (d, J= 6.4 Hz, 3H), 0.91 (s, 4H), 0.63 (d, J = 6.4 Hz, 3H).

[1148] Example 88 (25',47?)-4-hydroxy-l-((5)-2-(4-(((lR,3S)-3-((4-((lr,47?)-4-((8-isopropyl- 7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methyl)-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl)-7V-((5)-2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide

[1149]

[1150] The compound was prepared according to the procedures described for Example 86. LCMS (ESI): m / z 973.8 (M+H)+.XH NMR (400 MHz, DMSO-tL) d 8.97 (s, 1H), 8.61 - 8.51 (m, 2H), 7.89 (d, J= 11.6 Hz, 1H), 7.79 - 7.65 (m, 1H), 7.64 - 7.62 (m, 1H), 7.30 - 7.18 (m, 3H), 6.20 - 6.17 (m, 1H), 5.63 - 5.60 (m, 1H), 5.26 - 5.17 (m, 2H), 4.98 (t, J= 8.4 Hz, 1H), 4.49 (t, J = 8.0 Hz, 1H), 4.37 (s, 1H), 3.80 - 3.75 (m, 1H), 3.70 - 3.60 (m, 1H), 2.92 - 2.82 (m, 2H), 2.76 (d, J= 7.6 Hz, 1H), 2.65 (d, J= 7.6 Hz, 1H), 2.45 (s, 3H), 2.45 - 2.36 (m, 3H), 2.35 - 2.05 (m, 10H), 2.04 - 1.67 (m, 12H), 1.67 - 1.58 (m, 1H), 1.58 - 1.41 (m, 7H), 1.40 - 1.16 (m, 8H), 1.04 (d, J= 6.4 Hz, 3H), 0.63 (d, J= 6.0 Hz, 3H).

[1151] Example 89 (25,47?)-l-((S)-2-(4-(((17?,35)-3-((4-((lr,47?)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methyl)- 1H- 1,2,3 -tri azol- 1 -y l)-3 -methylbutanoyl )-4-hydroxy-N-((A')- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1152]

[1153] The compound was prepared according to the procedures described for Example 86. LCMS (ESI): m / z 1047.9 (M+H)+. 'H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.50 (d, J= 7.6 Hz, 1H), 8.37 (d, J= 4.0 Hz, 1H), 8.31 - 8.18 (m, 1H), 8.10 - 8.09 (m, 1H), 7.93 - 7.82 (m, 1H), 7.47 - 7.32 (m, 4H), 7.25 - 7.10 (m, 6H), 6.97 (d, J= 8.0 Hz, 1H), 6.60 - 6.58 (m, 1H), 5.20 (d, J= 10.4 Hz, 1H), 5.16 (s, 1H), 4.91 (t, J= 6.4 Hz, 1H), 4.38 (t, = 8.4 Hz, 1H), 4.31 (s, 1H), 3.76 - 3.74 (m, 1H), 3.66 - 3.56 (m, 2H), 2.75 (d, J= 8.0 Hz, 1H), 2.65 (d, J= 6.8 Hz, 2H), 2.45 (s, 3H), 2.44 - 2.38 (m, 7H), 2.36 - 2.05 (m, 10H), 2.00 - 1.90 (m, 2H), 1.82 - 1.70 (m, 4H), 1.38 (d, J= 6.8 Hz, 3H), 1.35 - 1.15 (m, 6H), 1.03 (d, J= 6.0 Hz, 3H), 0.92 (s, 4H), 0.63 (d, J= 6.0 Hz, 3H).

[1154] Example 90 (25',47?)-4-hydroxy-l-((5)-2-(4-(((U?,35)-3-((4-((lr,47?)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methyl)- 1H- 1,2,3 -tri azol- 1 -y l)-3 -methylbutanoyl )-N-(fS’)- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1155] H

[1156]

[1157] The compound was prepared according to the procedures described for Example 86. LCMS (ESI): m / z 467.5 (M / 2+H)+. 'H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.56 - 8.47 (m, 2H), 7.94 - 7.83 (m, 1H), 7.75 - 7.54 (m, 2H), 7.47 - 7.35 (m, 4H), 6.23 - 6.11 (m, 1H), 5.74 - 5.57 (m, 1H), 5.25 - 5.14 (m, 2H), 4.95 - 4.87 (m, 1H), 4.38 (t, J= 8.0 Hz, 1H), 4.32 - 4.30 (m, 1H), 3.75 - 3.70 (m, 1H), 3.68 - 3.60 (m, 1H), 2.77 - 2.75 (m, 1H), 2.68 - 2.65 (m, 1H), 2.45 (s, 3H), 2.44 - 2.36 (m, 4H), 2.35 - 2.25 (m, 5H), 2.19 - 2.14 (m, 1H), 2.14 - 2.03 (m, 3H), 2.02 - 1.96 (m, 2H), 1.95 - 1.90 (m, 1H), 1.89 - 1.82 (m, 2H), 1.81 - 1.74 (m, 3H), 1.55 - 1.46 (m, 7H), 1.42 - 1.35 (m, 3H), 1.34 - 1.21 (m, 7H), 1.03 (d, J= 6.4 Hz, 3H), 0.63 (d, J= 6.4 Hz, 3H).

[1158] Example 91 and Example 92 (25, 47?)-4-hydroxy-l-((R)-2-(3-(((17?,37?)-3-((4- ((lr,47?)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1159]

[1160]

[1161] Step 1: methyl 3 -(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane-l -carboxylate To a mixture of methyl 3-(hydroxymethyl)cyclobutanecarboxylate (10.0 g, 69.36 mmol) and 4H-imidazole (9.44 g, 138.73 mmol) in DCM (200 mL) was added TBDPSC1 (21.64 mL, 83.24 mmol) at 20 °C. Then the mixture was stirred at 20 °C for 16 h. After that, the reaction was quenched with water (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layer was washed by brine (300 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with 0 - 10% EtOAc in petroleum ether to afford the title compound (25 g, 94%) as a yellow oil. 'HNMR (400 MHz, CDCl3) d 7.70 - 7.63 (m, 4H), 7.40 (d, J= 7.6 Hz, 6H), 3.71 -3.57 (m, 5H), 3.14 - 2.95 (m, 1H), 2.62 - 2.41 (m, 1H), 2.38 - 2.11 (m, 4H), 1.06 (s, 9H).

[1162] Step 2: (3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanol

[1163] To a stirred solution of methyl 3 -[[tert- butyl (diphenyl) silyl] oxymethyl] cyclobutanecarboxylate (5 g, 13.1mmol) in THF (80 mL) was added 2.5 M LiAlH4 in THF (15.68 mL, 39.2 mmol) dropwise at 0 °C under N2 atmosphere. Then the reaction mixture was stirred at 20 °C for 3 h under nitrogen atmosphere. After that, the reaction was quenched with water (20 ml), extracted with EtOAc (20 mL x 2). The combined organic layer was dried over sodium sulfate and concentrated. The resulting mixture was purified by column chromatography on silica gel eluting with 0 - 20% ethyl acetate in petroleum ether to give the title compound (4.2 g, 90%) as a colorless oil. 'HNMR (400 MHz, CDCl3) 37.71 - 7.63 (m, 4H), 7.46 - 7.36 (m, 6H), 3.66 (t, J= 7.2 Hz, 2H), 3.56 (d, J= 6.0 Hz, 2H), 2.54 - 2.35 (m, 2H), 2.11 - 2.01 (m, 2H), 1.98 - 1.90 (m, 1H), 1.85 - 1.75 (m, 1H), 1.67 - 1.56 (m, 1H), 1.07 (s, 9H).

[1164] Step 3: 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane-l-carbaldehyde

[1165] To a stirred mixture of [3-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclobutyl]methanol (4.2 g, 11.85 mmol) and DIEA (12.4 mL, 71.1 mmol) in DCM (120 mL) was added sulfurtrioxide-pyridinecomplex (7.54 g, 47.38 mmol) in portions at 0 °C. Then the mixture was stirred at 20 °C for 3 h under N2 atmosphere. After that, the reaction mixture was diluted with water (20 ml) and adjusted the pH to 3 ~ 4 with 2 M HC1 in ethyl acetate. Then the resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (20 ml x 3), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting 0 - 30% ethyl acetate in petroleum ether to give the title compound (3.3 g, 79%) as a light yellow solid. 'H NMR (400 MHz, CDCI3) 39.80 - 9.65(m, 1H), 7.70 - 7.64 (m, 4H), 7.46 - 7.37 (m, 6H), 3.70 - 3.55 (m, 2H), 3.17 - 2.99 (m, 1H), 2.64 -2.44 (m, 1H), 2.38 - 2.28 (m, 1H), 2.20 - 2.13 (m, 2H), 2.12 - 2.06 (m, 1H), 1.07 (s, 9H).

[1166] Step 4: 2-(((lA,4r)-4-(4-(((lr,3A)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)piperazin-l-yl)cyclohexyl)amino)-8-isopropylpyrido[2,3- ]pyrimidin-7(8J7)-one

[1167] A mixture of 3-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclobutanecarbaldehyde (713.7 mg, 2.02 mmol) and 8-isopropyl-2-[(4-piperazin-l-ylcyclohexyl)amino]pyrido[2,3-d]pyrimidin-7-one (500.0 mg, 1.35 mmol) in MeOH (8 mL) was stirred at 20 °C for 1 h under N2 atmosphere. Then NaBH CN (101.8 mg, 1.6 mmol) was added into the reaction mixture at 20 °C. The resulting reaction mixture was stirred at 20 °C for another 16 h under N2 atmosphere. After that, the reaction mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel eluting with 0-10% MeOH in DCM to afford 2-(((lr,4r)-4-(4-((3 -(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)piperazin- 1 -yl)cyclohexyl)amino)-8-isopropylpyrido[2,3-d]pyrimidin-7(8H)-one (600 mg) as a mixture of isomers. It was further purified by SFC (Phenomenex Cellulose-2 (250 mm * 50 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH311H2O = 45 / 55; 140 mL / min) to afford the title compound (230 mg, 30%, first peak on SFC) as a yellow solid.

[1168] Step 5: 2-(((lA,4r)-4-(4-(((lr,3A)-3-(hydroxymethyl)cyclobutyl)methyl)piperazin-l-yl)cyclohexyl)amino)-8-isopropylpyrido[2,3-J]pyrimidin-7(8J7)-one

[1169] A solution of 2-[[4-[4-[[3-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclobutyl]methyl] piperazin-1 -yl]cyclohexyl]amino]-8-isopropyl-pyrido[2,3-J]pyrimidin-7-one (230.0 mg, 0.33 mmol) in THF (2 mL) was added TBAF (0.65 mL, IM in THF) at 25 °C and stirred at 25 °C for 2 h. Then the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (30 ml x 2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with 0 - 10% MeOH in DCM to afford the title compound (70 mg, 46%) as a yellow solid. LCMS (ESI): m / z 469.2 (M+H)+.

[1170] Step 6: ((lA,3r)-3-((4-((lr,4A)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)methyl)cyclobutyl)methyl 4-methylbenzenesulfonate

[1171] To a solution of 2-(((lA,4r)-4-(4-(((lr,3A)-3-(hydroxymethyl)cyclobutyl) methyl)piperazin-l-yl)cyclohexyl)amino)-8-isopropylpyrido[2,3-J]pyrimidin-7(8J7)-one (120.0 mg, 0.26mmol) in THF (2 mL) was added 60% NaH in mineral oil (30.7 mg, 0.77 mmol) at 0 °C under N2 atmosphere and the mixture was stirred at 0 °C for 0.5 h. Then 4-methylbenzenesulfonyl chloride (73.23 mg, 0.38 mmol) was added into the mixture at 0 °C, and the resulting reaction mixture was stirred at 20 °C for 16 h. After that, the reaction was quenched with water (2 ml), extracted with EtOAc (10 mL x 2). The combined organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with 0 - 10% MeOH in DCM to afford the title compound (50 mg, 31%) as a white solid. LCMS (ESI): m / z 645.2 (M+Na)+.

[1172] Step 7: methyl 3-methyl-2-(3-((2-(trimethylsilyl)ethoxy)methoxy)isoxazol-5-yl)butanoate

[1173] To a solution of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (4.3 g, 21.59 mmol) and DIPEA (11.28 mL, 64.76 mmol) in DCM (40 mL) was added SEMC1 (5.73 mL, 32.38 mmol) at 0 °C. Then the mixture was stirred at 20 °C for 16 h. After that, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude was purified by column chromatography on silica gel eluting with 0 - 20% EtOAc in petroleum ether to afford the title compound (3.0 g, 42%) as a colorless oil. 'H NMR (400 MHz, CDCI3) d 5.76 (s, 1H), 5.19 (s, 2H), 3.76 (s, 3H), 3.64 (t, J= 8.8 Hz, 2H), 3.30 (d, J = 8.8 Hz, 1H), 2.40 - 2.31 (m, 1H), 1.05 - 0.97 (m, 6H), 0.96 - 0.91 (m, 2H), 0.00 (s, 9H).

[1174] Step 8: (A)-3-methyl-2-(3-((2-(trimethylsilyl)ethoxy)methoxy)isoxazol-5-yl)butanoic acid

[1175] To a solution of methyl 3-methyl-2-(3-((2-(trimethylsilyl)ethoxy)methoxy)isoxazol-5-yl)butanoate (3.0 g, 9.1mmol) in MeOH (15mL), water (15 mL) and THF (15mL) was added LiOH H2O (872 mg, 36.4 mmol) at 20 °C. After stirring at 20 °C for 16 h, the mixture was diluted with water (80 mL) and adjusted to pH = 4 with HC1 (1 M) aqueous. Then resulting solution was extracted with EtOAc (60 mL x 2) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 3-methyl-2-(3-((2-(trimethylsilyl)ethoxy)methoxy)isoxazol-5-yl)butanoic acid (2.8 g, 98% yield) as a colorless oil. It was further separated by SFC (DAICEL CHIRALPAK IC (250 mm * 30 mm, 10 um), heptane / EtOH + 0.1% NEUOH = 80 / 20; 80 mL / min) to afford the title compound (1.2 g, 43% yield, the first peak on SFC) as a colorless oil. 'H NMR (400 MHz, CDCl3) 35.86 (s, 1H), 5.22 (s, 2H), 3.65 (t, J= 8.4 Hz, 2H), 3.33 (d, J= 8.4 Hz, 1H), 2.45 - 2.32 (m, 1H), 1.12 - 0.99 (m, 6H), 0.94 (t, J= 8.4 Hz, 2H), 0.00 (s, 9H).

[1176] Step 9: (A)-2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid

[1177] To a mixture of (A)-3-methyl-2-(3-((2-(trimethylsilyl)ethoxy)methoxy)isoxazol-5-yl)butanoic acid (1.5 g, 4.76 mmol) in DCM (20 mL) was added TFA (15.0 mL, 194.7 mmol) at 20 °C. After stirring at 20 °C for 16 h, the reaction mixture was concentrated under vacuum. The residue was diluted with water (80 mL) and adjusted to pH = 8 with Sat. NaHCCL aqueous. The resulting solution was extracted with EtOAc (60 mL x 2) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum, the crude was purified by column chromatography on silica gel eluting with 0 - 10% MeOH in DCM to afford the title compound (800.0 mg, 91%) as a colorless oil.

[1178] Step 10: (25,4A)-4-((tert-butyldiphenylsilyl)oxy)- 1 -(( / ?)-2-(3 -hydroxyisoxazol-5-yl)-3-methylbutanoyl)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a mixture of (A)-2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid (400.0 mg, 2.16mmol), (25,4A)-4-((tert-butyldiphenylsilyl)oxy)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1.29 g, 2.27 mmol) and DIPEA (1.88 mL, 10.8 mmol) in DMF (10 mL) was added HATU (985.0 mg, 2.59 mmol) at 0 °C. Then the reaction mixture was stirred at 20 °C for 16 h. After that, the reaction mixture was filtered and the filtrate was purified by pre-HPLC (acetonitrile 60 - 90 / 0.225% FA in water) to afford the title compound (300.0 mg, 19%) as a white solid. LCMS (ESI): m / z 737.5 (M+H)+.

[1179] Step 11: (25,4A)-4-((tert-butyldiphenylsilyl)oxy)-l-((A)-2-(3-(((lA,3A)-3-((4-((lr,4A)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methoxy)isoxazol-5-yl)-3 -methyl butanoyl )- / ' / -(( >')- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1180] and

[1181] (25,4A)-4-((tert-butyldiphenylsilyl)oxy)-l-((5)-2-(3-(((lA,35)-3-((4-((lr,4A)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methoxy)isoxazol-5-yl)-3 -methylbutanoyl)-A-((5)- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide A mixture of ((lA,3r)-3-((4-((lr,4A)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-t / ]pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)methyl)cyclobutyl)methyl 4-methylbenzenesulfonate (50.0 mg, 0.08 mmol), K2CO3 (33.29 mg, 0.24 mmol) and (25,4A)-4-[tert-butyl(diphenyl)silyl]oxy-l-[(25)-2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoyl]-A-[(15)-l-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (59.2 mg, 0.08 mmol) in DMF (1.0 mL) was stirred at 80 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was purified by pre-HPLC (acetonitrile 37 - 67 / 0.225% FA in water) to afford (25,4A)-4-((tert-butyldiphenylsilyl)oxy)-l-((A)-2-(3-(((lA,3A)-3-((4-((lr,4A)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl) piperazin-l-yl)methyl)cyclobutyl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (13 mg, 14%, first peak on HPLC) as a white solid and (25,4A)-4-((tert-butyldiphenylsilyl)oxy)-l-((5)-2-(3-(((lA,35)-3-((4-((lr,4A)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino) cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide (11 mg, 12%, second peak on HPLC) as a white solid. Absolute configuration was arbitrarily assigned to each isomer.

[1182] Step 12: (25,4A)-4-hydroxy-l-((A)-2-(3-(((lA,3A)-3-((4-((lr,4A)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1183] To a solution of (25,4A)-4-[tert-butyl(diphenyl)silyl]oxy-l-[(2A)-2-[3-[[3-[[4-[4-[(8-isopropyl-7-oxo-pyrido[2,3-J]pyrimidin-2-yl)amino]cyclohexyl]piperazin-l-yl]methyl]cyclobutyl]methoxy]isoxazol-5-yl]-3-methyl-butanoyl]-A-[(15)-l-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (10.0 mg, 0.01 mmol) in MeOH (1 mL) was added TBAF (0.1 mL, 1 M), then the mixture was stirred at 20 °C for 1 h. After that, the reaction mixture was purified by pre-HPLC (acetonitrile 58 - 88 / 0.225% FA in water) to afford Example 91 (5.4 mg, 68%) as a white solid. Absolute configuration was arbitrarily assigned. LCMS (ESI): m / z 949.5 (M+H)+. 'HNMR (400 MHz, CDCI3) d 8.68 (s, 1H), 8.38 (s, 1H), 7.45 - 7.30 (m, 7H), 6.38 - 6.30 (m, 1H), 5.86 (s, 1H), 5.80 - 5.71 (m, 1H), 5.30 - 5.19 (m, 1H), 5.12 - 5.02 (m, 1H), 4.73 - 4.60 (m, 2H), 4.30 - 4.20 (m, 2H), 3.85 - 3.70 (m, 2H), 3.65 -3.55 (m, 1H), 3.51 - 3.48 (m, 1H), 2.85 - 2.55 (m, 12H), 2.53 (s, 3H), 2.48 - 2.40 (m, 2H), 2.31 -2.24 (m, 4H), 2.10 - 1.85 (m, 12H), 1.51 - 1.50 (m, 3H), 1.27 - 1.25 (m, 4H), 0.95 (d, J= 6.0 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H). Step 13: (2N,4 / ?)-4-hydroxy-l -((N)-2-(3-(((l / ?,3N)-3-((4-((l / ',4 / ?)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methoxy)isoxazol-5-yl)-3 -methylbutanoyl )-M((N)- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1184] To a solution of (25,4A)-4-((tert-butyldiphenylsilyl)oxy)-l-((5)-2-(3-(((lR,3S)-3-((4-((lr,4A)-4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl) piperazin-1 -yl)methyl)cyclobutyl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (10.0 mg, O. Olmmol) in MeOH (1 mL) was added HCl / dioxane (2.0 mL, 4.0 M) at 20°C, and the mixture was stirred at 20 °C for 1 h. After that, the reaction mixture was concentrated and the residue was purified by pre-HPLC (acetonitrile 58-88 / 0.225% FA in water) to afford Example 92 (4.5 mg, 56%) as a white solid. Absolute configuration was arbitrarily assigned. LCMS (ESI): m / z 949.5 (M+H)+.XH NMR (400 MHz, CDCl3) d 8.68 (s, 1H), 8.43 (s, 1H), 7.45 - 7.30 (m, 7H), 6.35-6.32 (m, 1H), 5.83 (s, 1H), 5.74 - 5.72 (m, 1H), 5.24 - 5.20 (m, 1H), 5.05 - 4.95 (m, 1H), 4.80 - 4.73 (m, 1H), 4.70 - 4.60 (m, 1H), 4.30 - 4.20 (m, 2H), 3.90 - 3.76 (m, 1H), 3.75 - 3.65 (m, 1H), 3.51 - 3.48 (m, 2H), 2.80 - 2.55 (m, 12H), 2.53 (s, 3H), 2.48 - 2.40 (m, 2H), 2.31 - 2.24 (m, 4H), 2.15 - 1.80 (m, 12H), 1.51 - 1.50 (m, 3H), 1.27 - 1.25 (m, 4H), 0.95 (d, J= 6.4 Hz, 3H), 0.93 (d, J= 6.8 Hz, 3H).

[1185] Example 93 (25,4A)-4-hydroxy-l-((A)-2-(3-((lA,3A)-3-((4-((lr,4A)-4-((8-isopropyl-7-oxo-7, 8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutoxy)isoxazol-5-yl)-3-methylbutanoyl)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1186] H

[1187]

[1188] The compound was prepared according to the procedures described for Example 91. Absolute configuration was arbitrarily assigned. LCMS (ESI): m / z 935.6 (M+H)+. 'H NMR (400MHz, MeOD) 68.88 (s, 1H), 8.63 (d, J= 7.6 Hz, 1H), 8.51 (s, 1H), 7.66 (d, J= 9.6 Hz, 1H), 7.48 - 7.38 (m, 4H), 7.26 - 7.24 (m, 1H), 6.30 - 6.26 (m, 1H), 5.99 (s, 1H), 5.80 (s, 1H), 5.09 - 5.01 (m, 1H), 4.99 - 4.97 (m, 1H), 4.53 - 4.50 (m, 1H), 4.47 - 4.43 (m, 1H), 3.95 - 3.81 (m, 2H), 3.70 - 3.66 (m, 1H), 3.64 - 3.62 (m, 1H), 3.29 - 2.91 (m, 8H), 2.83 - 2.66 (m, 4H), 2.48 (s, 3H), 2.39 - 2.17 (m, 10H), 1.98 - 1.94 (m, 1H), 1.62 - 1.58 (m, 7H), 1.56 - 1.42 (m, 6H), 1.20 (m, 1H), 1.05 (d, J= 6.4 Hz, 3H), 0.95 - 0.85 (m, 3H).

[1189] Exampl e 94 (25,4A)-4-hy droxy- 1 - (R)-2-(3 -(( 1 R, 3 R)-3 -((4-(( 1 r,4A)-4-((8-isopropyl-7-oxo-7, 8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutoxy)isoxazol-5-yl)-3-methylbutanoyl)-7V-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1190]

[1191] The compound was prepared according to the procedures described for Example 92. Absolute configuration was arbitrarily assigned. LCMS (ESI): m / z 935.6 (M+H)+. 'H NMR (400MHz, MeOD) 38.88 (s, 1H), 8.54 - 8.45 (m, 1H), 7.66 (d, J= 9.6 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.40 - 7.35 (m, 2H), 7.25 - 7.22 (m, 1H), 6.30 - 6.26 (m, 1H), 6.00 (s, 1H), 5.85 - 5.75 (m, 1H), 5.04 - 4.99 (m, 1H), 4.98 - 4.96 (m, 1H), 4.58 - 4.56 (m, 1H), 4.44 - 4.42 (m, 1H), 3.90 -3.86 (m, 1H), 3.78 - 3.76 (m, 1H), 3.74 - 3.70 (m, 1H), 3.69 - 3.64 (m, 1H), 3.25 - 2.86 (m, 8H), 2.76 - 2.72 (m, 4H), 2.50 - 2.47 (m, 3H), 2.36 - 2.14 (m, 10H), 1.96 - 1.94 (m, 1H), 1.62 - 1.57 (m, 7H), 1.52 - 1.48 (m, 6H), 1.24 - 1.20 (m, 1H), 1.05 (d, J= 6.4 Hz, 3H), 0.95 - 0.85 (m, 3H).

[1192] Example 95 (25,4A)-l-((R)-2-(3-(((lA,3A)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methoxy)isoxazol-5-yl)-3 -methylbutanoyl)-4-hydroxy-7V-((S)- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1193]

[1194] The compound was prepared according to the procedures described for Example 91. Absolute configuration was arbitrarily assigned. LCMS (ESI): m / z 1063.6 (M+H)+. 'H NMR (400 MHz, DMSO-d6) d 8.99 (s, 1H), 8.47 - 8.40 (m, 1H), 8.38 (m, 1H), 8.32 - 8.20 (m, 1H), 8.10 (d, J= 4.8 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.40 - 7.34 (m, 2H), 7.26 - 7.22 (m, 2H), 7.20 -7.12 (m, 4H), 6.97 (d, J= 8.0 Hz, 1H), 6.66 - 6.48 (m, 1H), 6.12 - 5.83 (m, 1H), 5.11 (d, J = 3.6 Hz, 1H), 4.99 - 4.84 (m, 1H), 4.41 - 4.34 (m, 1H), 4.32 - 4.24 (m, 1H), 4.08 - 4.02 (m, 2H), 3.73 - 3.68 (m, 1H), 3.67 - 3.62 (m, 2H), 3.47 - 4.03 (m, 1H), 3.33 - 3.29 (m, 2H), 2.48 - 2.46 (m, 7H), 2.34 - 2.25 (m, 6H), 2.18 - 2.09 (m, 2H), 2.06 - 2.00 (m, 1H), 1.98 - 1.94 (m, 2H), 1.83 -1.77 (m, 3H), 1.52 - 1.42 (m, 3H), 1.40 - 1.36 (m, 3H), 1.26 - 1.23 (m, 6H), 1.00 - 0.97 (m, 2H), 0.95 - 0.92 (m, 4H), 0.85 - 0.78 (m, 4H).

[1195] Example 96 (25,4A)-l-((S)-2-(3-(((lA,3S)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methoxy)isoxazol-5-yl)-3 -methylbutanoyl)-4-hydroxy-A-((5)- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1196]

[1197] The compound was prepared according to the procedures described for Example 92. Absolute configuration was arbitrarily assigned. LCMS (ESI): m / z 1085.7 (M+Na)+. 'H NMR (400 MHz, DMSO-d6) d 9.03 - 8.96 (m, 1H), 8.40 - 8.36 (m, 1H), 8.32 - 8.20 (m, 2H), 8.10 (d, J = 5.2 Hz, 1H), 7.45 - 7.40 (m, 2H), 7.35 - 7.30 (m, 2H), 7.27 - 7.22 (m, 2H), 7.21 - 7.13 (m, 4H), 6.97 (d, J= 7.8 Hz, 1H), 6.66 - 6.54 (m, 1H), 6.16 - 6.05 (m, 1H), 5.15 - 5.11 (m, 1H), 4.93 -4.85 (m, 1H), 4.46 - 4.38 (m, 1H), 4.31 - 4.23 (m, 1H), 4.09 - 4.00 (m, 2H), 3.77 - 3.74 (m, 1H), 3.70 - 3.59 (m, 1H), 3.58 - 3.53 (m, 1H), 3.52 - 3.48 (m, 1H), 3.33 - 3.28 (m, 2H), 2.48 - 2.44 (m, 6H), 2.35 - 2.23 (m, 8H), 2.20 - 2.13 (m, 2H), 2.10 - 2.04 (m, 2H), 1.99 - 1.93 (m, 2H), 1.82 - 1.78 (m, 2H), 1.49 - 1.42 (m, 2H), 1.37 - 1.35 (m, 3H), 1.30 - 1.23 (m, 6H), 0.97 (m, 2H), 0.95 - 0.93 (m, 4H), 0.85 - 0.82 (m, 4H).

[1198] Example 97 (25,4A)-l-((A)-2-(3-(((15,3S)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methoxy)isoxazol-5-yl)-3 -methylbutanoyl)-4-hydroxy-7V-((S)- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1199]

[1200] The compound was prepared according to the procedures described for Example 95. Absolute configuration was arbitrarily assigned. LCMS (ESI): m / z 1063.6 (M+H)+. 'H NMR (400 MHz, DMSO-d6) <58.93 (s, 1H), 8.35 (d, J= 4.4 Hz, 1H), 8.26 (d, J= 7.2 Hz, 1H), 8.16 -8.08 (m, 2H), 7.47 - 7.41 (m, 2H), 7.40 - 7.34 (m, 2H), 7.26 - 7.19 (m, 2H), 7.18 - 7.12 (m, 4H), 6.67 (d, J= 5.2 Hz, 1H), 6.60 (d, J= 7.6 Hz, 1H), 6.07 - 5.86 (m, 1H), 5.06 - 4.77 (m, 2H), 4.43 (t, J= 7.6 Hz, 1H), 4.35 - 4.26 (m, 1H), 4.20 - 4.18 (m, 2H), 3.78 - 3.71 (m, 1H), 3.67 - 3.63 (m, 2H), 3.44 - 3.38 (m, 1H), 3.33 (s, 2H), 2.71 - 2.59 (m, 1H), 2.48 - 2.47 (m, 2H), 2.46 (s, 3H), 2.40 - 2.31 (m, 6H), 2.29 - 2.15 (m, 2H), 2.05 - 1.96 (m, 3H), 1.94 - 1.86 (m, 3H), 1.85 - 1.76 (m, 4H), 1.49 - 1.39 (m, 3H), 1.38 - 1.23 (m, 7H), 1.02 - 0.96 (m, 3H), 0.95 - 0.89 (m, 4H), 0.87 - 0.81 (m, 3H).

[1201] Example 98 (25,4A)-l-((S)-2-(3-(((15,3S)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutyl)methoxy)isoxazol-5-yl)-3 -methylbutanoyl)-4-hydroxy-7V-((S)- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1202]

[1203] The compound was prepared according to the procedures described for Example 96. LCMS (ESI): m / z 1063.9 (M+H)+. 'H NMR (400 MHz, DMSO-d6) d 8.97 (s, 1H), 8.37 (dd, J= 2.0, 4.8 Hz, 1H), 8.31 - 8.19 (m, 2H), 8.09 (d, J= 5.2Hz, 1H), 7.45 - 7.38 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.26 - 7.12 (m, 6H), 6.96 (d, J= 7.2 Hz, 1H), 6.63 - 6.53 (m, 1H), 6.16 - 6.05 (m, 1H), 5.15 - 4.99 (m, 1H), 4.98 - 4.96 (m, 1H), 4.55 - 4.37 (m, 1H), 4.31 - 4.22 (m, 1H), 4.21 -4.09 (m, 2H), 3.75 - 3.74 (m, 1H), 3.69 - 3.60 (m, 1H), 3.58 - 3.43 (m, 2H), 3.33 - 3.28 (m, 2H), 2.64 - 2.54 (m, 1H), 2.47 - 2.42 (m, 6H), 2.37 - 2.20 (m, 7H), 2.19 - 2.13 (m, 1H), 2.09 - 2.00 (m, 1H), 1.99 - 1.89 (m, 2H), 1.88 - 1.67 (m, 7H), 1.48 - 1.32 (m, 4H), 1.29 - 1.21 (m, 5H), 0.96 (m, 2H), 0.94 - 0.92 (m, 4H), 0.87 - 0.72 (m, 4H).

[1204] Example 99 and Example 100 (25',47?)-l-((7?)-2-(3-((U?,37?)-3-((4-((lr,47?)-4-((4- (2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-7V-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1205] and

[1206] (25',47?)-l-((5)-2-(3-((U?,35)-3-((4-((lr,47?)-4-((4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-7V-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carb oxami de OTBDPS step 3

[1207] O

[1208] H

[1209]

[1210] Step 1: methyl 3-((te / 7-butyldiphenylsilyl)oxy)cyclobutane-l -carboxylate

[1211] To a stirred mixture of methyl 3 -hydroxy cyclobutanecarboxylate (10.0 g, 76.84mmol) and imidazole (10.5 g, 153.7 mmol) in DCM (350 mL) was added / <? / 7-butyl-chloro- (cyclohexatrienyl)-phenyl-silane (25.25 g, 92.2 mmol) in portions at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel eluting with 0 - 10% ethyl acetate in petroleum ether to afford the title compound (18 g, 64%) as a colorless oil. 'H NMR (400 MHz, CDCh) 37.70 -7.62 (m, 4H), 7.46 - 7.35 (m, 6H), 4.16 - 4.12 (m, 1H), 3.68 (s, 3H), 2.50 - 2.27 (m, 5H), 1.08 -1.00 (m, 9H).

[1212] Step 2: ((l,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)methanol

[1213] To a stirred solution of methyl 3 -[tert-butyl(diphenyl)silyl]oxy cyclobutanecarboxylate (10.0 g, 27.1 mmol) in THF (100 mL) was added LiAlH4 (30.0 mL, 2.5 M in THF) dropwise at 0 °C under nitrogen atmosphere. Then the reaction mixture was stirred at 20 °C for another 3 h under nitrogen atmosphere. After that, the reaction was quenched by addition of water (100 mL) dropwise at 0 °C and extracted with ethyl acetate (150 mL x 2). The combined organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatography eluting with 0 - 20% ethyl acetate in petroleum ether to give [3-[tert-butyl(diphenyl)silyl]oxycy cl obutyl] methanol (3.7 g) as a colorless oil. It was further purified by SFC (Daicel Chiralcel OJ (250 mm * 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 90 / 10; 60 mL / min) to afford the title compound (1.1 g, 34 %, second peak on SFC) as a colorless oil. 'HNMR (400 MHz, CDCI3) 37.70 - 7.62 (m, 4H), 7.46 - 7.35 (m, 6H), 4.16 - 4.12 (m, 1H), 3.60 (d, J= 5.2 Hz, 2H), 2.27 - 2.22 (m, 2H), 1.89 - 1.76 (m, 3H), 1.07 (s, 9H).

[1214] Step 3: (ls,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutane-l-carbaldehyde

[1215] To a stirred mixture of [3-[tert-butyl(diphenyl)silyl]oxycyclobutyl]methanol (500.0 mg, 1.47 mmol) and SiC>2 (500.0 mg) in DCM (8 mL) was added pyridinium chlorochromate, PCC (633.0 mg, 2.9 mmol) at 0 °C. Then the reaction mixture was stirred at 20 °C for 2 h under N2 atmosphere. After that, the reaction mixture was filtered to remove the undissolved solid and the filtrate was concentrated under reduced pressure to give the title compound (400 mg) as a yellow oil. It was directly used in the next step.

[1216] Step 4: 4-(2-(l-benzylcyclopropoxy)pyridin-3-yl)-7V-((lA,4r)-4-(4-(((l,35')-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)methyl)piperazin-l-yl)cyclohexyl)pyrimidin-2-amine To a stirred solution of 4-[2-(l-benzylcyclopropoxy)-3-pyridyl]-A-(4-piperazin-l-ylcyclohexyl)pyrimidin-2-amine hydrochloride (600.0 mg, 1.15 mmol) in DMSO (10 mL) was added Et3N dropwise till the pH reached 7, then HO Ac was added to the reaction mixture till pH reached around 5. After that, cv.s-3-[tert-butyl(diphenyl)silyl]oxycyclobutanecarbaldehyde (490.0 mg, 1.45 mmol) in DCM (20 mL) was added. The resulting reaction mixture was stirred at 20 °C for 0.5 h under N2 atmosphere. Then NaBH(OAc)3 (366.0 mg, 1.73 mmol) was added to the reaction mixture. After stirring at 25 °C for 16 h under N2 atmosphere, the reaction was quenched with H2O (15 mL), extracted with DCM (20 mL x 2). The combined organic layer was washed by brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography eluting with 0 ~ 10% MeOH in DCM to afford the title compound (700 mg, 75%) as a colorless oil. LCMS (ESI): m / z 807.4 (M+H)+.

[1217] Step 5: (15,35)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)methyl)cy clobutan- 1 -ol

[1218] To a stirred solution of 4-[2-(l-benzylcyclopropoxy)-3-pyridyl]-A-[4-[4-[[3-[tert-butyl(diphenyl)silyl]oxycyclobutyl]methyl]piperazin-l-yl]cyclohexyl]pyrimidin-2-amine (700.0 mg, 0.87 mmol) in THF (10 mL) was added TBAF (5.0 mL, 0.87 mmol) at 20 °C. Then the resulting reaction mixture was stirred at 20°C for 4 h. After that, the reaction mixture was poured into ice-water (15 mL), extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (20 mL x 4), dried with anhydrous Na2SC>4 and concentrated to afford the title compound (270 mg, 55%) as a yellow oil.

[1219] Step 6: (15',35)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin- 1 -yl)methyl)cy clobutyl 4-m ethylbenzenesulfonate

[1220] To a stirred solution of cA-3-[[4-[4-[[4-[2-(l-benzylcyclopropoxy)-3-pyridyl]pyrimidin-2-yl]amino]cyclohexyl]piperazin-l-yl]methyl]cyclobutanol (130.0 mg, 0.23 mmol) in THF (2 mL) was added NaH (18.29 mg, 0.46 mmol) at 0 °C under N2 atmosphere. After stirring at 0 °C for 0.5 h, p-TsCl (87.15 mg, 0.46 mmol) was added to the reaction mixture. After stirring at 20 °C for another 16 h, the reaction mixture was poured into ice-water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layer was washed with brine (20 mL x 4), dried with Na2SO4, concentrated under reduced pressure. The residue was purified by pre-TLC (10% MeOH in DCM, Rf = 0.3) to afford the title compound (70 mg, 42%) as a colorless oil. LCMS (ESI): m / z 723.4 (M+H)+.

[1221] Step 7: (25, 4R)- 1 -((A)-2-(3 -(( 1 R, 3 R)-3 -((4-(( 1 r,4A)-4-((4-(2-( 1 -benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-7V-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1222] and

[1223] (25,4A)-l-((5)-2-(3-((lA,35)-3-((4-((1r,4R)-4-((4-(2-(1-benzylcyclopropoxy)pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)piperazin-l-yl)methyl)cyclobutoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carb oxami de

[1224] To a stirred mixture of [3-[[4-[4-[(8-isopropyl-7-oxo-pyrido[2,3-J]pyrimidin-2-yl)amino]cy cl ohexyl]piperazin-l-yl]methyl]cy clobutyl] 4-methylbenzenesulfonate (70.0 mg, 0.11 mmol) and K2CO3 (47.68 mg, 0.34 mmol) in DMF (4 mL) was added (25,4A)-4-[tert-butyl(diphenyl)silyl]oxy-l-[(25)-2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoyl]-A-[(15)-l-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (102.0 mg, 0.14 mmol) at 20 °C, then the mixture was stirred ...

Claims

CLAIMS1. A compound having the formula:PTBM-L-E3BMor a pharmaceutically acceptable salt, enantiomer, stereoisomer or solvate thereof, wherein:the PTBM is an IRE 1 -binding moiety;the L is a chemical linking moiety connecting the PTBM and the E3BM; andthe E3BM is an E3 ubiquitin ligase-binding moiety.

2. The compound of claim 1, wherein the E3BM is:whereindashed lines - indicate attachment of any carbon or nitrogen atom of E3BM to L; Ring B is a 5-membered heteroaryl;Y is selected from a bond, C1-C12 alkyl, C1-C12 heteroalkyl, C3-C20 cycloalkyl, and C1-C20 heteroaryl;(R6)oX is selected from a bond, H, C1-C12 alkyl, andRing A is optionally substituted cyclohexyl or optionally substituted phenyl;R1is selected from a bond, H, C1-C12 alkyl, and C3-C20 cycloalkyl;R2is selected from H, C1-C12 alkyl, C1-C12 haloalkyl, C1-C12 alkoxy, and -CONR2aR2b, or when X is:, then R2together with Ring A form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring;R2aand R2bare each independently H or Ci-Ce alkyl, or R2aand R2btogether with the nitrogen atom they are attached to form a heterocyclyl;R3is H;R5is selected from CN, C1-C12 haloalkyl, and a five-, six-, or seven-membered heteroaryl or heterocyclyl ring;each R6is independently selected from hydroxy, halo, CN, C1-C12 haloalkyl, and C1-C12 alkyl; where o is 0, 1 or 2; andeach alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkoxy, alkynyl, alkynyldiyl, haloalkyl, heteroalkyl, heteroalkyl diyl, aryl, aryldiyl, cycloalkyl, cycloalkyldiyl, haloalkyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryl diyl, is independently and optionally substituted with one or more groups selected from F, Cl, Br, I, -CN, -CH3, -CH2CH3, -COCH2, -C=CH, -C =CCH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CH2OP(O)(OH)2, -CH2F, -CHF2, -CF3, -CH2CF3, -CH2CHF2, -CH(CH3)CN, -C(CH3)2CN, -CH2CN, -CH2NH2, -CH2NHSO2CH3, -CH2NHCH3, -CH2N(CH3)2, -CO2H, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, -CONH2, -CONHCH3, -CON(CH3)2, -C(CH3)2CONH2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3, -NHS(O)2CH2CH2CF3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, -NHC(=NH)H, -NHC(=NH)CH3, -NHC(=NH)NH2, -NHC(=0)NH2, -NO2, =0, -OH, -0CH3, -OCH2CH3, -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, -0CH2F, -0CHF2, -0CF3, -OP(O)(OH)2, -S(O)2N(CH3)2, -SCH3, -S(O)2CH3, and -S(O)3H.

3. The compound of claim 1 or 2, wherein the E3BM is selected from the formulas:(R6)OOH OHandwherein R4is C1-C12 alkyl or C3-C20 cycloalkyl; andwherein a dashed lineindicates the attachment point in E3BM to the L.

4. The compound of claim 3, wherein the E3BM is:

5. The compound of claim 3, wherein the E3BM is:

6. The compound of claim 3, wherein the E3BM is:

7. The compound of claim 3, wherein the E3BM is:

8. The compound of claim 3, wherein the E3BM is:

9. The compound of claim 8, wherein the E3BM is:wherein R4is optionally substituted C3-C6 cycloalkyl.

10. The compound of claim 9, wherein the E3BM is:

11. The compound of claim 9, wherein the E3BM is:(R6)O12. The compound of claim 9, wherein R4is selected from cyclopropyl and 1-fluorocyclopropyl.

13. The compound of claim 2 or 3, wherein Ring B is selected from optionally substituted 1,2,3-triazolyl and optionally substituted isoxazolyl.

14. The compound of claim 2 or 3, wherein Ring B is substituted with one or more groups independently selected from -CH3, -CH(CH3)2, -C(CH3)3, and optionally substituted cyclopropyl.

15. The compound of claim 2 or 3, wherein Y is selected from C1-C12 alkyl and Ci -Ci 2 heteroalkyl.

16. The compound of claim 2 or 3, wherein Y is C3-C20 cycloalkyl.

17. The compound of claim 16, wherein Y is selected from cyclopropyl and 1-fluorocyclopropyl.

18. The compound of claim 2 or 3, wherein X is:

19. The compound of claim 18, wherein A is cyclohexyl.

20. The compound of claim 18, wherein A is phenyl.

21. The compound of claim 18, wherein R5is selected from an optionally substituted ring selected from thiazole, pyridine, and pyrazole.

22. The compound of claim 21, wherein R5is thiazole substituted with -CH3.

23. The compound of claim 18, wherein R6is independently selected from F and - CH3, and o is 1 or 2.

24. The compound of claim 2 or 3, wherein Xis25. The compound of claim 2 or 3, wherein R1is selected from H, -CH3, - CH(CH3)2, and -C(CH3)3.

26. The compound of claim 2 or 3, wherein R2is selected from H, -CH3, -CH(CH3)2, and -C(CH3)3.

27. The compound of claim 2 or 3, wherein R2together with Ring A form a ring selected from cyclopentyl, cyclohexyl, and cycloheptyl.

28. The compound of claim 27, wherein R2together with Ring A form:

29. The compound of claim 3, wherein R4is selected from cyclopropyl and 1-fluorocyclopropyl.

30. The compound of claim 1, wherein L is selected from the group consisting of O, NH, C1-C12 alkyldiyl, Ci-Ceo heteroalkyldiyl, C3-C2o carbocyclyldiyl, C2-C2o heterocyclyldiyl, C6-C20aryldiyl, C1-C40 heteroaryl diyl, -(C3-C2o carbocyclyldiyl)-(Ci-C6o heteroalkyldiyl)-, — (C3— C2o carbocyclyldiyl)-(Ci-Ci2alkyldiyl)-, -(C2-C2o heterocyclyldiyl)-(Ci-C6o heteroalkyldiyl)-, -(C2-C2o heterocyclyldiyl)-(Ci-Ci2alkyldiyl)-, -(C2-C2o heterocyclyldiyl)-(C2-C2o heterocyclyldiyl)-, and -(C1-C20 heteroaryldiyl)-(C3-C2o carbocyclyldiyl)-(Ci-C6o heteroalkyldiyl)-.

31. The compound of claim 1, wherein L is selected from the structures:oandwhere the single asterisk * indicates the point of attachment to E3BM, and the double asterisk ** indicates the point of attachment to PTBM.

32. The compound of any one of claims 1-31, wherein PTBM is selected from the formula:X2whereinthe dashed line indicates the attachment to L;R7is selected from H and C1-C12 alkyl;X1and X2are independently selected from H, C1-C12 alkyl, C1-C20 heteroalkyl, C1-C20 heteroaryl and C2-C20 heterocyclyl; or X1and X2together form a five, six, or seven-membered heteroaryl or heterocyclyl ring.

33. The compound of claim 32, wherein X1and X2together form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring.

34. The compound of claim 33, wherein PTBM is selected from the formulas:whereinR8is selected from H, C1-C12 alkyl, C1-C20 heteroalkyl, C3-C20 carbocyclyl, C6-C20 aryl, and C2-C20 heterocyclyl; andeach R9is independently selected from H, halide, C1-C12 alkyl, -N(R8)2, -OR8, C1-C20 heteroalkyl, C6-C20 aryl, C3-C20 carbocyclyl, and C2-C20 heterocyclyl.

35. The compound of claim 34, wherein the PTBM is:

36. The compound of claim 34 or 35, wherein the PTBM is37. The compound of claim 34 or 35, wherein the PTBM isR738. The compound of claim 34, wherein the PTBM isR7I.O39. The compound of claim 38, wherein the PTBM is40. The compound of claim 39, wherein the PTBM is41. The compound of claim 39, wherein the PTBM isH42. The compound of any one of claims 34-40, wherein one R9is:

43. The compound of claim 34, wherein the PTBM is selected from:

44. The compound of claim 32, wherein one of X1and X2is H and the other is C1-C20 heteroaryl.

45. The compound of claim 44, wherein one of X1and X2is H and the other is selected from pyridinyl and pyrimidinyl.

46. The compound of claim 45, wherein the pyridinyl or pyrimidinyl are substituted with one or more groups selected from -O-(C3-C20 carbocyclyldiyl), -O-(C6-C20 aryl), -O-(C1-C20 heteroaryl), and -O-(C2-C20 heterocyclyl).

47. The compound of claim 45, wherein the pyridinyl or pyrimidinyl are substituted with:- O- (Ce- C20 aryl) where C6-C20 aryl is naphthyl substituted with -NHS(O)2R10; or - O- (C3- C20 carbocyclyldiyl) where C3-C20 carbocyclyldiyl is cyclopropyl substituted with -NHS(O)2R10;where R10is selected from the group consisting of C1-C12 alkyl, C1-C20 heteroalkyl, C6-C20 aryl, C3-C20 carbocyclyl, -(C1-C12 alkyldiyl)-(C6-C20 aryl), -(C1-C12 alkyldiyl)— ( C3-C20 carbocyclyl).

48. The compound of claim 47, wherein the PTBM is:R7Iwherein R11is -O-(C3-C20 carbocyclyldiyl)-(C1-C6 alkyldiyl)-(C6-C20 aryl).

49. The compound of claim 48, wherein R11is cyclopropyl substituted with -(C1-C6 alkyldiyl)-(C6-C20 aryl).

50. The compound of claim 48 or 49, wherein R11is:

51. The compound of any one of claims 1-31, wherein PTBM is selected from the structures:wherein any carbon or nitrogen atom of the structures is the point of attachment to L.

52. The compound of any one of claims 1-3, wherein PTBM-L is selected from the structures:where the asterisk * indicates the point of attachment of the PTBM-L to the E3BM.

53. A compound of claim 1 selected from Table 1.

54. A pharmaceutical composition comprising the compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

55. The pharmaceutical composition of claim 54, wherein the compound is formulated as a sterile injectable preparation.

56. A method for treating a disease or disorder mediated, at least in part, by IRE1 in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 54.

57. The method of claim 56, wherein the disease or disorder is a cancer selected from the group consisting of squamous cell carcinoma, small- cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell lung cancer, peritoneum cancer, hepatocellular cancer, stomach cancer, gastrointestinal cancer, esophageal cancer, pancreaticcancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, and head and neck cancer.

58. The method of claim 56, wherein the disease or disorder is a cancer selected from the group consisting of lymphoma, lymphocytic leukemia, multiple myeloma (MM), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), and myeloproliferative disease (MPD).

59. The method of claim 58, wherein the disease or disorder is multiple myeloma.

60. The method of any one of claims 56-59, further comprising administering one or more additional therapeutic agents selected from the group consisting of an anti-inflammatory agent, a corticosteroid, an immunomodulatory agent, anti-cancer agent, an apoptosis-enhancer, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, an agent for treating metabolic disorders, an agent for treating autoimmune disorders, and an agent for treating immunodeficiency disorders.

61. A compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 54, for use in treating a disease or disorder mediated, at least in part, by IRE1 comprising administering an effective amount of the compound to a subject in need thereof, wherein the disease or disorder is a cancer selected from the group consisting of squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell lung cancer, peritoneum cancer, hepatocellular cancer, stomach cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, and head and neck cancer.

62. Use of a compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 54, in the manufacture of a medicament for the treatment of an IRE1 -mediated disease or disorder, wherein the disease or disorder is a cancer selected from the group consisting of squamous cell carcinoma, small- cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell lung cancer, peritoneum cancer, hepatocellular cancer, stomach cancer, gastrointestinal cancer,esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, and head and neck cancer.

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