CBL-b inhibitor and uses thereof

Abstract

Compounds and compositions for inhibition of the Cbl-b enzyme and methods of use thereof in modulating the immune system, treatment of diseases. Some compounds in this disclosure are covalent Cbl-b inhibitors, which can form a covalent bond with a cysteine in the Cbl-b protein. Also disclosed herein are methods for use of a Cbl-b inhibitor in treating cancer. Formula (I) or tautomer, stereoisomers or a pharmaceutically acceptable salt thereof, wherein: W is (a) or (b), wherein the (c) represents a double or triple bond and the R1b and R1d are absent when the (d) represents a triple bond.

Description

[0001] Attorney Docket No.: 51728-013WO2 CBL-B INHIBITOR AND USES THEREOF Technical field Provided herein are compounds and compositions for inhibition of the Cbl-b enzyme and methods of use thereof in modulating the immune system, treatment of diseases. 5 Background of the invention The following discussion is provided to aid the reader in understanding the disclosure and is not admitted to describe or constitute prior art thereto. Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b, CBL-b or CBL-B) is an E3 ubiquitin ligase that negatively regulates T-cell activation. Studies have found that Cbl b-deficient T-cells 10 display lower thresholds for activation by antigen recognition receptors and co-stimulatory molecules (e.g., CD28). One study showed that Cbl -b- / - CD8+ T-cells are resistant to T regulatory cell-mediated suppression and exhibit enhanced activation and tumor infiltration. Therapeutic transfer of naive Cbl -b- / - CD8+ T-cells was sufficient to mediate rejection of established tumors (see Loeser et al, J Exp Med., 204: 879-891, 2007). Recent studies have shown that Cbl-b also 15 plays a role in NK-cell activation. Genetic deletion of Cbl-b or targeted inactivation of its E3 ligase activity allowed NK-cells to spontaneously reject metastatic tumors in a mouse model (see Paolino et al, Nature, 507: 508-512, 2014). Modulation of Cbl-b has been shown to be a therapeutic target for a diseases and disorders. There remains a need for comounds that inhibit Cbl-b. Summary of the invention 20 Disclosed herein are compounds and compositions for inhibition of the Cbl-b enzyme and methods of use thereof in modulating the immune system, treatment of diseases. In some aspects, this disclosure provides Cbl-b inhibitors that can form a covalent bond with a cysteine residue in the CBLB protein. Also disclosed herein are methods for use of a Cbl-b inhibitor in treating cancer. Brief description of the drawings 25 Fig. 1, Mass spec identified Cys289 as a binding site in CBL-b for compound 24 Fig. 2, Mutation on Cys289 reduced compound 24 labeling on CBL-b Detailed description Before the present invention is further described, it is to be understood that the invention is 30 not limited to the particular embodiments set forth herein, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Compounds In one aspect, provided herein is a compound of Formula (I), that inhibiting the Cbl-b enzyme: 1

[0002] Attorney Docket No.: 51728-013WO2 or tautomers, stereoisomers or a pharmaceutically acceptable salt thereof, wherein: , represents a double or triple bond, and the R1band R1dare absent when the represents a triple bond; 5 R1ais selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl or - C1-6alkoxy; R1b is selected from the group consisting of is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, or - C1-6 alkoxy； R1c is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy,10C1-6 alkylene-O- C2-6 alkenyl, C1-6 alkylene-O- C2-6 alkynyl, or C1-6 alkylene-NR2aR2b; wherein the R2aand R2bis independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, -C1-6alkoxy, or C1-6alkylene-5-10 membered heteroaryl (preferably optionally C1-6alkyl substituted 1,2,3-triazole, 2,3,4-triazole or 1,2,4-triazole); R1dis selected from the group consisting of hydrogen, fluoro, cyano and methyl; 15 L is selected from ; wherein 2 Attorney Docket No.: 51728-013WO2 represents the position attaching to the ring， represents the position attaching to the W; X is N or O; T is C, N, O or S; 5 n is integers ranging from 0, 1, 2, 3 or 4; m is integers ranging from 0, 1, 2, 3 or 4; When X is O, Ra1is absent; when X is N, Ra1is selected from the group consisting of hydrogen, OH, CN, halogen, C1-6alkyl, C3-6cycloalkyl, C2-6cycloalkoxy, C1-6haloalkyl, C1-6haloalkoxy, C1-6 alkoxy, alkoxyalkyl, hydroxy, carboxyl, alkoxycarbonyl; 10 each Rb1 or each Rb2 is independently selected from the group consisting of hydrogen, OH, CN, halogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 cycloalkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1- 6 alkoxy, alkoxyalkyl, hydroxy, carboxyl, alkoxycarbonyl; Rc1or Rc2is independently selected from the group consisting of hydrogen, OH, CN, halogen, C1-6alkyl, C3-6cycloalkyl, C2-6cycloalkoxy, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkoxy, 15 alkoxyalkyl, hydroxy, carboxyl, alkoxycarbonyl; when T is O or S, Rc1and Rc2is absent; Rd1 or Rd2 is independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 cycloalkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, alkoxyalkyl, alkoxycarbonyl; optionally, Ra1 and Rb1 are taken together with the carbon atom to which they are attached20to form a Re1 substituted saturated or unsaturated 4-8 membered heterocyclyl; optionally, Ra1and Rc1are taken together with the carbon atom to which they are attached to form a Re1substituted saturated or unsaturated 4-8 membered heterocyclyl; optionally, Ra1and Rd1are taken together with the carbon atom to which they are attached to form a Re1 substituted saturated or unsaturated 4-8 membered heterocycly; 25 optionally, Ra1 and Rc1 are taken together with the carbon atom and Rc2 and R1a are taken together with the carbon atom to form Re1 and / or Re2 substituted saturated or unsaturated 7-11 membered spiro ring systems; optionally, Ra1and Rc1are taken together with the carbon atom and Rc1and R1aare taken together with the carbon atom to form Re1and / or Re2substituted saturated or unsaturated 30 7-11 membered fused ring systems; optionally, Ra1and R1aare taken together with the carbon atom to which they are attached to form a Re2 substituted saturated or unsaturated 4-8 membered heterocyclyl; 3 Attorney Docket No.: 51728-013WO2 optionally, Rd1and R1aare taken together with the carbon atom to which they are attached to form a Re2 substituted saturated or unsaturated 4-8 membered heterocyclyl; optionally, Rc1 and R1a are taken together with the carbon atom to which they are attached to form a Re2 substituted saturated or unsaturated 4-8 membered heterocyclyl; and / or 5 optionally, Rb1and Rb2are taken together with the carbon atom to which they are attached to form a Re1substituted saturated or unsaturated 4-8 membered cycloalkyl or heterocyclyl; and wherein each Re1is independently selected from the group consisting of hydrogen, OH, CN, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkenyl, 10 optionally substituted C1-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted C2-6 cycloalkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, optionally substituted saturated or unsaturated 4-8 membered heterocyclyl or 5-10 membered heteroaryl (preferably optionally substituted 1,2,3-triazole, 2,3,4-triazole or 1,2,34- triazole); wherein each substitutes on Re1is independently selected from the group 15 consisting of hydrogen, OH, CN, halogen, C1-6alkyl, C3-6cycloalkyl, C3-6heterocycloalkyl, C2-6cycloalkoxy, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkoxy, C6-10aryl or C6-10 heteroaryl; wherein each Re2 is independently selected from the group consisting of hydrogen, OH, CN, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkenyl,20optionally substituted C1-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted C2-6cycloalkoxy, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkoxy, optionally substituted saturated or unsaturated 4-8 membered heterocyclyl or 5-10 membered heteroaryl (preferably optionally substituted 1,2,3-triazole, 2,3,4-triazole or 1,2,34- triazole); wherein each substitutes on Re2 is independently selected from the group 25 consisting of hydrogen, OH, CN, halogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 cycloalkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy; Rf1 is selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, or C3-C6 cycloalkyl; V is C or N; 30 Z is CH or N; Y is absent, C1-C3alkylene, or C1-C3haloalkylene, preferably CH2or CH-halogen; Xd1is N or O; Xd2 is C, N or S; Xd3 is C or S; 4 Attorney Docket No.: 51728-013WO2 R1or R1´is selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, or C3-C6cycloalkyl; when Xd2is S, R1is absent; when Xd3is S, R1´is absent; each R2 and R3 is independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, 4-8 membered heterocyclyl or C3-C6 cycloalkyl, wherein the heterocyclyl or cycloalkyl 5 groups are optionally substituted by one to three R6groups; or R2and R3are taken together with C, N or O atom(s) to which they are attached to form a C3-C10cycloalkyl or 4-10 membered heterocyclyl, wherein the C3-C10cycloalkyl or 4-10 membered heterocyclyl is mono, fused, spiro or bridged ring systems; each R6 is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, 10 hydroxy, -O-C1-6 alkyl, -CN, C1-6 alkyl-CN, C1-6 alkyl-OH or C1-6 haloalkyl; or two R6 are taken together with C, N or O atom(s) to which they are attached to form a C3-C10 cycloalkyl or 4-10 membered heterocyclyl; R4is halogen, R7, OR7or NR7R8, R7or R8is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl or C1-6alkoxy, 3-6 membered 15 cycloalkyl; or R7and R8formed 3-6 membered cycloalkyl; R5is selected from the group consisting of C1-6haloalkyl or C3-6cycloalkyl; represents a single or double bond, and the two adjacent are not simultaneouslydouble bonds. In some embodiments, W is selected from the group consisting of 20 , In some embodiments, W is selected from the group consisting of 5

[0003] Attorney Docket No.: 51728-013WO25 .In some embodiments, L is selected from the group consisting of 6 Attorney Docket No.: 51728-013WO2 , or . In some embodiments, the L is selected from the group consisting of 5 p is integers ranging from 0, 1, 2 or 3. In some embodiments, the L is selected from the group consisting of 7

[0004] Attorney Docket No.: 51728-013WO2 . 5 In some embodiments, the -L-W is selected from the group consisting of 9

[0005] Attorney Docket No.: 51728-013WO2 ; 5 p or r independently is integers ranging from 0, 1, 2 or 3. In some embodiments, the -L-W is selected from the group consisting of: 13 Attorney Docket No.: 51728-013WO2 19

[0006] Attorney Docket No.: 51728-013WO2 . In some embodiments, the formula I is selected from the group consisting of 20

[0007] Attorney Docket No.: 51728-013WO2 ， , 21

[0008] Attorney Docket No.: 51728-013WO2 . In some embodiments, the D ring is selected from the group consisting of 5 In some embodiments, the formula I is selected from the group consisting of formula I(A)to I(G), II (A) to II(F), III (A) to III(F), or IV (A) to IV(F), 22 Attorney Docket No.: 51728-013WO2 25

[0009] Attorney Docket No.: 51728-013WO2 III(C) 26 Attorney Docket No.: 51728-013WO2 27 Attorney Docket No.: 51728-013WO2 IV(B)V(C) IV(D)V(E) 28

[0010] Attorney Docket No.: 51728-013WO2 Wherein the L, V, W, Y, Z, R1, R1’, R2, R3, R4, R5, R6, R1a, R1b, R1c, R1d are defined in any one of preceding embodiments; or tautomers, stereoisomers or a pharmaceutically acceptable salt thereof. In some embodiments, R5is selected from the group consisting of -CF3or cyclopropyl. 5 In some embodiments, R1is selected from the group consisting of hydrogen, C1-C3alkyl, C1- C3haloalkyl, or C3-C4cycloalkyl; preferably hydrogen, -CH3, -CHF2or cyclopropyl. In some embodiments, R6is independently selected from the group consisting of hydrogen, CH3, fluoro, hydroxy, -OCH3, -CN, -CH2CN, -CH2OH or -CF3; or two R6 are taken together with C or O atom(s) to which they are attached to form a C3-C6 cycloalkyl or 4- to 6-membered 10 heterocyclyl. In some embodiments, this disclosure provides compounds that can form a covalent bond with a cysteine in the CBl-b protein. In certain embodiments, the compounds described herein include one or more warheads that covalently modify Cys289. Examples of such compounds include compounds of Formula I, I(A), I(B), I(C) II (A), II(B) or II(C). In some embodiments, the 15 warheads are equivalent to the W group in the Formulation of the compounds. In some embodiments, the compound is selected from Table 1 as below, or tautomers, stereoisomers or a pharmaceutically acceptable salt thereof Table 1 CBL-b Inhibitor Compounds 29 Attorney Docket No.: 51728-013WO2 30 Attorney Docket No.: 51728-013WO2 13 60 31

[0011] Attorney Docket No.: 51728-013WO2 27 74 28 75 29 76 30 77 32 Attorney Docket No.: 51728-013WO2 33 Attorney Docket No.: 51728-013WO2 34 Attorney Docket No.: 51728-013WO2 35 Attorney Docket No.: 51728-013WO2 36 Attorney Docket No.: 51728-013WO2 37 Attorney Docket No.: 51728-013WO2 38 Attorney Docket No.: 51728-013WO2 39 Attorney Docket No.: 51728-013WO2 40 Attorney Docket No.: 51728-013WO2 41 Attorney Docket No.: 51728-013WO2 42 Attorney Docket No.: 51728-013WO2 disclosure. For example, when compounds of the present disclosure contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups. The protected derivatives of compounds of the present 5 disclosure can be prepared by methods well known in the art. The present disclosure also includes prodrugs of the compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) or a pharmaceutically acceptable salt thereof. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of 10 the present invention. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal 15 patch reservoir with a suitable enzyme or chemical reagent. Certain compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of Formula (I) may 20 exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. Certain compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) possess asymmetric carbon atoms (optical centers) or double bonds; the 25 racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention. When a stereochemical depiction is shown, it is meant to refer to the compound in which one of the isomers is present and substantially free of the other isomer. ‘Substantially free of another isomer indicates at least an 80 / 20 ratio of the two isomers, more preferably 90 / 10, or 95 / 5 or more. In 30 some embodiments, one of the isomers will be present in an amount of at least 99%. Certain compounds of the present disclosure can exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure. The compounds of Formula (I) and any embodiment thereof disclosed herein including 35 specific compounds may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from 43 Attorney Docket No.: 51728-013WO2 the amount found in nature to an amount 100% of the atom in question that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention, such as a compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) include isotopes of hydrogen, carbon, 5 nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C, 13N,15N,15O,17O,18O,32P,33P,35S,18F,36C1,123I, and125I, respectively. Isotopically labeled compounds (e.g., those labeled with3H and14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium 10 (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds disclosed herein, including in Table 1 above, one or more hydrogen atoms of the compounds are replaced by2H or3H, or one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as15O,13N,14C, and15F are useful for positron emission 15 tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent. Composition 20 In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt therefo and at least one pharmaceutically acceptable carrier. In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount. The pharmaceutical compositions may be 25 used in the methods disclosed herein; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic methods and uses described herein. In one particular variation, the composition is a solid formulation adapted for oral administration. In another particular variation, the composition is a liquid formulation adapted for 30 oral administration. In yet another particular variation, the composition is a tablet. In still another particular variation, the composition is a liquid formulation adapted for parenteral administration. The present invention also provides a pharmaceutical composition comprising a compound according to any one of the above embodiments and variations, wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, 35 intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, and intrathecally. Methods and Uses 44 Attorney Docket No.: 51728-013WO2 In another aspect, the present invention provides a method for treating a tumor by modulating activity of an immune cell, the method comprising contacting the immune cell with an effective amount of a covalent Cbl-b inhibitor, wherein the covalent Cbl-b inhibitor is a compound of any one of preceding embodiments, or tautomers, stereoisomers or a pharmaceutically acceptable salt 5 thereof. In another aspect, the present invention provides the compound of any one of preceding embodiments or tautomers, stereoisomers or a pharmaceutically acceptable salt thereof, for use as a medicament for treating a tumor by modulating activity of an immune cell; or In another aspect, the present invention provides a use of the compound of any one of 10 preceding embodiments or tautomers, stereoisomers or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of preceding embodiments in the manufacture of a medicament for treating a tumor by modulating activity of an immune cell. In some embodiments, the cancer is a hematologic cancer. In some embodiments, the hematologic cancer is a lymphoma, a leukemia, or a myeloma. In some embodiments, the cancer 15 is a non-hematologic cancer. In some embodiments, the non-hematologic cancer is a sarcoma, a carcinoma, or a melanoma. Routes of Administration Compounds of Formula (I), or a pharmaceutically acceptable salt thereof and compositions containing the same may be administered in any appropriate manner. Suitable routes of 20 administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracistemal, intraarticular, intraperitoneal, intracerebral (intraparenchymal) and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal and inhalation. Depot injections, which are generally administered subcutaneously or intramuscularly, may also be utilized to administer the compounds 25 of Formula (I), or a pharmaceutically acceptable salt thereof over a defined period of time. Particular embodiments of the present invention contemplate oral administration. Combination Therapy The present invention contemplates the use of compounds of Formula (I), or a pharmaceutically acceptable salt thereof in combination with one or more active therapeutic agents 30 (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modalities (e.g., radiation). Dosing The compounds of Formula (I), or a pharmaceutically acceptable salt thereof provided herein may be administered to a subject in an amount that is dependent upon, for example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical 35 condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof. The dosing regimen may also take into consideration the existence, nature, and extent of any adverse effects associated with the agent(s) being administered. Effective dosage amounts and dosage regimens can readily be 45 Attorney Docket No.: 51728-013WO2 determined from, for example, safety and dose-escalation trials, in vivo studies (e.g., animal models), and other methods known to the skilled artisan. Definitions Unless otherwise stated, the following terms used in the specification and claims are defined 5 for the purposes of this Application and have the following meaning: The singular forms “a,” “an,” and “the” as used herein and in the appended claims include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology such as “solely”, “only” and the like in 10 connection with the recitation of claim elements, or use of a “negative” limitation. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may 15 independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention 20 belongs. The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e. C1-8means one to eight carbons). Alkyl can include any number of carbons, such as C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6and C5-6. Examples of25 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n- pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term "alkylene" refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated, and linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom or 30 different atoms of the alkylene group. For instance, a straight chain alkylene can be the bivalent radical of -(CH2)n-, where n is 1, 2, 3, 4, 5 or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, hexylene, and the like. The term "cycloalkyl" refers to a saturated or partially unsaturated hydrocarbon ring having35the indicated number of ring atoms (e.g., C3-10 cycloalkyl). Cycloalkyl can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, C6-8, C3-9, and C3-10. Partially unsaturated cycloalkyl groups have one or more double or triple bonds in the ring, but cycloalkyl groups are not aromatic. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 46 Attorney Docket No.: 51728-013WO2 The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term “alkenyl” refer to straight and branched chain and cycloalkyl groups as defined above, with one or more double bonds between two carbon atoms. Alkenyl groups may have 2 to 5 about 6 carbon atoms, or 1, 2, 3 or 4 carbon atoms in other embodiments. Alkenyl groups may be substituted or unsubstituted. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di-, or tri-substituted. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3). -CH=C(CH3)2, - C(CH3)=CH2, cyclopentenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl, among 10 others. The term “alkynyl” refer to straight and branched chain and cycloalkyl groups as defined above, with one or more triple bonds between two carbon atoms. Alkynyl groups may have 2 to about 6 carbon atoms, or 1, 2, 3 or 4 carbon atoms in some embodiments. Alkynyl groups may be substituted or unsubstituted. Representative substituted alkynyl groups may be mono-substituted 15 or substituted more than once, such as, but not limited to, mono-, di-, or tri-substituted. Exemplary alkynyl groups include, but are not limited to, ethynyl, propargyl, and -C≡C(CH3), among others. The term “cycloalkyl” or “cyclic alkyl” or “cycloalkyl” refer to univalent groups derived from cycloalkanes by removal of a hydrogen atom from a ring carbon atom. Cycloalkyl groups are saturated or partially saturated non-aromatic structures with a single ring or multiple rings 20 including isolated, fused, bridged, and spiro ring systems, having 3 to 14 carbon atoms, or in some embodiments, from 3 to 12, or 3 to 10, or 3 to 8, or 3, 4, 5, 6 or 7 carbon atoms. Cycloalkyl groups may be substituted or unsubstituted. Representative substituted cycloalkyl groups may be mono- substituted or substituted more than once, such as, but not limited to, mono-, di-, or tri -substituted. Examples of monocyclic cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, 25 cyclopentyl, and cyclohexyl groups. Examples of multi-cyclic ring systems include, but are not limited to, bicycle[4.4.0] decane, bicycle[2.2.1]heptane, spiro[2.2]pentane, and the like. The term "aryl" refer to cyclic aromatic hydrocarbons that include single and multiple ring compounds, including multiple ring compounds that contain separate and / or fused aryl groups. Aryl groups may contain from 6 to about 18 ring carbons, or in some embodiments from 6 to 14 30 ring carbons or even 6 to 10 ring carbons in other embodiments. Aryl group also includes heteroaryl groups, which are aromatic ring compounds containing 5 or more ring members, one or more ring carbon atoms of which are replaced with heteroatom such as, but not limited to, N, O, and S. Aryl groups may be substituted or unsubstituted. Representative substituted aryl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di-, or 35 tri-substituted. Aryl groups include, but are not limited to, phenyl, biphenylenyl, triphenylenyl, naphthyl, anthryl, and pyrenyl groups. The term "heteroatom" includes oxygen (O), nitrogen (N), sulfur (S). The term "heteroaryl" refers to cyclic groups with atoms of at least two different elements as members of its rings, of which one or more is a heteroatom such as, but not limited to, N, O, or S. 40 Heterocyclyl groups may include 3 to about 20 ring members, or 3 to 18 in some embodiments, 47 Attorney Docket No.: 51728-013WO2 or about 3 to 15, 3 to 12, 3 to 10, or 3 to 6 ring members. The ring systems in heterocyclyl groups may be unsaturated, partially saturated, and / or saturated. Heterocyclyl groups may be substituted or unsubstituted. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di-, or tri-substituted. Exemplary 5 heterocyclyl groups include, but are not limited to, pyrrolidmyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, aziridinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazolinyl, triazolyl (1,2,3-triazolyl, 2,3,4-triazolyl or 1,2,4-triazoly), tetrazolyl, 10 oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, oxetanyl, thietanyl, homopiperidyl, oxepanyl, thiepanyl, oxazepmyl, diazepinyl, thiazepinyl, 1,2, 3, 6- tetrahydropyridyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxolanyl, dioxanyl, purinyl, quinolizinyl, cinnolmyl, phthalazinyl, pteridinyl, and benzothiazolyl groups. “Haloalkyl,” “haloalkylene,” “haloaryl,” “haloarylene,” “haloheteroaryl,” and similar terms15 refer to a moiety substituted with at least one halo group. Where a haloalkyl moiety or other halo- substituted moiety is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. For example, dihaloaryl, dihaloalkyl, trihaloaryl, trihaloalkyl, etc., refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halo; thus, for example, the 20 haloaryl group 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. As for alkyl group, haloalkyl groups can have any suitable number of carbon atoms, such as C1-6. For example, the term "C1-4haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like. The subset of haloalkyl groups in which each hydrogen (H) of an alkyl group is replaced with a halo group is referred to as a “perhaloalkyl.” A particular perhaloalkyl 25 group is trifluoroalkyl (-CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each hydrogen (H) in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a haloalkoxy group is trifluoromethoxy (-OCF3). “Haloalkyl” includes monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, and any other number of halo substituents possible on an alkyl group; and similarly for other groups such as haloalkylene, 30 haloaryl, haloarylene, haloheteroaryl, etc. The term "alkoxy" refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. As for an alkyl group, alkoxy groups can have any suitable number of carbon atoms, such as C1-6, and can be straight or branced. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec- 35 butoxy, tert-butoxy, pentoxy, hexoxy, etc. “Optionally substituted,” unless otherwise specified, means that a group is unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group, in which the substituents may be the same or different. In one embodiment, an optionally substituted group is unsubstituted. In one embodiment, an optionally substituted group has one substituent. In 40 another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, or 1 to 5 substituents. When multiple substituents are present, each substituent 48 Attorney Docket No.: 51728-013WO2 is independently chosen unless indicated otherwise. For example, each (C1-C4alkyl) substituent on the group -N(C1-C4 alkyl)(C1-C4 alkyl) can be selected independently from the other, so as to generate groups such as -N(CH3)(CH2CH3), etc. In addition to the disclosure herein, the term “substituted,” when used to modify a specified 5 group or radical, can also mean that one or more hydrogen atoms (H) of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined herein. In some embodiments, a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent. 10 Examples Synthetic examples Presented below are examples discussing synthesis and characterization of CBL-b inhibitors contemplated for the discussed applications. The following examples are provided to 15 further illustrate the embodiments of the present invention, but are not intended to limit the scope of the invention. While they are typical of those that might be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used. As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent 20 with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: ESI (electrospray ionization), HPLC (high pressure liquid chromatography), SFC (supercritical fluid chromatography), g (grams), mg (milligrams), mL (milliliters), µL (microliters), mM 25 (millimolar), µM (micromolar), Hz (Hertz), MHz (megahertz), mmol (millimoles), umol (micromoles), h, hr, or hrs (hours); min (minutes); MS (mass spectrometry); ppm (parts per million); r.t. or rt (room temperature); sat. (saturated); TLC (thin layer chromatography); ACN (acetonitrile); BOC (t-butyloxycarbonyl); DCM (dichloromethane); DIEA (di- isopropylethylamine); DMSO (dimethylsulfoxide); DMSO-d6(deuterated dimethylsulfoxide);30 dppf (1,1′-bis(diphenylphosphino)ferrocene); Xantphos (4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene), Xphos (2-(Dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl), ACN (acetonitrile), EA (ethyl acetate); Hex (hexanes), EDCI (1-ethyl-3-(3-dimethylamino propyl)carbodiimide), EtOAc (ethyl acetate), PE (petroleum ether), IPA (isopropyl acetate), DAST (diethylaminosulfur trifluoride), FmocOSu or Fmoc-OSu (N-(9-fluorenylmethoxy 35 carbonyloxy)succinimide), IBX (2-Iodoxybenzoic acid), MeOH (methanol), MsCl (mesyl chloride), MTBE (Methyl tert-butyl ether), THF (tetrahydrofuran), TEA (triethylamine); HATU (hexafluorophosphate azabenzotriazole tetramethyl Uronium), HOBT (hydroxybenzotriazole), Red-Al (sodium bis(2-methoxyethoxy)aluminium hydride), DMF (dimethylformamide), DMP (Dess-Martin periodinane), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene ), NBS (N- 40 bromosuccinimide ), NCS (N-chlorosuccinimide ), TBAF (tetra-n-butylammonium fluoride), 49 Attorney Docket No.: 51728-013WO2 LiHMDS (Lithium bis(trimethylsilyl)amide ), HMPA (Hexamethylphosphoramide), AcOH (acetic acid), TMSOTf (trimethylsilyl trifluoromethanesulfonate), TBAB (tetrabutylammonium bromide), mCPBA(meta-chloroperoxybenzoic acid), DIBALH (diisobutylaluminium hydride), LAH (lithium aluminum hydride), LDA (lithium diisopropylamide), TBSCl (tert- 5 butyldimethylsilyl chloride), TFA (trifluoroacetic acid); and T4P (1,3,5,2,4,6- Trioxatriphosphorinane, 2,4,6-tributyl-, 2,4,6-trioxide). Absolute stereochemistry of all compounds by HPLC or SFC separation is ether based on literature or arbitrary assigned without further determination. 10 Scheme 1 General Synthesis of some compounds of formula (I) Scheme 1 illustrates general synthesis of some compounds of formula (I) according to some aspects and embodiments of the present disclosure. Method A is based on the nucleophilic reaction 15 of amine with OH (Mitsunobu reaction) or with MsO or Cl; Method B is based on reductive amination of amine with aldehyde (H) or ketone (alkyl). The warhead can be installed into amine part first, or installed at a late stage after amine reaction occurs based on Method A or B. Reactions may give different stereoisomers, which are either mixtures or separated by chromatography or HPLC (High-Performance Liquid Chromatography) or SFC (Supercritical Fluid 20 Chromatography). Stereochemistry assignment is either based on literatures or arbitrary assignment without further determination. Compounds of Formula (I) may be prepared by other routes, and several of these are described in synthetic examples. Example Int-1: Methyl 2-(bromomethyl)-5-formyl-3-(trifluoromethyl)benzoate Int-1 25 Step 1: Synthesis of methyl 5-bromo-2-methyl-3-(trifluoromethyl)benzoate Int-1-B 50 Attorney Docket No.: 51728-013WO2 To a solution of methyl 2-methyl-3-(trifluoromethyl)benzoate Int-1-A (10 g, 45.8 mmol, 1 eq) in HOAc (60 mL) was added HNO3(28.7 g, 319 mmol, 20.5 mL, 70% purity, 6.95 eq) and Br2(8.07 g, 50.5 mmol, 2.60 mL, 1.10 eq) followed by dropwise addition of the solution AgNO35 (2.50 M, 23.9 mL, 1.30 eq) in H2O (24 mL), the mixture was stirred at 20 °C for 16 hr. After completion, the mixture was poured on ice 100 mL, then diluted with 1N NaOH solution 1000 mL, the mixture was extracted with EA (500 mL x 3), the organic layer was washed with sat. NaHCO3(500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude. The crude was purified by flash silica gel chromatography 10 (PE:EA=20:1 to 10:1) to afford methyl 5-bromo-2-methyl-3-(trifluoromethyl)benzoate Int-1-B (11 g, 75.9% yield, 94% purity) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 3.86 (s, 3H), 2.51 (d, J = 1.4 Hz, 3H). Step 2: Synthesis of 3-methoxycarbonyl-4-methyl-5-(trifluoromethyl) benzoic acid Int-1-C 15 To a solution of methyl 5-bromo-2-methyl-3-(trifluoromethyl)benzoate Int-1-B (8.8 g, 29.6 mmol, 1 eq) oxalic acid (4.00 g, 44.4 mmol, 3.92 mL, 1.5 eq) in DMF (100 mL) was added DIEA (5.74 g, 44.4 mmol, 7.7 mL, 1.5 eq), Ac2O (4.54 g, 44.4 mmol, 4.2 mL, 1.5 eq), Pd(OAc)2(665 mg, 2.96 mmol, 0.1 eq) and xantphos (3.43 g, 5.92 mmol, 0.2 eq) under N2 atmosphere, and 20 the mixture was heated at 100 °C under N2 atmosphere for 16 hr. The reaction mixture was diluted with 0.5N HCl (1000 mL), and extracted with EA (250 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude. The crude was purified by prep-HPLC (column: Phenomenex luna c18250mm*100mm * 10um; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 35%-65% B over 20.0 min). to afford 3- 25 methoxycarbonyl-4-methyl-5-(trifluoromethyl)benzoic acid Int-1-C (5.7 g, 55.0% yield, 75% purity) as a yellow solid. MS (ESI) m / z 261.0 [M-H]+;1H NMR (400 MHz, DMSO-d6) δ 14.08 - 13.43 (m, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 3.89 (s, 3H), 2.61 (s, 3H). Step 3: Synthesis of 4-(bromomethyl)-3-methoxycarbonyl-5-(trifluoromethyl)benzoic acid Int-1-D 51 Attorney Docket No.: 51728-013WO2 To a solution of 3-methoxycarbonyl-4-methyl-5-(trifluoromethyl)benzoic acid Int-1-C (5.7 g, 21.7 mmol, 1 eq) in CHCl3(100 mL) were added NBS (11.6 g, 65.2 mmol, 3 eq) and AIBN (714 mg, 4.35 mmol, 0.2 eq), the mixture was stirred at 65 °C for 16 hr. The mixture was 5 concentrated under reduced pressure to give the crude. The crude was purified by flash silica gel chromatography (PE:EA = 1:1) to afford 4-(bromomethyl)-3-methoxycarbonyl-5-(trifluoromethyl) benzoic acid Int-1-D (6.1 g, 74.0% yield, 90% purity) as a light-yellow solid. MS (ESI) m / z 338.9, 340.9 [M-H]+;1H NMR (400 MHz, DMSO-d6) δ 14.29 - 13.37 (m, 1H), 8.56 (d, J = 1.2 Hz, 1H), 8.34 (s, 1H), 5.06 (s, 2H), 3.94 (s, 3H). 10 Step 4: Synthesis of methyl 2-(bromomethyl)-5-(hydroxymethyl)-3-(trifluoromethyl) benzoate To a solution of 4-(bromomethyl)-3-methoxycarbonyl-5-(trifluoromethyl) benzoic acid Int-1-D (6.1 g, 17.9 mmol, 1 eq) in THF (70 mL) in a 250 mL three -neck flask bottle was added 15 BH3·THF (1 M, 53.7 mL, 3 eq) dropwise at 0 °C under N2atmosphere, then the mixture was stirred between 0 to 20 °C for 2 hr. After completion, the mixture was quenched with MeOH (30 mL) dropwise between 0 to 20 °C, then concentrated under reduced pressure to give the crude. The crude was purified by flash silica gel chromatography (PE:EA = 10:1 to 5:1) to afford methyl 2-(bromomethyl)-5-(hydroxymethyl)-3-(trifluoromethyl)benzoate Int-1-E (4 g, 61.5% yield, 90% 20 purity) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.90 (s, 1H), 5.57 (br s, 1H), 5.03 (s, 2H), 4.63 (s, 2H), 3.92 (s, 3H). Step 5: Synthesis of methyl 2-(bromomethyl)-5-formyl-3-(trifluoromethyl) benzoate 25 To a solution of methyl 2-(bromomethyl)-5-(hydroxymethyl)-3-(trifluoromethyl)benzoate Int-1-E (4 g, 12.23 mmol, 1 eq) in DCM (60 mL) was added Dess-Martin (7.78 g, 18.3 mmol, 1.5 eq), and the mixture was stirred at 20 °C for 2 hr. TLC (SiO2, PE:EA=3:1) indicated the reaction was completed. The mixture was diluted with sat. Na2S2O3 / NaHCO3( 1:1, 150 mL), then extracted 52 Attorney Docket No.: 51728-013WO2 with DCM (50 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude. The crude was purified by flash silica gel chromatography (PE:EA = 10:1 to 5:1) to afford methyl 2-(bromomethyl)-5-formyl-3- (trifluoromethyl)benzoate Int-1 (3.6 g, 81.5% yield, 90% purity) as a colorless oil.1H NMR (400 5 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 5.11 - 5.05 (m, 2H), 3.98 - 3.94 (m, 3H). Example Int-2: 2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- (trifluoromethyl)isoindoline-5-carbaldehyde Int-2 Step 1: Synthesis of methyl 3-methyl-1-(3-nitrophenyl)cyclobutene carboxylate Int- 10 2-B To a solution of methyl 2-(3-nitrophenyl)acetate Int-2-A (15 g, 76.9 mmol, 1 eq) and 1,3- dibromo-2-methyl-propane (16.6 g, 76.9 mmol, 1 eq) in DMF (45 mL) was added Cs2CO3(125 g, 384 mmol, 5 eq), and the mixture was stirred at 20 °C for 16 hr. The mixture was diluted with H2O 15 (2000 mL), then extracted with EA (500 mL x 3). The organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude. The crude was purified by flash silica gel chromatography (PE:EA = 10:1 to 5:1) to afford methyl 3-methyl-1-(3-nitrophenyl)cyclobutanecarboxylate Int-2-B (12.5 g, 58.7% yield, 90% purity) as a colorless oil. MS (ESI) m / z 250.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.23 - 20 8.07 (m, 2H), 8.01 - 7.81 (m, 1H), 7.75 - 7.58 (m, 1H), 3.62 - 3.53 (m, 3H), 2.76 - 2.61 (m, 1H), 3.04 - 2.58 (m, 1H), 2.16 - 2.11 (m, 1H), 2.30 - 2.02 (m, 1H), 2.45 - 1.96 (m, 1H), 1.12 - 0.96 (m, 3H). Step 2: Synthesis of 3-methyl-1-(3-nitrophenyl)cyclobutanecarbohydrazide Int-2-C 25 To a solution of methyl 3-methyl-1-(3-nitrophenyl)cyclobutanecarboxylate Int-2-B (12.5 g, 50.2 mmol, 1 eq) in EtOH (125 mL) was added NH2NH2·H2O (15.1 g, 301 mmol, 14.6 mL, 6 eq), and the mixture was stirred at 80 °C for 48 hr. After completion, the mixture was concentrated to remove the solvent, then diluted with NH4Cl (100 mL) and extracted with EA (100 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated30 under reduced pressure to give the crude compound of 3-methyl-1-(3- nitrophenyl)cyclobutenecarbohydrazide Int-2-C (12 g, crude) as a light-yellow oil. MS (ESI) m / z 250.2 [M+H]+. Step 3: Synthesis of 1-methyl-3-[[3-methyl-1-(3-nitrophenyl)cyclobutene carbonyl] amino]thiourea Int-2-D 53 Attorney Docket No.: 51728-013WO2 To a solution of 3-methyl-1-(3-nitrophenyl)cyclobutanecarbohydrazide Int-2-C (12 g, 48.1 mmol, 1 eq) in THF (150 mL) was added methylimino(thioxo)methane (7.04 g, 96.3 mmol, 6.60 mL, 2 eq), and the mixture was stirred at 20 °C for 2 hr. The mixture was diluted with H2O 5 (100 mL), then extracted with EA (100 mL x 3). The organic was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound of 1-methyl-3-[[3-methyl-1-(3-nitrophenyl)cyclobutanecarbonyl]amino]thiourea Int-2-D (16 g, crude) as a light-yellow solid. MS (ESI) m / z 323.1 [M+H]+. Step 4: Synthesis of 4-methyl-5-[3-methyl-1-(3-nitrophenyl)cyclobutyl]-1,2,4- 10 triazole-3-thiol To a solution of 1-methyl-3-[[3-methyl-1-(3-nitrophenyl)cyclobutanecarbonyl] amino] thiourea Int-2-D (16 g, 49.6 mmol, 1 eq) in H2O (150 mL) was NaOH (19.9 g, 496 mmol, 10 eq), and the mixture was stirred at 20 °C for 16 hr. The mixture was quenched by aqueous HCl solution15 (1N, 500 mL) to PH = 5, then filtered. The solid was collected to give the crude compound of 4- methyl-5-[3-methyl-1-(3-nitrophenyl) cyclobutyl]-1,2,4-triazole-3-thiol Int-2-E (12 g, crude) as a light-yellow solid. MS (ESI) m / z 305.1 [M+H]+. Step 5: Synthesis of 4-methyl-3-[3-methyl-1-(3-nitrophenyl)cyclobutyl]-1,2,4-triazole Int-2-F 20 To a solution of 4-methyl-5-[3-methyl-1-(3-nitrophenyl)cyclobutyl]-1,2,4-triazole-3-thiol Int-2-E (12 g, 39.4 mmol, 1 eq) in DCM (120 mL) was added AcOH (4.74 g, 78.9 mmol, 4.5 mL, 2 eq), then H2O2(22.4 g, 197 mmol, 18.9 mL, 30% purity, 5 eq) was added dropwise at 0 °C, the mixture was stirred at between 0 and 20 °C for 1 hr. After completion, the mixture was diluted 25 with 10% NaHSO3and NaHCO3solution (1:1, 100 mL), then extracted with DCM (100 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude. The crude was purified by flash silica gel chromatography (PE:EA = 0:1). To afford 4-methyl-3-[3-methyl-1-(3-nitrophenyl)cyclobutyl]- 54 Attorney Docket No.: 51728-013WO2 1,2,4-triazole Int-2-F (9 g, 29.8 mmol, 75.5% yield, 90% purity) as a light-yellow oil. MS (ESI) m / z 273.1 [M+H]+. Step 6: Synthesis of 3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] aniline 5 To a solution of 4-methyl-3-[3-methyl-1-(3-nitrophenyl)cyclobutyl]-1,2,4-triazole Int-2- F (9 g, 33.1 mmol, 1 eq) in the mixture of EtOH (80 mL) and H2O (20 mL) was added NH4Cl (7.07 g, 132 mmol, 4 eq) at 20 °C followed by the slow addition of Fe (9.23 g, 165 mmol, 5 eq) at 70 °C. The mixture was stirred at 70 °C for 2 hr. The mixture was filtered and concentrated under 10 reduced pressure to give the crude which was purified by flash silica gel chromatography (EA:MeOH = 20:1) to afford diastereoisomers of 3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]aniline (7.6 g, 85.4% yield, 90% purity) as a light-yellow solid. The diastereoisomer mixture was purified by prep-SFC (column: ChiralPak IH, 250*50mm, 10um;mobile phase: [CO2- MeOH];B%:15%, isocratic elution mode) to afford pure isomer 3-[3-methyl-1-(4-methyl-1,2,4- 15 triazol-3-yl) cyclobutyl]aniline Int-2-G1 (3.4 g, 52.1% yield, 92% purity) as a light-yellow solid, and pure isomer 3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]aniline Int-2-G2 (2 g, 31.7% yield, 95% purity) as a light-yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.49 - 6.36 (m, 3H), 5.06 (s, 2H), 3.15 (s, 3H), 2.78 - 2.66 (m, 2H), 2.50 (s, 3H), 1.05 (d, J = 6.0 Hz, 3H). 20 Step 7: Synthesis of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 To a solution of methyl 2-(bromomethyl)-5-formyl-3-(trifluoromethyl)benzoate Int-1 (704 mg, 2.17 mmol, 1.05 eq) and 3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]aniline 25 Int-2-G1 (500 mg, 2.06 mmol, 1 eq) in the mixture of MeCN (15 mL) H2O (5 mL) was added AgNO3 (1.05 g, 6.19 mmol, 3 eq) dropwise at 0 °C. The mixture was stirred at 0 °C for 1hr, then at 60 °C for 15hr. After completion, the mixture was filtered and concentrated under reduced pressure to give the crude. The crude was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 3 um; mobile phase: [H2O(0.2% FA)-ACN]; gradient:20%-50% B over 8.0 min)30 to afford 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- (trifluoromethyl) isoindoline-5-carbaldehyde Int-2 (500 mg, 51.2% yield, 96% purity) as a yellow solid. MS (ESI) m / z 455.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.55 - 8.46 (m, 2H), 8.30 (s, 1H), 8.08 (s, 1H), 7.71 (m, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 5.34 (s, 2H), 3.22 (s, 3H), 2.94 - 2.82 (m, 2H), 2.63 - 2.53 (m, 3H), 1.13 - 1.05 (m, 3H). 55 Attorney Docket No.: 51728-013WO2 Example Int-3-OMs: [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3- oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl methanesulfonate Int-3-OMs Step 1: Synthesis of 6-(hydroxymethyl)-2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl] phenyl]-4-(trifluoromethyl)isoindolin-1-one Int-3 5 To a solution of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo- 7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (200 mg, 440 μmol, 1 eq) in MeOH (2 mL) was added NaBH4 (50 mg, 1.32 mmol, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr.10Upon completion, the reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) at 0 °C, then extracted with EA (30 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 6-(hydroxymethyl)-2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-4-(trifluoromethyl)isoindolin-1-one Int-3 (200 mg, crude) as a yellow oil. MS (ESI) m / z 457.3 [M+H]+. 15 Step 2: Synthesis of [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl methanesulfonate Int-3- OMs To a solution of 6-(hydroxymethyl)-2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) 20 cyclobutyl]phenyl]-4-(trifluoromethyl)isoindolin-1-one Int-3 (200 mg, 438 μmol, 1 eq) in DCM (3 mL)was added TEA (133 mg, 1.31 mmol, 183 μL, 3 eq) and MsCl (60 mg, 526 μmol, 40.7 μL, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr. Upon completion, the reaction mixture was quenched with water (30ml), then extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under25 reduced pressure to afford crude [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoro methyl)isoindolin-5-yl]methyl methanesulfonate Int-3- OMs (234 mg) as a yellow oil. MS (ESI) m / z 535.3 [M+H]+. Example Int-3-Cl: 6-(chloromethyl)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-4-(trifluoromethyl)isoindolin-1-one Int-3-Cl 56 Attorney Docket No.: 51728-013WO2 To a solution of 6-(hydroxymethyl)-2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-4-(trifluoromethyl)isoindolin-1-one Int-3 (0.5 g, 1.10 mmol, 1 eq) in CHCl3(5 mL) was added SOCl2(391 mg, 3.29 mmol, 239 μL, 3 eq), and the mixture was stirred at 60 °C 5 for 2 h. After the completion, the mixture was diluted with sat. NaHCO3aqueous solution (30 mL), then extracted with DCM (20 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under the reduced pressure to give the crude. The crude was purified by silica chromatography (DCM:MeOH = 20:1) to afford `6- (chloromethyl)-2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4- 10 (trifluoromethyl) isoindolin-1-one Int-3-Cl (480 mg, 90.9% yield, 98.5% purity) as a yellow solid. MS (ESI) m / z 475.2 [M+H]+. Example Int-4: 3-[1-(3-bromo-5-nitro-phenyl)-3-methyl-cyclobutyl]-4-methyl- 1,2,4-triazole Int-4 Step 1: Synthesis of 3-Bromo-5-nitro-benzoyl chloride Int-4-B 15 To a solution of 3-bromo-5-nitro-benzoic acid Int-4-A (20 g, 81.3 mmol, 1 eq) in SOCl2(328 g, 2.75 mol, 200 mL, 33.9 eq) at 0 °C was added DMF (297 mg, 4.06 mmol, 313 μL, 0.05 eq), then the mixture was stirred at 80 °C for 2 hr. TLC (SiO2, PE:EA = 0:1) indicated the reaction was completed. The mixture was cooled to 25 °C, then concentrated under reduced pressure to 20 give the crude 3-bromo-5-nitro-benzoyl chloride Int-4-B (22 g) as a light-yellow oil. Step 2: Synthesis of 2-(3-bromo-5-nitro-phenyl)-2-oxo-ethanediazonium Int-4-C To a solution of 3-bromo-5-nitro-benzoyl chloride Int-4-B (22 g, 83.2 mmol, 1 eq) in THF (200 mL) was added TEA (12.6 g, 125 mmol, 17.4 mL, 1.5 eq) followed by dropwise addition of 25 diazomethyl(trimethyl)silane (2 M, 62.4 mL, 1.5 eq) at 0°C. The mixture was stirred at between 0 and 20 °C for 16hr. TLC (SiO2, PE:EA = 3:1) indicated one new spot. The mixture was diluted with sat. aqueous NaHCO3 (300 mL), then extracted with EA (100 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced 57 Attorney Docket No.: 51728-013WO2 pressure to give the crude 2-(3-bromo-5-nitro-phenyl)-2-oxo-ethanediazonium Int-4-C (23 g) as a black brown solid. Step 3: Synthesis of methyl 2-(3-bromo-5-nitro-phenyl)acetate Int-4-D 5 To a solution of 2-(3-bromo-5-nitro-phenyl)-2-oxo-ethanediazonium Int-4-C (22 g, 81.2 mmol, 1 eq) in MeOH (220 mL) was added Ag2O (18.8 g, 81.2 mmol, 1 eq) at 60 °C, then the mixture was stirred at 60 °C for 16 hr and at 70 °C for 6 hr. The mixture was filtered and concentrated under reduced pressure to give the crude. The crude was purified by flash silica gel chromatography (PE:EA = 20:1 to 10:1) to afford methyl 2-(3-bromo-5-nitro-phenyl)acetate Int- 10 4-D (13.4 g, 46.5 mmol, 57.2% yield, 95% purity) as a light-yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 8.29 (t, J = 1.8 Hz, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 3.94 (s, 2H), 3.65 (s, 3H). Step 4: Synthesis of methyl 1-(3-bromo-5-nitro-phenyl)-3-methyl-cyclobutane carboxylate I 15 To a solution of methyl 2-(3-bromo-5-nitro-phenyl)acetate Int-4-D (13.4 g, 48.9 mmol, 1 eq) in DMF (200 mL) were added 1,3-dibromo-2-methyl-propane (10.56 g, 48.89 mmol, 1 eq) and Cs2CO3 (79.7 g, 245 mmol, 5 eq), and the mixture was stirred at 20 °C for 16 hr. The mixture was diluted with H2O (2 L), then extracted with EA (200 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 20 the crude. The crude was purified by flash silica gel chromatography (PE:EA = 20:1 to 5:1) to afford methyl 1-(3-bromo-5-nitro-phenyl)-3-methyl-cyclobutanecarboxylate Int-4-E (12.5 g, 36.2 mmol, 74.0% yield, 95% purity) as a light-yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.31 - 8.26 (m, 1H), 8.12 - 7.76 (m, 2H), 3.65 - 3.56 (m, 3H), 3.01 - 2.63 (m, 2H), 2.44 - 2.03 (m, 3H), 1.11 - 0.97 (m, 3H). 25 Step 5: Synthesis of 1-(3-bromo-5-nitro-phenyl)-3-methyl-cyclobutane carbohydrazide I 58 Attorney Docket No.: 51728-013WO2 To a solution of methyl 1-(3-bromo-5-nitro-phenyl)-3-methyl-cyclobutane carboxylate Int-4-E (12.5 g, 38.1 mmol, 1 eq) in EtOH (120 mL) was added NH2NH2·H2O (25 g, 499 mmol, 24.2 mL, 13.1 eq), and the mixture was stirred at 80 °C for 16 hr. After completion, the mixture was concentrated under reduced pressure to remove the solvent, then diluted with NH4Cl (100 5 mL), filtered and washed with H2O (30 mL x 3). The solid was collected and dried to give the crude 1-(3-bromo-5-nitro-phenyl)-3-methyl-cyclobutanecarbohydrazide Int-4-F (10 g) as a light- yellow solid. MS (ESI) m / z 328.0 and 330.0 [M+H]+. Step 6: Synthesis of 1-[[1-(3-bromo-5-nitro-phenyl)-3-methyl-cyclobutane carbonyl] amino]-3-methyl-thiourea Int-4-G 10 To a solution of 1-(3-bromo-5-nitro-phenyl)-3-methyl-cyclobutane carbohydrazide Int-4- F (10 g, 30.5 mmol, 1 eq) in THF (100 mL) was added methylimino(thioxo)methane (4.46 g, 61 mmol, 4.2 mL, 2 eq), and the mixture was stirred at 20 °C for 4 hr. The mixture was diluted with H2O (200 mL), filtered to give the crude portion 1. The filtrate was extracted with EA (100 mL x 15 3), washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude portion 2. Two crude portions were combined to give 1-[[1-(3-bromo- 5-nitro-phenyl)-3-methyl-cyclobutanecarbonyl]amino]-3-methyl-thiourea Int-4-G (13 g) as a light-yellow solid. MS (ESI) m / z 401.0 and 403.0 [M+H]+. Step 7: Synthesis of 5-[1-(3-bromo-5-nitro-phenyl)-3-methyl-cyclobutyl]-4-methyl- 20 1,2,4-triazole-3-thiol Int-4-H To a solution of 1-[[1-(3-bromo-5-nitro-phenyl)-3-methyl-cyclobutanecarbonyl] amino]- 3-methyl-thiourea Int-4-G (13 g, 32.4 mmol, 1 eq) in H2O (150 mL) was NaOH (13 g, 324 mmol, 10 eq), and the mixture was stirred at 20 °C for 16 hr. The mixture pH was adjusted to 5 with25 aqueous HCl (1N), then filtered and dried to give the crude 5-[1-(3-bromo-5-nitro-phenyl)-3- methyl-cyclobutyl]-4-methyl-1,2,4-triazole-3-thiol Int-4-H (13 g) as a light-yellow solid. MS (ESI) m / z 383.0 and 385.0 [M+H]+. Step 8: Synthesis of 3-[1-(3-bromo-5-nitro-phenyl)-3-methyl-cyclobutyl]-4-methyl- 1,2,4-triazole Int-4 and Int-4-isomer 59 Attorney Docket No.: 51728-013WO2 To a solution of 5-[1-(3-bromo-5-nitro-phenyl)-3-methyl-cyclobutyl]-4-methyl-1,2,4- triazole-3-thiol Int-4-H (13 g, 33.9 mmol, 1 eq) in DCM (130 mL) was added AcOH (4.07 g, 67.8 mmol, 3.9 mL, 2 eq), followed by dropwise addition of H2O2 (19.2 g, 170 mmol, 16.3 mL, 30% 5 purity, 5 eq) at 0 °C. The mixture was stirred between 0 and 20 °C for 1hr. After completion, the mixture was diluted with mixture of NaHSO3 and NaHCO3 solution (1:1, 10%, 100 mL), organic layer was separated and aqueous layer was extracted with DCM (30 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude. The crude was purified by flash silica gel10 chromatography (EA). 3-[1-(3-Bromo-5-nitro-phenyl)-3-methyl-cyclobutyl]-4-methyl-1,2,4- triazole Int-4-mix (7 g, 55.8% yield, 95% purity) was obtained as a light-yellow solid. 3-[1-(3- Bromo-5-nitro-phenyl)-3-methyl-cyclobutyl]-4-methyl-1,2,4-triazole Int-3-mix (6 g) was purified by SFC column: DAICEL CHIRALPAK AD(250mm * 30 mm, 10 um); mobile phase: [CO2- EtOH(0.1%NH3H2O)]; B%:27%, isocratic elution mode. 3-[1-(3-Bromo-5-nitro-phenyl)-3- 15 methyl-cyclobutyl]-4-methyl-1,2,4-triazole Int-4 (3.4 g, 56.7% yield, 100% purity) was obtained as a light-yellow solid;1H NMR (400 MHz, CDCl3) δ = 8.26 (br d, J = 10.8 Hz, 2H), 8.05 (s, 1H), 7.76 (s, 1H), 3.25 (s, 3H), 2.92 - 2.82 (m, 2H), 2.74 (br t, J = 10.4 Hz, 2H), 2.70 - 2.59 (m, 1H), 1.16 (d, J = 6.4 Hz, 3H). 3-[1-(3-Bromo-5-nitro-phenyl)-3-methyl-cyclobutyl]-4-methyl-1,2,4- triazole Int-4-isomer (1.2 g, 19.0% yield, 95% purity) was obtained as a white solid;1H NMR 20 (400 MHz, Methano-d4) δ 8.40 (s, 1H), 8.31 - 8.28 (m, 1H), 8.04 - 8.00 (m, 1H), 7.78 (s, 1H), 3.34 (s, 3H), 3.22 - 3.12 (m, 2H), 2.55 - 2.44 (m, 1H), 2.42 - 2.33 (m, 2H), 1.16 (d, J = 6.4 Hz, 3H). Example Int-5: 6-(1-chloroethyl)-2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-4-(trifluoromethyl)isoindolin-1-one 25 Step 1: Synthesis of 6-(1-hydroxyethyl)-2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-4-(trifluoromethyl)isoindolin-1-one Int-5-A To a solution of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl] -3-oxo- 7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (500 mg, 1.10 mmol, 1 eq) in THF (7 mL)30 was added bromo(methyl)magnesium (3 M, 734 μL, 2 eq) at -75 °C. The mixture was stirred at - 75 °C for 1 h. Upon completion, the reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) at 0 °C, then extracted with EA (15 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under the reduced pressure to give the residue. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 8:1) to give 6-(1-35 hydroxyethyl)-2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoro- 60 Attorney Docket No.: 51728-013WO2 methyl)isoindolin-1-one Int-5-A (360 mg, 66.8% yield, 96% purity) as a yellow solid. MS (ESI) m / z 471.1 [M+H]+. Step 2: Synthesis of 6-(1-chloroethyl)-2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-4-(trifluoromethyl)isoindolin-1-one Int-5 5 To a solution of 6-(1-hydroxyethyl)-2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-4-(trifluoromethyl)isoindolin-1-one Int-5-A (2 g, 4.25 mmol, 1 eq) in CHCl3 (20 mL) was added SOCl2 (1.52 g, 12.8 mmol, 926 μL, 3 eq), and the mixture was stirred at 60 °C for 1 h. After the completion, the mixture was concentrated under the reduecd pressure to give the10 crude 6-(1-chloroethyl)-2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4- (trifluoromethyl)isoindolin-1-one Int-5 (2.2 g, crude) as a light-yellow solid, which was used directly in the next step without further purification. MS (ESI) m / z 489.1 [M+H]+. Example Int-6: 3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl)methyl]aniline Int-6 Step 1: Synthesis of methyl 2-cyclobutyl-2-(3-nitrophenyl)acetate Int-6-A 15 Three parallel reactions were run. To a solution of Cs2CO3 (417 g, 1.28 mol, 5 eq) in DMF (400 mL) was added methyl 2-(3- nitrophenyl)acetate (50 g, 256.18 mmol, 1 eq) in DMF (100 mL) at 0 °C under N2, and the mixture was stirred at 0 °C for 2 h. Then bromocyclobutane (104 g, 769 mmol, 72.4 mL, 3 eq) was added 20 and stirred at 25 °C for 16 h. TLC (PE: EA=5:1) indicated completion of the reaction. The reaction mixture was diluted with EtOAc (500 mL), filtrated through celite pad, and the filter cake was washed with EtOAc (500 mL). The filtrate was quenched with H2O (1 L), then extracted with EA (500 mL x 3), washed with brine (100 mLx 3), dried over anhydrous Na2SO4, filtered and concentrated under the reduced pressure to give a crude product. The crude was purified by MPLC 25 (ISCO, PE:EA=1:0~25:1) to give methyl 2-cyclobutyl-2-(3-nitrophenyl)acetate Int-6-A (180 g, 89.3% yield, 95% purity) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ 8.17 (s, 1H), 8.13 (dd, J = 1.1, 8.2 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.54 - 7.46 (m, 1H), 3.70 - 3.65 (m, 4H), 3.09 - 2.93 (m, 1H), 2.30 - 2.15 (m, 1H), 1.95 - 1.78 (m, 4H), 1.64 - 1.55 (m, 1H). Step 2: Synthesis of 2-cyclobutyl-2-(3-nitrophenyl)acetohydrazide Int-6-B 61 Attorney Docket No.: 51728-013WO2 Three parallel reactions were run. To a solution of methyl 2-cyclobutyl-2-(3-nitrophenyl)acetate Int-6-A (65 g, 261 mmol, 1 eq) in EtOH (650 mL) in a 3-neck bottle (3L) was added N2H4·H2O (326 g, 6.52 mol, 316 mL, 5 100% purity, 25 eq). The mixture was stirred at 80 °C for 16 h. Upon completion, the reaction was diluted by water (1800 mL) at room temperature (temperature controlled < 30 °C). The aqueous layer was extracted with DCM (300 mL x 3), and washed with brine (400 mL x 4). The combined organic layers were concentrated under the reduced pressure to give 2-cyclobutyl-2-(3-nitrophenyl) acetohydrazide Int-6-B (200 g, crude) as a white solid. The crude was used directly without 10 purification. MS (ESI) m / z 250.2 [M+H]+;1H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (t, J = 1.8 Hz, 1H), 8.13 (td, J = 1.0, 8.2 Hz, 1H), 7.71 (d, J = 7.8Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 3.35 (d, J = 10.8 Hz, 1H), 3.14 - 3.00 (m, 1H), 2.31 - 2.16 (m, 1H), 1.98 - 1.73 (m, 4H), 1.65 - 1.44 (m, 1H). Step 3: Synthesis of 1-[[2-cyclobutyl-2-(3-nitrophenyl)acetyl]amino]-3-methyl- 15 thiourea Int-6-C To a solution of 2-cyclobutyl-2-(3-nitrophenyl)acetohydrazide Int-6-B (200 g, 802 mmol, 1 eq) in THF (2 L) was added methylimino(thioxo)methane (147 g, 2.01 mol, 137 mL, 2.5 eq). Then the mixture was stirred at 25 °C for 2 h under N2atmosphere. TLC (SiO2, PE / EA=1:1) and LCMS 20 showed the starting material was consumed completely. The resulting mixture was diluted with water (2 L) and filtered. The filter cake was washed with water (300 mL x 3), and dried under the reduced pressure to give 1-[[2-cyclobutyl-2-(3-nitrophenyl)acetyl]amino]-3-methyl-thiourea Int- 6-C (250 g, crude) as a white solid. MS (ESI) m / z 323.1[M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.98 (br s, 1H), 9.26 (s, 1H), 8.20 (t, J = 1.7 Hz, 1H), 8.14 - 8.08 (m, 1H), 7.77 (d,J = 7.9 Hz, 25 1H), 7.70 - 7.59 (m, 2H), 3.65 (br d, J = 10.5 Hz, 1H), 2.93 - 2.80 (m, 4H), 2.09 - 1.90 (m, 2H), 1.85 - 1.68(m, 4H), 1.64 - 1.50 (m, 1H). Step 4: Synthesis of 3-[cyclobutyl-(3-nitrophenyl)methyl]-4-methyl-1H-1,2,4-triazole- 5-thione Int-6-D 62 Attorney Docket No.: 51728-013WO2 Solid NaOH (300 g, 7.50 mol, 9.67 eq) was dissolved in H2O (8 L), then 1-[[2-cyclobutyl- 2-(3-nitrophenyl)acetyl]amino]-3-methyl-thiourea Int-6-C (250 g, 776 mmol, 1 eq) was added. The mixture was stirred at 20 °C for 16 h under N2 atmosphere. The reaction mixture was adjusted 5 to pH = 5 by HCl (2N) and filtered. The filter cake was collected and dried under the reduced pressure to give 3-[cyclobutyl-(3-nitrophenyl) methyl]-4-methyl-1H-1,2,4-triazole-5-thione Int- 6-D (183 g, 77.5% yield) as a white solid. MS (ESI) m / z 305.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 13.74 (s, 1H), 8.16 - 8.10 (m, 2H), 7.74 - 7.69 (m, 1H), 7.68 - 7.61 (m, 1H), 4.49 (d, J = 10.5 Hz, 1H), 3.23 (s, 3H), 3.07 - 2.87 (m, 1H), 2.15 - 2.05 (m, 1H), 1.89 - 1.73 (m, 4H), 1.71 10 - 1.58 (m, 1H). Step 5: Synthesis of 3-[cyclobutyl-(3-nitrophenyl)methyl]-4-methyl-1,2,4-triazole Int- 6-E Solution 1 (S1): 3-[cyclobutyl-(3-nitrophenyl)methyl]-4-methyl-1H-1,2,4-triazole-5-thione 15 Int-6-D (166 g, 545 mmol, 1 eq) in DCE (830 mL) and ACN (830 mL) . Solution 2 (S2): H2O2(186 g, 1.64 mol, 157 mL, 30% purity, 3 eq) in ACN (1850 mL). The solution 1 was pumped by Pump 1 (S1, P1, 27.494 mL / min) to flow reactor 1 (FLR1, GL, CSTRs, 100 mL, 60 °C) to flow reactor 2 (FLR2, GL, CSTRs, 100 mL, 60 °C ) to flow reactor 3 (FLR3, GL, CSTRs, 100 mL, 60 °C). The solution 2 was pumped by Pump 2 (S2, P2, 22.506 mL / min) to flow reactor 1 (FLR1, 20 GL, CSTRs, 100 mL, 60 °C) to flow reactor 2 (FLR2, GL,CSTRs, 100 mL, 60 °C) to flow reactor 3 (FLR3, GL, CSTRs, 100 mL, 60 °C). The residence time of flow reactor 1 was (FLR1, 2 min). The residence time of flow reactor 2 was (FLR2, 2.000 min). The residence time of flow reactor 3 was (FLR3, 2.000 min). The mixture was collected with a bottle (contained 1500 mL aqueous Na2SO3). The Pump 1 and Pump 2 started at the same time. The reaction mixture was collected 25 after running 6 mins, then extracted with DCM / MeOH (10:1) (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under the reduced pressure to give a residue. The residue was purified by silica chromatography (SiO2, DCM / MeOH =99 / 1 to 20 / 1) to give 3-[cyclobutyl-(3-nitrophenyl)methyl]-4-methyl-1,2,4- triazole Int-6-E (118 g, 79.5% yield) as a white solid. MS (ESI) m / z 273.1 [M+H]+;1H NMR (400 30 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.15 (d, J = 1.5 Hz, 1H), 8.13 - 8.07 (m, 1H), 7.76 (d, J = 7.6 Hz,1H), 7.65 - 7.57 (m, 1H), 4.47 (d, J = 10.6 Hz, 1H), 3.45 (s, 3H), 3.20 - 3.05 (m, 1H), 2.13 - 1.99 (m, 1H), 1.85 - 1.65(m, 5H). Step 6: Synthesis of 3-[(R)-cyclobutyl-(3-nitrophenyl)methyl]-4-methyl-1,2,4-triazole 63 Attorney Docket No.: 51728-013WO2 Int-6-E and 3-[(S)-cyclobutyl-(3-nitrophenyl)methyl]-4-methyl-1,2,4-triazole Int-6-E-isomer 3-[Cyclobutyl-(3-nitrophenyl)methyl]-4-methyl-1,2,4-triazole Int-6-E-rac (140g) was purified by SFC (column: DAICEL CHIRALPAK IC (250mm * 50mm, 10um); mobile phase: 5 [CO2-MeOH(0.1%NH3H2O)]; B%:50%, isocratic elution mode) give 3-[(R)-cyclobutyl-(3- nitrophenyl)methyl]-4-methyl-1,2,4-triazole Int-6-E (retention time by SFC: 2.721 min) (67 g, 47.9% yield) as yellow oil and 3-[(S)-cyclobutyl-(3-nitrophenyl)methyl]-4-methyl-1,2,4-triazole Int-6-E-isomer (retention time by SFC: 3.095 min) (65 g, 46.4% yield) as yellow oil. MS (ESI) m / z 273.1 [M+H]+. 10 Step 7: Synthesis of N-[[3-[6-[(2-ethynyl-1-piperidyl)methyl]-1-oxo-4- (trifluoromethyl)isoindolin-2-yl]-5-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]methyl]prop-2-enamide Int-6 Solution 1 (S1): 3-[(R)-cyclobutyl-(3-nitrophenyl)methyl]-4-methyl-1,2,4-triazole Int-6-E 15 (55.8 g, 205 mmol, 1 eq) } in MeOH (1116 mL). The fixed bed (named FLR1, volume 500 mL) was completely packed with granular catalyst Pd / Al2O3(40 g, 9.62 mmol, 5% purity, 4.69e-2 eq) (WXC1035). The H2 back pressure regulator was adjusted to 1.5 MPa, and the flow rate of H2 was 2 mL / min. Then the solution 1 (S1) was pumped by Pump 1 (S1, P1, 2.0 mL / min) to the fixed bed (FLR1, SS, fixed bed, 6.350(1 / 4) mm, 5 mL, 50 °C). Then the reaction solution was collected 20 from the reactor output. The whole process time was 16 h. Upon completion, the reaction mixture was concentrated under the reduced pressure. The crude product was triturated with MeOH: EA=10: 1 at 25 °C for 30 min to give 3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl)methyl] aniline Int-6 (43.7 g, 84.73% yield, 96.2% purity) as a white solid. MS (ESI) m / z 243.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 6.91 (t, J = 7.7 Hz, 1H), 6.37 ( t, J = 8.4 Hz, 2H), 25 6.32 (s, 1H), 5.00 (s, 2H), 3.91 (d, J = 10.5 Hz, 1H), 3.35 (s, 3H), 3.16 - 3.03 (m, 1H), 2.14 - 2.03 (m, 1H), 1.85 - 1.71 (m, 4H), 1.67 - 1.56 (m, 1H);1H NMR (400 MHz, DMSO+D2O-d6) δ 8.28 (s, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.42 - 6.35 (m, 2H), 6.34 (d, J = 1.8 Hz, 1H), 3.90 (d, J = 10.6 Hz, 1H), 3.34 (s, 3H), 3.15 - 3.02 (m, 1H), 2.12 - 2.01 (m, 1H), 1.83 - 1.68 (m, 4H), 1.64 - 1.52 (m, 1H). 30 Example Int-7: 2-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl)methyl]phenyl]-3- oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-7 Step 1: Synthesis of 2-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl)methyl] phenyl]- 6-(hydroxymethyl)-4-(trifluoromethyl)isoindolin-1-one Int-7-A 64 Attorney Docket No.: 51728-013WO2 To a solution of 3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl)methyl]aniline Int-6 (85.0 mg, 351 μmol, 1 eq) and methyl 2-(bromomethyl)-5-(hydroxymethyl)-3-(trifluoromethyl) benzoate Int-1-E (126 mg, 386 μmol, 1.1 eq) in MeOH (4 mL) was added TEA (71 mg, 702 μmol, 5 97.7 μL, 2 eq). The mixture was stirred at 60 °C for 16 h. The mixture was concentrated under the reduced pressure to give the crude. The crude was diluted with DCM (200 mL), then washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under the reduced pressure to give the crude. The crude was purified by prep-TLC (SiO2, DCM:MeOH = 10:1) to give 2-[3- [(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl)methyl]phenyl]-6-(hydroxymethyl)-4- 10 (trifluoromethyl)isoindolin-1-one Int-7-A (130 mg, 77.1% yield, 95% purity) as a yellow solid. MS (ESI) m / z 457.1 [M+H]+. Step 2: Synthesis of 2-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl) methyl]phenyl]- 3-oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-7 15 To a solution of 2-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl)methyl]phenyl] -6- (hydroxymethyl)-4-(trifluoromethyl)isoindolin-1-one Int-7-A (130 mg, 285 μmol, 1 eq) in DCM (5 mL) was added MnO2(248 mg, 2.85 mmol, 10 eq), and the mixture was stirredd at 35 °C for 72 h. The mixture was filtered and concentrated under the reduced pressure to give the residue. The residue was diluted with EtOAc (100 mL) and filtered again to remove the remaining MnO2. 20 The solution was concentrated under the reduecd pressure to give 2-[3-[(R)-cyclobutyl-(4-methyl- 1,2,4-triazol-3-yl)methyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-7 (60 mg, crude) as a light-yellow solid. MS (ESI) m / z 455.2 [M+H]+. Example Int-7-Cl: 6-(chloromethyl)-2-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3- yl)methyl]phenyl]-4-(trifluoromethyl)isoindolin-1-one Int-7-Cl 25 Step 1: Synthesis of 6-(chloromethyl)-2-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3- yl)methyl]phenyl]-4-(trifluoromethyl)isoindolin-1-one Int-7-Cl 65 Attorney Docket No.: 51728-013WO2 To a solution of 2-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl)methyl] phenyl]-6- (hydroxymethyl)-4-(trifluoromethyl)isoindolin-1-one Int-7-A (0.2 g, 438 μmol, 1 eq) in CHCl3(3 mL) was added SOCl2(156 mg, 1.31 mmol, 95.5 μL, 3 eq). The mixture was stirred at 60 °C for 5 1 h. Upon completion, the reaction was concentrated under the reduced pressure to give 6- (chloromethyl)-2-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl)methyl]phenyl]-4- (trifluoromethyl)isoindolin-1-one Int-7-Cl (260 mg, crude) as a yellow solid. MS (ESI) m / z 475.1 [M+H]+. Example Int-7-Me-Cl : 6-(1-chloroethyl)-2-(3-((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3- 10 yl)methyl)phenyl)-4-(trifluoromethyl)isoindolin-1-one Step 1: Synthesis of 2-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl) methyl]phenyl]- 6-(1-hydroxyethyl)-4-(trifluoromethyl)isoindolin-1-one Int-7-Me-OH To a solution of 2-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl)methyl] phenyl]-3-oxo-7- 15 (trifluoromethyl)isoindoline-5-carbaldehyde Int-7 (0.4 g, 880 μmol, 1 eq) in THF (8 mL) was added MeMgBr (3 M, 880 μL, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL) at 0 °C, then extracted with EA (5 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under the reduced pressure to give a 20 residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1) to give 2-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl)methyl]phenyl]-6-(1-hydroxyethyl)-4- (trifluoromethyl)isoindolin-1-one Int-7-Me-OH (303 mg, 53.4% yield, 73% purity) as a yellow solid. MS (ESI) m / z 471.1 [M+H]+. Step 2: Synthesis of 6-(1-chloroethyl)-2-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3- 25 yl)methyl]phenyl]-4-(trifluoromethyl)isoindolin-1-one Int-7-Me-Cl 66 Attorney Docket No.: 51728-013WO2 To a solution of 2-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl) methyl] phenyl]-6-(1- hydroxyethyl)-4-(trifluoromethyl)isoindolin-1-one Int-7-Me-OH (303 mg, 644 μmol, 1 eq) in CHCl3(6 mL) was added SOCl2(230 mg, 1.93 mmol, 140 μL, 3 eq). The mixture was stirred at 5 60 °C for 1 h. Upon completion, the reaction mixture was concentrated under the reduced pressure to give 6-(1-chloroethyl)-2-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl)methyl]phenyl]-4- (trifluoromethyl) isoindolin-1-one Int-7-Me-Cl (320 mg, crude) as a yellow solid. MS (ESI) m / z 489.2 [M+H]+. Example 1: N-[2-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]- 10 3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino]ethyl]prop-2-enamide 1 Step 1: Synthesis of tert-butyl N-[2-(prop-2-enoylamino)ethyl]carbamate B-1-2 To a solution of tert-butyl N-(2-aminoethyl)carbamate B-1-1 (200 mg, 1.25 mmol, 197 μL, 1 eq) in DCM (4 mL) was added TEA (253 mg, 2.50 mmol, 348 μL, 2 eq), then prop-2-enoyl 15 chloride (124 mg, 1.37 mmol, 112 μL, 1.1 eq) in DCM (0.5 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5h. The reaction was quenched by H2O (0.02 mL), then concentrated under reduced pressure to give the crude which was purified by flash silica gel chromatography (PE:EA = 1:1) to afford tert-butyl N-[2-(prop-2-enoylamino)ethyl]carbamate B- 1-2 (200 mg, 74.8% yield, 100% purity) as a colorless oil. MS (ESI) m / z 237.1 [M+Na]+. 20 Step 2: Synthesis of N-(2-aminoethyl)prop-2-enamide trifluoroacetate B-1 To a solution of tert-butyl N-[2-(prop-2-enoylamino)ethyl]carbamate B-1-2 (200 mg, 933 μmol, 1 eq) in DCM (3 mL) was added TFA (1 mL), and the mixture was stirred at 20 °C for 0.5hr. The mixture was concentrated under reduced pressure to give crude compound of N-(2- 25 aminoethyl)prop-2-enamide trifluoroacetate B-1 (230 mg) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ 8.37 - 8.22 (m, 1H), 7.91 - 7.61 (m, 3H), 6.27 - 6.16 (m, 1H), 6.15 - 6.06 (m, 1H), 5.64 (dd, J = 2.4, 9.8 Hz, 1H), 3.36 (q, J = 6.2 Hz, 2H), 2.95 - 2.81 (m, 2H). Step3: Synthesis of N-[2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino] ethyl]prop-2-enamide 1 67 Attorney Docket No.: 51728-013WO2 To a solution of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo- 7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (50 mg, 110 μmol, 1 eq) and N-(2- aminoethyl) prop-2-enamide trifluoroacetate B-1(75 mg, 330 μmol, 3 eq) in DCM (3 mL) were 5 added TEA (33 mg, 330μmol, 46 μL, 3 eq) and NaBH(OAc)3(35 mg, 165 μmol, 1.5 eq). The mixture was stirred at 20°C for 16 hr. The mixture was concentrated under reduced pressure to give the crude. The crude was purified by prep-HPLC (column: 3_Phenomenex Luna C1875 * 30 mm * 3 um; mobile phase: [H2O(0.1% TFA)-ACN];gradient:10%-40% B over 8.0 min) to afford N-[2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- 10 (trifluoromethyl)isoindolin-5-yl] methylamino]ethyl]prop-2-enamide 1 (30.7 mg, 41.3% yield, 98.6% purity, TFA salt) as a white solid. MS (ESI) m / z 553.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.09 (br d, 2H), 8.70 (s, 1H), 8.40 (t, J = 5.6 Hz, 1H), 8.28 - 8.23 (m, 1H), 8.21 - 8.15 (m, 1H), 8.01 (s, 1H), 7.78 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.27 - 6.08 (m, 2H), 5.66 (m, 1H), 5.28 (s, 2H), 4.44 (br s, 2H), 3.47 (q, J = 6.0 Hz, 2H), 3.30 (s, 3H), 3.09 15 (br s, 2H), 2.96 - 2.84 (m, 2H), 2.65 - 2.52 (m, 3H), 1.10 (d, J = 5.6 Hz, 3H). Example 2: N-[(3S)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3- oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]prop-2-enamide 2 Step 1: Synthesis of tert-Butyl (3S)-3-(prop-2-enoylamino)piperidine-1-carboxylate B-2-2 20 To a solution of tert-butyl (3S)-3-aminopiperidine-1-carboxylate B-2-1 (200 mg, 999 μmol, 1 eq) in DCM (2 mL) was added TEA (202 mg, 2.00 mmol, 278 μL, 2 eq) and prop-2-enoyl chloride (91 mg, 999 μmol, 81 μL, 1 eq). The mixture was stirred at 25 °C for 0.5 hr. Upon completion, the reaction mixture was quenched with water (0.1 mL) and concentrated under 25 reduced pressure to give the residue. The residue was purified by prep-TLC (SiO2, EA) to afford tert-butyl (3S)-3-(prop-2-enoylamino) piperidine-1-carboxylate B-2-2(210 mg, 78.6% yield, 95% purity) as a yellow oil. MS (ESI) m / z 255.2 [M+H]+. Step 2: Synthesis of N-[(3S)-3-Piperidyl]prop-2-enamide trifluoroacetate B-2 30 To a solution of tert-butyl (3S)-3-(prop-2-enoylamino)piperidine-1-carboxylate B-2-2 (200 68 Attorney Docket No.: 51728-013WO2 mg, 786 μmol, 1 eq) in DCM (2 mL) was added TFA (768 mg, 6.73 mmol, 0.5 mL, 8.6 eq). The mixture was stirred at 25 °C for 0.5 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude N-[(3S)-3-piperidyl]prop-2-enamide trifluoroacetate B-2 (210 mg) as a light-yellow solid. MS(ESI) m / z 155.3 [M+H]+. 5 Step 3: Synthesis of N-[(3S)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]prop-2- enamide 2 To a solution of N-[(3S)-3-piperidyl]prop-2-enamide trifluoroacetate B-2 (94mg, 352 μmol,10 2 eq) and 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoro- methyl)isoindoline-5-carbaldehyde Int-2 (80 mg, 176 μmol, 1 eq) in DCM (1.5 mL) were added NaBH(OAc)3(75 mg, 352 μmol, 2 eq) and TEA (36 mg, 352 μmol, 49 μL, 2 eq). The mixture was stirred at 25 °C for 2 hr. The reaction was quenched with water (0.1 mL) and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex 15 Luna C1875 * 30 mm * 3um; mobile phase: [H2O (0.1% TFA) - ACN]; gradient: 10% - 40% B over 8.0 min) to afford N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl] prop-2- enamide 2 (30.3 mg, 29.1% yield, 100% purity) as a white solid. MS (ESI)m / z 593.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.21 (d, J = 18.0 Hz, 2H), 8.00 (s, 1H), 7.76 - 7.69 20 (m, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 6.28 - 6.01 (m, 2H), 5.74 - 5.55 (m, 1H), 5.26 (s, 2H), 4.56 (s, 2H), 4.02 (br s, 1H), 3.43 - 3.28 (m, 5H), 2.97 - 2.84 (m, 3H), 2.72 (br t, J = 10.6 Hz, 1H), 2.61 - 2.53 (m, 3H), 2.00 - 1.81 (m, 2H), 1.74 - 1.35 (m, 2H), 1.08 (br d, J = 5.4 Hz, 3H). Example 3: N-Methyl-N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-25 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]prop-2- enamide 3 Step 1: Synthesis of tert-butyl (3S)-3-[methyl(prop-2-enoyl)amino] piperidine-1- carboxylate B-3-2 30 To a solution of tert-butyl (3S)-3-(methylamino)piperidine-1-carboxylate B-3-1 (200 mg, 933 μmol, 1 eq) in DCM (2 mL) were added TEA (189 mg, 1.87 mmol, 260 μL, 2 eq) and prop- 2-enoyl chloride (85 mg, 933 μmol, 76 μL, 1 eq). The mixture was stirred at 25 °C for 0.5 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, EA). Compound tert-butyl (3S)-3-[methyl(prop-2- 69 Attorney Docket No.: 51728-013WO2 enoyl)amino]piperidine-1-carboxylate B-3-2 (200 mg, 75.9% yield, 95% purity) was obtained as a yellow oil MS (ESI) m / z 213.1 [M+H-tBu]+. Step 2: Synthesis of N-methyl-N-[(3S)-3-piperidyl]prop-2-enamide trifluoroacetate B-3 5 To a solution of tert-butyl (3S)-3-[methyl(prop-2-enoyl)amino]piperidine-1-carboxylate B-3-2 (190 mg, 708 μmol, 1 eq) in DCM (2 mL) was added TFA (768 mg, 6.73 mmol, 0.5 mL, 8.6 eq). The mixture was stirred at 25 °C for 0.5 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-methyl-N-[(3S)-3-piperidyl]prop-2-enamide 10 trifluoroacetate B-3 (200 mg, crude, TFA salt) as a light-yellow solid MS (ESI)m / z 169.3 [M+H]+. Step3: Synthesis of N-methyl-N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]prop-2- enamide 3 15 To a solution of N-methyl-N-[(3S)-3-piperidyl]prop-2-enamide trifluoroacetate B-3 (99 mg, 352 μmol, 2 eq) and 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3- oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (80 mg, 176 μmol, 1 eq) in DCM (1.5 mL) were added NaBH(OAc)3 (75 mg, 352 μmol, 2 eq), and TEA (36 mg, 352 μmol, 49 μL, 2 eq). The mixture was stirred at 25 °C for 2 hr. The reaction was quenched with water (0.1 mL) and 20 concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex Luna C1875 * 30 mm * 3um; mobile phase: [H2O (0.1% TFA) - ACN]; gradient: 10% - 40% B over 8.0 min) to afford N-methyl-N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4- triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3- piperidyl]prop-2-enamide 3 (45.1 mg, 42.3% yield, 100% purity) as a white solid. MS (ESI) m / z 25 607.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.22 (br d, J = 19.8 Hz, 2H), 8.00 (s, 1H), 7.73 (br d, J = 8.3 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.72 (br dd, J = 10.4, 16.7 Hz, 1H), 6.12 (br d, J = 16.6 Hz, 1H), 5.73 (br d, J = 12.0 Hz, 1H), 5.26 (s, 2H), 4.75 - 4.63 (m, 1H), 4.55 (br s, 2H), 3.36 (br d, J = 11.0 Hz, 1H), 3.30 (s, 3H), 3.21 - 3.16 (m, 1H), 3.01 - 2.85 (m, 6H), 2.78 (br s, 1H), 2.60 - 2.54 (m, 3H), 1.97 (br d, J = 12.4 Hz, 1H), 1.83 - 1.64 30 (m, 3H), 1.09 (d, J = 5.4 Hz, 3H). Example 4: N-[3-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo- 7-(trifluoromethyl)isoindolin-5-yl]methylamino]propyl]prop-2-enamide 4 Step 1: Synthesis of tert-butyl N-[3-(prop-2-enoylamino)propyl]carbamate B-4-2 70 Attorney Docket No.: 51728-013WO2 To a solution of tert-butyl N-(3-aminopropyl)carbamate B-4-1 (200 mg, 1.15 mmol, 200 μL, 1 eq) in DCM (4 mL) was added TEA (232 mg, 2.30 mmol, 320 μL, 2 eq) followed by dropwise addition of prop-2-enoyl chloride (114 mg, 1.26 mmol, 103 μL, 1.1 eq) in DCM (0.5 5 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5hr. The reaction was quenched by H2O (0.02 mL), then concentrated under reduced pressure to give the crude. The crude was purified by flash silica gel chromatography (PE:EA = 1:1) to afford tert-butyl N-[3-(prop-2-enoylamino)propyl] carbamate B-4-2 (200 mg, 76.3% yield, 100% purity) as a colorless oil. MS (ESI) m / z 251.1 [M+Na]+. 10 Step 2: Synthesis of N-(3-aminopropyl)prop-2-enamide trifluoroacetate B-4 To a solution of tert-butyl N-[3-(prop-2-enoylamino)propyl]carbamate B-4-2 (200 mg, 876 μmol, 1 eq) in DCM (3 mL) was added TFA (1 mL) , and the mixture was stirred at 20 °C for 0.5 hr. The reaction was concentrated under reduced pressure to afford crude N-(3- 15 aminopropyl)prop-2-enamide trifluoroacetate B-4 (230 mg) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ 8.40 - 8.16 (m, 1H), 7.87 - 7.46 (m, 3H), 6.28 (s, 1H), 6.14 - 6.00 (m, 1H), 5.61 (m, 1H), 3.20 (m, 2H), 2.90 - 2.70 (m, 2H), 1.83 - 1.55 (m, 2H). Step 3: Synthesis of N-[3-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino] propyl]prop- 20 2-enamide 4 To a solution of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo- 7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (50 mg, 110 μmol, 1 eq) and N-(3- aminopropyl)prop-2-enamide trifluoroacetate B-4 (80 mg, 330 μmol, 3 eq) in DCM (3 mL) was 25 added TEA (23 mg, 220 μmol, 31 μL, 2 eq) and NaBH(OAc)3(35 mg, 165 μmol, 1.5 eq). The mixture was stirred at 20 °C for 16 hr. The mixture was added water (0.1 mL) and concentrated under reduced pressure to give the crude. The crude was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75 * 30mm * 3um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient:5%-35% B over 8.0 min) to afford N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-30 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino]propyl] prop-2- enamide 4 (33 mg, 52.6% yield, 99.4% purity) as a white solid. MS (ESI) m / z 567.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.01 (br s, 2H), 8.80 - 8.61 (m, 1H), 8.31 (br s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.78 (br d, J = 8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.23 (br d, J = 7.6 Hz, 1H), 6.29 - 6.02 (m, 2H), 5.61 (m, 1H), 5.28 (s, 2H), 4.41 (br t, J = 5.2 Hz, 2H), 3.30 (m, 3H), 35 3.23 (q, J = 6.8 Hz, 2H), 3.06 - 2.95 (m, 2H), 2.94 - 2.84 (m, 2H), 2.65 - 2.53 (m, 3H), 1.82 (m, 71 Attorney Docket No.: 51728-013WO2 2H), 1.10 (d, J = 5.6 Hz, 3H). Example 5: N-[3-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo- 7-(trifluoromethyl)isoindolin-5-yl]methylamino]propyl]-N-prop-2-ynyl-prop-2-enamide 5 Step 1: Synthesis of tert-Butyl N-[3-(prop-2-ynylamino)propyl]carbamate B-5-2 5 To a solution of tert-butyl N-(3-aminopropyl)carbamate B-5-1(1 g, 5.74 mmol, 1.00 mL, 1 eq) in MeCN (20 mL) were added K2CO3(1.59 g, 11.5 mmol, 2 eq) and 3-bromoprop-1-yne (853 mg, 5.74 mmol, 618 μL, 1 eq). The mixture was stirred at 60 °C for 16 hr. The mixture was filtered and concentrated to give the crude which was purified by flash silica gel chromatography (EA) to 10 afford tert-butyl N-[3-(prop-2-ynylamino)propyl]carbamate B-5-2 (1.3 g, 53.4% yield, 100% purity) as a light-yellow oil.1H NMR (400 MHz, DMSO-d6) δ 6.88 - 6.65 (m, 1H), 3.26 (d, J = 2.0 Hz, 2H), 3.01 (t, J = 2.4 Hz, 1H), 2.93 (q, J = 6.8 Hz, 2H), 2.52 (br s, 1H), 2.49 - 2.47 (m, 1H), 1.48 (m, 2H), 1.37 (s, 9H). Step 2: Synthesis of tert-Butyl N-[3-[prop-2-enoyl(prop-2-ynyl)amino] propyl] 15 carbamate To a solution of tert-butyl N-[3-(prop-2-ynylamino)propyl]carbamate B-5-2 (1.3 g, 4.29 mmol, 1 eq) in DCM (15 mL) was added TEA (868 mg, 8.57 mmol, 1.2 mL, 2 eq) followed by dropwise addition of prop-2-enoyl chloride (388 mg, 4.29 mmol, 348 μL, 1 eq) in DCM (5 mL) 20 at 0 °C. The mixture was stirred at 0 °C for 0.5hr. TLC (SiO2, DCM:MeOH = 10:1) indicated the reaction was completed. The reaction was diluted with H2O (30 mL), then extracted with DCM (20 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude. The crude was purified by flash silica gel chromatography (PE:EA = 10:1 to 5:1) to afford tert-butyl N-[3-[prop-2-enoyl(prop-2- 25 ynyl)amino]propyl]carbamate B-5-3 (540 mg, 47.3% yield, 100% purity) as a light-yellow oil. MS (ESI) m / z 289.1 [M+Na]+. Step 3: Synthesis of N-(3-Aminopropyl)-N-prop-2-ynyl-prop-2-enamide trifluoroacetate B-5 30 To a solution of tert-butyl N-[3-[prop-2-enoyl(prop-2-ynyl)amino]propyl] carbamate B-5- 3 (200 mg, 751 μmol, 1 eq) in DCM (3 mL) was added TFA (1 mL), then the mixture was stirred at 20 °C for 0.5hr. The mixture was concentrated under reduced pressure to give N-(3- aminopropyl)-N-prop-2-ynyl-prop-2-enamide trifluoroacetate B-5 (210 mg, crude) as a light- yellow oil. MS (ESI) m / z 167.1 [M+H]+. 72 Attorney Docket No.: 51728-013WO2 Step 4: Synthesis of N-[3-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl] phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino]propyl] -N-prop-2-ynyl- prop-2-enamide 5 5 To a solution of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo- 7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (50 mg, 110 μmol, 1 eq) and N-(3- aminopropyl)-N-prop-2-ynyl-prop-2-enamide trifluoroacetate B-5 (93 mg, 330 μmol, 3 eq) in DCM (3 mL) was added TEA (34 mg, 330 μmol, 46 μL, 3 eq). The mixture was stirred at 20 °C for 2 hr, then NaBH(OAc)3(117 mg, 550 μmol, 5 eq) was added. The resulting solution continued 10 to stir for 1hr at 20 °C. The mixture was diluted with sat. NaHCO3(20 ml), then extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude. The crude was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [H2O (10mM NH4HCO3)- ACN]; gradient: 35%-55% B over 8.0 min). N-[3-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-15 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl] methylamino]propyl]-N-prop-2- ynyl-prop-2-enamide 5 (27 mg, 39% yield, 96% purity) was obtained as a white solid. MS (ESI)m / z 605.3 [M+H]+;1H NMR (400 MHz, METHANOL-d4) δ 8.30 (s, 1H), 8.08 (s, 2H), 7.99 (s, 1H), 7.69 (m, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.24 (br d, J = 8.0 Hz, 1H), 6.78 (m, 1H), 6.27 (m, 1H), 5.77 (m, 1H), 5.15 (s, 2H), 4.26 (d, J = 2.4 Hz, 2H), 3.95 (d, J = 10.0 Hz, 2H), 3.70 - 3.53 20 (m, 2H), 3.33 (s, 3H), 3.03 - 2.91 (m, 2H), 2.75 - 2.53 (m, 6H), 1.89 (m, 2H), 1.16 (d, J = 6.0 Hz, 3H). Example 6 and 7: N-[(3S)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-5- prop-2-ynoxy-phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]prop-2- enamide 6 and N-methyl-N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-25 yl)cyclobutyl]-5-prop-2-ynoxy-phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3- piperidyl]prop-2-enamide 7 Step 1: Synthesis of 3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-5-nitro- phenol 30 To a solution of 3-[1-(3-bromo-5-nitro-phenyl)-3-methyl-cyclobutyl]-4-methyl-1,2,4- triazole Int-4 (1.00 g, 2.85 mmol, 1 eq) in dioxane (10 mL) were added KOH (639 mg, 11.4 mmol, 4 eq) in H2O (5 mL), Pd2(dba)3(261 mg, 285 μmol, 0.1 eq) and t-Bu Xphos (121 mg, 285 μmol, 0.1 eq) under N2atmosphere, and the mixture was stirred at 100 °C for 2 hr. The mixture cooled down to room temperature, was filtered and concentrated under reduced pressure to give the crude. 73 Attorney Docket No.: 51728-013WO2 The crude was purified by prep-HPLC (column: Waters Xbridge BEH C 18250 * 50 mm * 10 um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:20%-50% B over 10.0 min. 3-[3- Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-5-nitro-phenol B-6-1(650 mg, 75.2% yield, 95% purity) was obtained as a light brown solid.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.36 5 (m, 2H), 7.05 (s, 1H), 3.17 (s, 3H), 2.84 - 2.66 (m, 2H), 2.44 (br s, 1H), 1.05 (d, J = 5.2 Hz, 3H). Step 2: Synthesis of 4-methyl-3-[3-methyl-1-(3-nitro-5-prop-2-ynoxy-phenyl) cyclobutyl]-1,2,4-triazole B-6-2 To a solution of 3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-5-nitro-phenol B- 10 6-1 (600 mg, 2.08 mmol, 1 eq) in MeCN (10 mL) were added Cs2CO3 (1.36 g, 4.16 mmol, 2 eq) and 3-bromoprop-1-yne (928 mg, 6.24 mmol, 673μL, 3 eq), and the mixture was stirred at 20 °C for 16 hr. The mixture was filtered and concentrated under reduced pressure to give the crude. The crude was purified by flash silica chromatography (EA) to afford 4-methyl-3-[3-methyl-1-(3-nitro -5-prop-2-ynoxy-phenyl)cyclobutyl]-1,2,4-triazole B-6-2 (500 mg, 70% yield, 95% purity) as a 15 light-yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 7.42 (s, 1H), 4.99 (d, J = 2.0 Hz, 2H), 3.70 - 3.63 (m, 1H), 3.19 (s, 3H), 2.93 - 2.79 (m, 2H), 2.62 - 2.51 (m, 3H), 1.07 (br d, J = 5.2 Hz, 3H). Step 3: Synthesis of 3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-5-prop-2- ynoxy-aniline 20 To a solution of 4-methyl-3-[3-methyl-1-(3-nitro-5-prop-2-ynoxy-phenyl) cyclobutyl]- 1,2,4-triazole B-6-2 (500 mg, 1.53 mmol, 1 eq) in EtOH (5 mL) and H2O (1 mL) was added NH4Cl (327.81 mg, 6.13 mmol, 4 eq) at 20 °C, followed by slow addition of Fe (427.84 mg, 7.66 mmol, 5 eq) at 70 °C. The mixture was stirred at 70 °C for 2 hr. The mixture cooled down, was filtered 25 and concentrated under reduced pressure to give the crude. The crude was purified by prep-TLC (SiO2, DCM:MeOH = 10:1) to afford 3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-5- prop-2-ynoxy-aniline B-6-3 (340 mg, 71.1% yield, 95% purity) as a light-yellow solid. MS (ESI) m / z 297.1 [M+H]+. Step 4: Synthesis of 2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl) 30 cyclobutyl]-5-prop-2-ynoxy-phenyl]-3-oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde B-6-4 74 Attorney Docket No.: 51728-013WO2 To a solution of methyl 2-(bromomethyl)-5-formyl-3-(trifluoromethyl)benzoate Int-1 (208 mg, 641μmol, 1 eq) and 3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]-5-prop-2- ynoxy-aniline B-6-3 (190 mg, 641 μmol, 1 eq) in MeCN (3 mL) and H2O (1 mL) was added 5 AgNO3(163 mg, 962 μmol, 1.5 eq) at 0°C, and the mixture was stirred at 0 °C for 1hr, then at 20 °C for 16 hr. Upon completion, the mixture filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, DCM:MeOH = 10:1) to afford 2-[3-[3- Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-5-prop-2-ynoxy-phenyl]-3-oxo-7- (trifluoromethyl)isoindoline-5-carbaldehyde B-6-4 (80 mg, 20.9% yield, 85% purity) as a yellow10solid. MS (ESI) m / z 509.2 [M+H]+. Step 5A: Synthesis of N-[rac-(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]-5-prop-2-ynoxy-phenyl]-3-oxo-7-(trifluoromethyl) isoindolin-5-yl]methyl]-3- piperidyl]prop-2-enamide 6 15 To a solution of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-5-prop-2- ynoxy-phenyl]-3-oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde B-6-4 (50 mg, 98 μmol, 1 eq) and N-[(3S)-3-piperidyl]prop-2-enamide trifluoroacetate B-2 (53 mg, 197 μmol, 2 eq) in EtOH (3 mL) was added TEA (19.9 mg, 197 μmol, 27.4 μL, 2 eq) so that pH value was between 7 and 8, followed by Ti(i-PrO)4 (56 mg, 197 μmol, 58 μL, 2 eq). The mixture was stirred at 20 °C for 1520h, then NaBH3CN (12.4 mg, 197 μmol, 2 eq) was added, and the mixture was stirred at 20 °C for 1 hr. The mixture was diluted with sat. aqueous NaHCO3(30 mL), then extracted with EA (20 mL x 3). The organic layer washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude. The crude was purified by prep-HPLC (column: Phenomenex Luna C18 80 * 30 mm * 3 um; mobile phase: [H2O (0.1%TFA)-ACN]; gradient:25 15%-45% B over 8.0 min). N-[(3S)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]-5-prop-2-ynoxy-phenyl]-3-oxo-7-(trifluoro methyl)isoindolin-5-yl]methyl]-3- piperidyl]prop-2-enamide 6 (16 mg, 24.9% yield, 98.9% purity, TFA salt) was obtained as a white solid. MS (ESI)m / z 647.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.99 - 9.76 (m, 1H), 8.52 (s, 1H), 8.39 - 8.29 (m, 1H), 8.22 (br d, J = 15.0 Hz, 2H), 7.57 (s, 1H), 7.43 (s, 1H), 6.85 (s, 1H), 30 6.30 - 6.00 (m, 2H), 5.72 - 5.58 (m, 1H), 5.26 (s, 2H), 4.86 (d, J = 2.0 Hz, 2H), 4.69 - 4.49 (m, 2H), 4.09 - 3.99 (m, 1H), 3.59 (br d, J = 2.2 Hz, 2H), 3.48 - 3.40 (m, 2H), 3.35 (br d, J = 11.0 Hz, 2H), 3.28 (s, 3H), 2.89 (br d, J = 3.0 Hz, 3H), 2.76 - 2.64 (m, 1H), 2.56 (br d, J = 6.4 Hz, 3H), 75 Attorney Docket No.: 51728-013WO2 1.91 (br t, J = 16.6 Hz, 2H), 1.75 - 1.56 (m, 1H), 1.50 - 1.35 (m, 1H), 1.09 (br d, J = 5.0 Hz, 3H); 1H NMR (400 MHz, DMSO+D2O-d6) δ 8.66 (s, 1H), 8.18 (d, J = 15.6 Hz, 2H), 7.55 (s, 1H), 7.41 (s, 1H), 6.82 (s, 1H), 6.22 - 6.00 (m, 2H), 5.70 - 5.59 (m, 1H), 5.23 (s, 2H), 4.83 (d, J = 2.2 Hz, 2H), 4.53 (s, 2H), 4.00 (br s, 1H), 3.46 (t, J = 2.2 Hz, 1H), 3.41 - 3.24 (m, 5H), 2.88 (br d, J = 3.2 5 Hz, 3H), 2.78 - 2.67 (m, 1H), 2.53 (br d, J = 6.6 Hz, 3H), 1.98 - 1.80 (m, 2H), 1.75 - 1.60 (m, 1H), 1.52 - 1.36 (m, 1H), 1.07 (br d, J = 5.0 Hz, 3H). Step 5B: Synthesis of N-methyl-N-[(3S)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol- 3-yl) cyclobutyl]-5-prop-2-ynoxy-phenyl]-3-oxo-7-(trifluoromethyl) isoindolin-5-yl]methyl]- 3-piperidyl]prop-2-enamide 7 10 To a solution of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-5-prop-2- ynoxy-phenyl]-3-oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde B-6-4 (50 mg, 98 μmol, 1 eq) and N-methyl-N-[(3S)-3-piperidyl]prop-2-enamide trifluoroacetate (56mg, 197 μmol, 2 eq) in EtOH (3 mL) was added TEA (19.9 mg, 197 μmol, 27.4 μL, 2 eq) so that pH value was between 15 7 and 8, then Ti(i-PrO)4 (55.9 mg, 197 μmol, 58 μL, 2 eq) was added. The mixture was stirred at 20 °C for 2 h, then NaBH3CN (62 mg, 983 μmol, 10 eq) was added, and the mixture was stirred at 20 °C for additional 1 hr. The mixture was diluted with sat. aqueous NaHCO3 (30 mL), then extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude. The crude was 20 purified by prep-HPLC (column: Phenomenex Luna C 1880 * 30 mm * 3 um; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 15%-45% B over 8.0 min). N-Methyl-N-[(3S)-1-[[2-[3-[3-methyl-1- (4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-5-prop-2-ynoxy-phenyl]-3-oxo-7- (trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]prop-2-enamide 7 (24 mg, 30.2% yield, 95.8% purity, TFA salt) was obtained as a white solid. MS (ESI)m / z 661.3 [M+H]+;1H NMR (400 MHz, 25 DMSO-d6) δ 10.03 - 9.84 (m, 1H), 8.61 (s, 1H), 8.23 (br d, J = 14.4 Hz, 2H), 7.57 (s, 1H), 7.44 (s, 1H), 6.85 (s, 1H), 6.78 - 6.59 (m, 1H), 6.17 - 6.04 (m, 1H), 5.76 - 5.65 (m, 1H), 5.26 (s, 2H), 4.87 (d, J = 2.4 Hz, 2H), 4.83 - 4.81 (m, 1H), 4.69 (br d, J = 8.6 Hz, 1H), 4.55 (br s, 2H), 3.59 (t, J = 2.4 Hz, 1H), 3.37 (br d, J = 11.8 Hz, 1H), 3.30 (s, 3H), 3.26 - 3.09 (m, 2H), 2.99 - 2.83 (m, 5H), 2.78 (br s, 1H), 2.62 - 2.53 (m, 3H), 2.01 - 1.92 (m, 1H), 1.85 - 1.62 (m, 3H), 1.09 (br d, J = 5.4 30 Hz, 3H). Example 8: N-[3-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo- 7-(trifluoromethyl)isoindolin-5-yl]methylamino]propyl]but-2-ynamide 8 Step 1: Synthesis of tert-Butyl N-[3-(but-2-ynoylamino)propyl]carbamate B-8-1 35 To a solution of but-2-ynoic acid (100 mg, 1.19 mmol, 1 eq) in DCM (2 mL) were added 76 Attorney Docket No.: 51728-013WO2 DIEA (307 mg, 2.38 mmol, 415 μL, 2 eq), tert-butyl N-(3-aminopropyl)carbamate B-4-1 (228 mg, 1.31 mmol, 228 μL, 1.1 eq) and HATU (678 mg, 1.78 mmol, 1.5 eq). The mixture was stirred at 25 ℃ for 1 hr. Upon completion, the reaction mixture was quenched by addition H2O (4 mL) at 0 ℃, then extracted with DCM (5 mL x 3). The combined organic layer was dried over anhydrous 5 Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, PE / EA = 1 / 1) to give tert-butyl N-[3-(but-2-ynoylamino) propyl]carbamate B-8- 1 (190 mg, 66.5% yield) as a colorless oil. MS (ESI)m / z 263.1 [M+Na]+. Step 2: Synthesis of N-(3-aminopropyl)but-2-ynamide hydrochloride B-8-2 10 To a solution of tert-butyl N-[3-(but-2-ynoylamino)propyl]carbamate B-8-1 (170 mg, 707 μmol, 1 eq) was added HCl dioxane (4 M in dioxane, 177 μL, 1 eq). The mixture was stirred at 25 ℃ for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude N-(3-aminopropyl)but-2-ynamide hydrochloride B-8-2 (124 mg) as a white solid. MS (ESI)m / z 141.1 [M+H]+. 15 Step 3: Synthesis of N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino] propyl]but-2- ynamide To a solution of N-(3-aminopropyl)but-2-ynamide hydrochloride B-8-2 (58 mg, 330 μmol,20 3 eq) and 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoro- methyl)isoindoline-5-carbaldehyde Int-2 (50 mg, 110 μmol, 1 eq) in EtOH (2 mL) were added TEA (11 mg, 110 μmol, 15.3 μL, 1 eq) and Ti(i-PrO)4(125 mg, 440 μmol, 130 μL, 4 eq). The mixture was stirred at 25 ℃ for 15 h, then NaBH3CN (69 mg, 1.10 mmol, 10 eq) was added. The mixture was stirred at 25 ℃ for additional 1 h. Upon completion, the reaction mixture was 25 quenched by addition of H2O (5 mL), and then extracted with EA (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*3 um; mobile phase: [H2O(0.1%TFA)-ACN];gradient:5%-35% B over 8.0 min) to give N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoro- 30 methyl)isoindolin-5-yl]methylamino] propyl]but-2-ynamide 8 (33 mg, 42.7% yield, 98.7% purity, TFA salt) as a white solid. MS (ESI) m / z 579.4 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.86 (br d, J = 2.6 Hz, 2H), 8.62 (br t, J = 5.7 Hz, 1H), 8.56 (s, 1H), 8.26 - 8.13 (m, 2H), 8.00 (s, 1H), 7.81 - 7.70 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 5.28 (s, 2H), 4.40 (br t, J = 5.6 Hz, 2H), 3.27 (s, 3H), 3.15 (q, J = 6.6 Hz, 2H), 3.02 - 2.93 (m, 2H), 2.92 - 2.85 (m, 2H), 2.63 35 - 2.53 (m, 3H), 1.96 (s, 3H), 1.77 (q, J = 7.3 Hz, 2H), 1.10 (d, J = 5.4 Hz, 3H). Example 9: N-[(3S)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3- oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]-N-prop-2-ynyl-prop-2-enamide 77 Attorney Docket No.: 51728-013WO2 9 Step 1: Synthesis of tert-butyl (3S)-3-(prop-2-ynylamino)piperidine-1-carboxylate B- 9-1 5 To a solution of tert-butyl (3S)-3-aminopiperidine-1-carboxylate B-2-1 (500 mg, 2.50 mmol, 1 eq) in ACN (5 mL) were added K2CO3 (1.04 g, 7.49 mmol, 3 eq) and 3-bromoprop-1- yne (297 mg, 2.00 mmol, 215 μL, 0.8 eq). The mixture was stirred at 25 ℃ for 16 hr. Upon completion, the reaction mixture was quenched by adding H2O (50 mL), then extracted with DCM (25 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and 10 concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, PE: EA = 1:1) to give tert-butyl (3S)-3-(prop-2-ynylamino)piperidine-1-carboxylate B-9-1 (145 mg, 24.4% yield) as a colorless oil. MS (ESI) m / z 239.0 [M+H]+. Step 2: Synthesis of tert-butyl (3S)-3-[prop-2-enoyl(prop-2-ynyl)amino] piperidine-1- carboxylate B-9-2 15 To a solution of tert-butyl (3S)-3-(prop-2-ynylamino)piperidine-1-carboxylate B-9-1 (135 mg, 567 μmol, 1 eq) in DCM (3 mL) were added TEA (172 mg, 1.70 mmol, 237 μL, 3 eq) and prop-2-enoyl chloride (56 mg, 623 μmol, 50.6 μL, 1.1 eq) in DCM (0.5 mL) at 0 ℃. The mixture stirred at 25 ℃ for 0.5 hr. Upon completion, the reaction mixture was quenched by adding H2O 20 (10 mL), then extracted with DCM (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, PE: EA = 2:1) to give tert-butyl (3S)-3-[prop-2-enoyl(prop-2- ynyl)amino] piperidine-1-carboxylate B-9-2 (115 mg, 64.68% yield, 93% purity) as a white solid. MS (ESI) m / z 293.0 [M+H]+. 25 Step 3: Synthesis of N-[(3S)-3-piperidyl]-N-prop-2-ynyl-prop-2-enamide trifluoroacetate B-9-3 To a solution of tert-butyl (3S)-3-[prop-2-enoyl(prop-2-ynyl)amino]piperidine-1- carboxylate B-9-2 (100 mg, 342 μmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol, 30 1 mL, 39.4 eq). The mixture was stirred at 25 ℃ for 0.5 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude N-[(3S)-3-piperidyl]-N-prop-2-ynyl-prop- 2-enamide trifluoroacetate B-9-3 (65 mg) as a colorless oil. MS (ESI) m / z 193.1 [M+H]+. Step 4: Synthesis of N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- 78 Attorney Docket No.: 51728-013WO2 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]-N- prop-2-ynyl-prop-2-enamide To a solution of N-[(3S)-3-piperidyl]-N-prop-2-ynyl-prop-2-enamide trifluoroacetate B-9- 5 3 (64 mg, 330 μmol, 3 eq) and 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]- 3-oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (50 mg, 110 μmol, 1 eq) in EtOH (2 mL) was added TEA (11 mg, 110 μmol, 15.3 μL, 1 eq) and Ti(i-PrO)4(125 mg, 440 μmol, 130 μL, 4 eq). The mixture was stirred at 25 ℃ for 15 hr, then NaBH3CN (69 mg, 1.10 mmol, 10 eq) was added. The mixture was stirred at 25 ℃ for additional 1 hr. Upon completion, the reaction mixture 10 was quenched by adding H2O (5 mL), then extracted with EA (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*3 um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:10%-40% B over 8.0 min) to afford N-[(3S)- 1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl) 15 isoindolin-5-yl]methyl]-3-piperidyl]-N-prop-2-ynyl-prop-2-enamide 9 (27 mg, 37.7% yield, 96.8% purity) as a white solid. MS (ESI) m / z 631.5 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.07 - 9.85 (m, 1H), 8.59 (s, 1H), 8.22 (br d, J = 18.4 Hz, 2H), 7.99 (s, 1H), 7.74 (br d, J = 8.5 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.23 (br d, J = 7.7 Hz, 1H), 6.74 (br dd, J = 10.4, 16.5 Hz, 1H), 6.29 - 6.11 (m, 1H), 5.81 (br d, J = 10.1 Hz, 1H), 5.28 (s, 2H), 4.75 - 4.53 (m, 3H), 4.30 - 4.19 (m, 2H), 20 3.43 - 3.16 (m, 6H), 2.98 - 2.81 (m, 3H), 2.64 - 2.53 (m, 3H), 2.01 - 1.69 (m, 4H), 1.10 (br d, J = 5.4 Hz, 3H). Example 10: (E)-4-(methyl(prop-2-yn-1-yl)amino)-N-((S)-1-((2-(3-((1s,3R)-3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5- yl)methyl)piperidin-3-yl)but-2-enamide 10 25 Step 1: Synthesis of tert-butyl (S,E)-3-(4-(methyl(prop-2-yn-1-yl)amino) but-2- enamido) piperidine-1-carboxylate B-10-2 To a solution of (E)-4-[methyl(prop-2-ynyl)amino]but-2-enoic acid B-10-1 (200 mg, 836 μmol, 1 eq) and tert-butyl (3S)-3-aminopiperidine-1-carboxylate B-2-1 (184 mg, 919 μmol, 1.1 30 eq) in the mixture of DCM (2 mL) and DMF (1 mL) were added DIEA (324 mg, 2.51 mmol, 437 μL, 3 eq) and HATU (635 mg, 1.67 mmol, 2 eq). The mixture was stirred at 20 °C for 1 hr. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with DCM (3mL x 3). The combined organic layers were concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, EA) to give tert-butyl (3S)-3-[[(E)-4-[methyl(prop-2- 35 ynyl)amino]but-2-enoyl] amino]piperidine-1-carboxylate B-10-2 (351 mg , 92.3% yield, 73.7% 79 Attorney Docket No.: 51728-013WO2 purity) as a yellow oil. MS (ESI) m / z 336.0 [M+H]+. Step 2: Synthesis of (S,E)-4-(methyl(prop-2-yn-1-yl)amino)-N-(piperidin-3-yl)but-2- enamide hydrochloride B-10-3 5 The solution of tert-Butyl (3S)-3-[[(E)-4-[methyl(prop-2-ynyl)amino]but-2-enoyl]amino] piperidine-1-carboxylate B-10-2 (100 mg, 298 μmol, 1 eq) in HCl solution (4 M in dioxane, 1 mL, 13.4 eq) was stirred at 20 °C for 1 hr under N2 atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude (E)-4-[methyl(prop-2-ynyl)amino]-N- [(3S)-3-piperidyl]but-2-enamide hydrochloride B-10-3 (81 mg, 100% yield) as a yellow oil.10 Step 3: Synthesis of (E)-4-(Methyl(prop-2-yn-1-yl)amino)-N-((S)-1-((2-(3-((1s,3R)-3- methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl) isoindolin-5-yl)methyl)piperidin-3-yl)but-2-enamide 10 To a solution of (E)-4-[methyl(prop-2-ynyl)amino]-N-[(3S)-3-piperidyl]but-2-enamide15 hydrochloride B-10-3 (79 mg, 292 μmol, 2.65 eq) and 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol- 3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (50 mg, 110 μmol, 1 eq) in EtOH (3 mL) were added TEA (11 mg, 110 μmol, 15.3 μL, 1 eq) and Ti(i-PrO)4(125 mg, 440 μmol, 130 μL, 4 eq). The mixture was stirred at 20 °C for 16 hr, then NaBH3CN (138 mg, 2.20 mmol, 20 eq) was added at 20 °C. The resulting mixture was stirred at 50 °C for 2 20 hr. Upon completion, the reaction mixture was quenched by adding water (10 mL) at 20°C, then extracted with DCM (5 mL x 3). The combined organic layers were filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um; mobile phase: [H2O(0.1%TFA)-ACN];gradient:10%-40% B over 8.0 min) to afford (E)-N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-25 oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]-4-[methyl(prop-2-ynyl)amino]but- 2-enamide 10 (54.8 mg, 72.7% yield, 98.4% purity) as a white solid. MS (ESI) m / z 674.5 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 10.17 - 9.70 (m, 1H), 8.56 - 8.33 (m, 2H), 8.22 (br d, J = 16.2 Hz, 2H), 8.00 (s, 1H), 7.72 (br d, J = 8.2 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.23 (br d, J = 7.6 Hz, 1H), 6.66 - 6.50 (m, 1H), 6.22 (br d, J = 15.6 Hz, 1H), 5.28 (s, 2H), 4.60 (br s, 3H), 4.02 (br s, 30 3H), 3.86 (br s, 3H), 3.51 - 3.29 (m, 2H), 3.25 (s, 3H), 2.96 - 2.83 (m, 3H), 2.73 (s, 3H), 2.57 (br d, J = 7.2 Hz, 3H), 2.02 - 1.82 (m, 2H), 1.76 - 1.60 (m, 1H), 1.51 - 1.33 (m, 1H), 1.09 (br d, J = 5.0 Hz, 3H). Example 11: N-[(3S)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3- oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]but-2-ynamide 11 35 Step 1: Synthesis of tert-butyl (3S)-3-(but-2-ynoylamino)piperidine-1-carboxylate B- 11-1 80 Attorney Docket No.: 51728-013WO2 To a solution of tert-butyl (3S)-3-aminopiperidine-1-carboxylate B-2-1 (200 mg, 999 μmol, 1 eq) in DCM (5 mL) was added DIEA (774 mg, 5.99 mmol, 1.04 mL, 6 eq), but-2-ynoic acid (101 mg, 1.20 mmol, 1.2 eq) and T4P (2.16 g, 3.00 mmol, 50% purity, 3 eq). The mixture was 5 stirred at 20 °C for 2 hr. Upon completion, the reaction mixture was quenched by addition H2O (10 mL), then extracted with EA (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, PE: EA = 0:1). tert-Butyl (3S)-3-(but-2-ynoylamino) piperidine-1-carboxylate B-11-1 (240 mg, 81.2% yield, 90% purity) was obtained as a yellow oil. 10 MS (ESI) m / z 211.0 [(M+H)-Boc]+. Step 2: Synthesis of N-[(3S)-3-piperidyl]but-2-ynamide hydrochloride B-11-2 To a solution of tert-butyl (3S)-3-(but-2-ynoylamino)piperidine-1-carboxylate B-11-1 (240 mg, 901 μmol, 1 eq) in HCl / dioxane (4 M, 4.3 mL, 19.0 eq). The mixture was stirred at 20 °C 15 for 0.5 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude N-[(3S)-3-piperidyl]but-2-ynamide hydrochloride B-11-2 (190 mg) was obtained as a white solid. MS (ESI) m / z 167.3 [M+H]+. Step 3: Synthesis of N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]but-2- 20 ynamide 11 To a solution of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo- 7-(trifluoromethyl)isoindoline-5-carbaldehyde (50 mg, 110 μmol, 1 eq) Int-2 in DCM (2 mL) were added Ti(i-PrO)4(78 mg, 275 μmol, 81 μL, 2.5 eq), N-[(3S)-3-piperidyl]but-2-ynamide 25 hydrochloride B-11-2 (67 mg, 330 μmol, 3 eq), NaBH3CN (69 mg, 1.10 mmol, 10 eq) and TEA (28mg, 275 μmol, 38 μL, 2.5 eq). The mixture was stirred at 20 °C for 2 hr. Upon completion, the reaction mixture was quenched with water (0.1 mL) and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: 3_Phenomenex Luna C1875 * 30 mm * 3 um; mobile phase: [H2O (0.1% TFA) - ACN]; gradient: 15%-45% B over 8.0 min). N-[(3S)-1-[[2-[3-[3-methyl- 81 Attorney Docket No.: 51728-013WO2 1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl) isoindolin-5- yl]methyl]-3-piperidyl]but-2-ynamide 11 (27.9 mg, 41.6% yield, 99.3% purity, TFA salt) was obtained as a white solid. MS (ESI) m / z 605.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.06 - 9.76 (m, 1H), 8.78 (br d, J = 7.2 Hz, 1H), 8.62 (br s, 1H), 8.21 (br d, J = 18.4 Hz, 2H), 8.01 (s, 5 1H), 7.74 (br d, J = 7.8 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.23 (br d, J = 7.8 Hz, 1H), 5.28 (br s, 2H), 4.67 - 4.51 (m, 2H), 3.96 (br s, 1H), 3.46 - 3.25 (m, 5H), 2.89 (br s, 3H), 2.77 - 2.63 (m, 1H), 2.62 - 2.54 (m, 3H), 1.96 (s, 3H), 1.93 - 1.78 (m, 2H), 1.71 - 1.32 (m, 2H), 1.10 (br d, J = 4.4 Hz, 3H). Example 12: (E)-4-(Methyl(prop-2-yn-1-yl)amino)-N-(2-(((2-(3-((1s,3s)-3-methyl-1-(4- 10 methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5 yl)methyl) amino) ethyl)but-2-enamide 12 Step 1: Synthesis of methyl (E)-4-(methyl(prop-2-yn-1-yl)amino)but-2-enoate B-12-2 To a solution of N-methylprop-2-yn-1-amine B-12-1 (425 mg, 6.14 mmol, 512 μL, 1.1 eq) 15 in THF (17 mL) were added methyl (E)-4-bromobut-2-enoate (1 g, 5.59 mmol, 657 μL, 1 eq) and K2CO3 (2.32 g, 16.8 mmol, 3 eq). The mixture was stirred at 20 °C for 16 hr. Upon completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash silica20 gel chromatography (PE / EA = 10 / 1 to 0 / 1) to give methyl (E)-4-[methyl(prop-2-ynyl)amino]but- 2-enoate B-12-2 (814 mg, 82.8% yield, 95% purity) as a yellow oil. Step 2: Synthesis of (E)-4-(methyl(prop-2-yn-1-yl)amino)but-2-enoic acid B-12-3 To a solution of methyl (E)-4-[methyl(prop-2-ynyl)amino]but-2-enoate B-12-2 (764 mg, 25 4.57 mmol, 1 eq) in H2O (7.5 mL) and THF (30 mL) was added LiOH·H2O (575 mg, 13.7 mmol, 3 eq). The mixture was stirred at 50 °C for 2 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give (E)-4-[methyl(prop-2-ynyl)amino]but-2-enoic acid B-12-3 (1.1 g, crude) as a light-yellow solid. MS (ESI)m / z 154.1 [M+H]+. Step 3: Synthesis of tert-butyl (E)-(2-(4-(methyl(prop-2-yn-1-yl)amino)but-2- 30 enamido To a solution of (E)-4-[methyl(prop-2-ynyl)amino]but-2-enoic acid B-12-3 (200 mg, 836 μmol, 1 eq) and tert-butyl N-(2-aminoethyl)carbamate (147 mg, 919 μmol, 145 μL, 1.1 eq) in DCM (2 mL) and DMF (1 mL) were added DIEA (324 mg, 2.51 mmol, 437 μL, 3 eq) and HATU 35 (635 mg, 1.67 mmol, 2 eq). The mixture was stirred at 20 °C for 1 hr. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with DCM (3mL x 3). The combined 82 Attorney Docket No.: 51728-013WO2 organic layers were concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, EA) to give tert-butyl N-[2-[[(E)-4-[methyl(prop-2-ynyl)amino]but-2- enoyl]amino] ethyl] carbamate B-12-4 (163.5 mg, 55.6% yield, 84% purity) as a yellow oil. MS (ESI) m / z 296.0 [M+H]+. 5 Step 2: Synthesis of (E)-N-(2-aminoethyl)-4-(methyl(prop-2-yn-1-yl)amino) but-2- enamide hydrochloride B-12-5 tert-Butyl N-[2-[[(E)-4-[methyl(prop-2-ynyl)amino]but-2-enoyl]amino]ethyl] carbamate B-12-4 (100 mg, 339 μmol, 1 eq) in HCl / dioxane (4 M, 2 mL, 23.6 eq) was stirred at 20 °C for 110hr under N2 atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude (E)-N-(2-aminoethyl)-4-[methyl(prop-2-ynyl)amino]but-2-enamide hydrochloride B-12-5 (79 mg) as a yellow oil. Step 3: Synthesis of (E)-4-(methyl(prop-2-yn-1-yl)amino)-N-(2-(((2-(3-((1s,3s)-3- methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl) 15 isoindolin-5-yl) methyl)amino)ethyl)but-2-enamide 12 To a solution of (E)-N-(2-aminoethyl)-4-[methyl(prop-2-ynyl)amino]but-2-enamide hydrochloride B-12-5 (77 mg, 330 μmol, 3 eq) and 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl] phenyl]-3-oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (50 mg, 110 20 μmol, 1 eq) in EtOH (3 mL) were added TEA (11 mg, 110 μmol, 15.3 μL, 1 eq) and Ti(i-PrO)4 (125 mg, 440 μmol, 130 μL, 4 eq). The mixture was stirred at 20 °C for 16 hr, then NaBH3CN (138 mg, 2.20 mmol, 20 eq) was added at 20 °C, the mixture was stirred at 50 °C for additional 2 hr. Upon completion, the reaction mixture was quenched with water (10 mL) at 20°C, then extracted with DCM (5mL x 3). The combined organic layers were dried over anhydrous Na2SO4,25 filtered and concentrated under reduced pressure. The residue obtained was purified by prep- HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN]; gradient:10%-40% B over 8.0 min) to afford (E)-N-[2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol- 3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoro methyl)isoindolin-5-yl]methylamino]ethyl]-4- [methyl(prop-2-ynyl)amino]but-2-enamide 12 (42 mg, 50.3% yield, 98.5% purity, TFA salt) as a30white solid. MS (ESI)m / z 634.5 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.13 (br s, 2H), 8.66 - 8.47 (m, 2H), 8.24 (s, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.81 - 7.71 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.68 - 6.52 (m, 1H), 6.26 (d, J = 15.4 Hz, 1H), 5.28 (s, 2H), 4.44 (br s, 2H), 4.05 (br s, 2H), 3.92 - 3.86 (m, 2H), 3.56 - 3.42 (m, 2H), 3.27 (s, 3H), 3.09 (br s, 2H), 2.96 - 2.81 (m, 3H), 2.75 (s, 3H), 2.63 - 2.52 (m, 3H), 1.10 (d, J = 5.6 Hz, 3H). 35 Example 13: N-[2-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo- 7-(trifluoromethyl)isoindolin-5-yl]methylamino]ethyl]but-2-ynamide 13 Step 1: Synthesis of tert-butyl N-[2-(but-2-ynoylamino)ethyl]carbamate B-13-1 83 Attorney Docket No.: 51728-013WO2 To a solution of but-2-ynoic acid (100 mg, 1.19 mmol, 1 eq) in DCM (1 mL) were added DIEA (307 mg, 2.38 mmol, 414 μL, 2 eq), tert-butyl N-(2-aminoethyl)carbamate B-1-1 (210 mg, 1.31 mmol, 206 μL, 1.1 eq) and then HATU (678.39 mg, 1.78 mmol, 1.5 eq). The mixture was 5 stirred at 25 ℃ for 1 hr. Upon completion, the reaction mixture was quenched with H2O (4 mL) at 0 ℃, then extracted with DCM 15 mL (5mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, PE / EA = 1 / 1) to give tert-butyl N-[2-(but-2-ynoyl amino)ethyl] carbamate B-13-1(140 mg, 52.0% yield) as a white solid. MS (ESI) m / z 259.2 [M+H]+. 10 Step 2: Synthesis of N-(2-aminoethyl)but-2-ynamide hydrochloride B-13-2 The solution of tert-butyl N-[2-(but-2-ynoylamino)ethyl]carbamate B-13-1 (120 mg, 530 μmol, 1 eq) in HCl / dioxane (4 M, 1.3 mL, 10 eq) was stirred at 25 ℃ for 1 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude N-(2-aminoethyl)but- 15 2-ynamide hydrochloride B-13-2 (86 mg) as a white solid. MS (ESI) m / z 127.1 [M+H]+. Step 3: Synthesis of N-[2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino] ethyl]but-2-ynamide 13 To a solution of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo-20 7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (50 mg, 110 μmol, 1 eq) and N-(2- aminoethyl)but-2-ynamide hydrochloride B-13-2 (54 mg, 330 μmol, 3 eq) in EtOH (2 mL) were added TEA (11.1 mg, 110 μmol, 15.3 μL, 1 eq) and Ti(i-PrO)4(125 mg, 440 μmol, 130 μL, 4 eq). The mixture was stirred at 25 ℃ for 15 hr, then NaBH3CN (69 mg, 1.10 mmol, 10 eq) was added. The mixture was stirred at 25 ℃ for additional 1 hr. Upon completion, the reaction mixture was 25 quenched with H2O (5 mL), then extracted with EA 45 mL (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*3 um; mobile phase: [H2O(0.1%TFA)-ACN];gradient:5%-35% B over 8.0 min) as a white solid, which was further separated by prep-HPLC (column: Phenomenex luna C18100*40mm*3 um;mobile30 phase: [H2O(0.1%TFA)-ACN]; gradient:5%-35% B over 8.0 min) to afford N-[2-[[2-[3-[3- methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin- 5-yl]methylamino]ethyl]but-2-ynamide 13(27 mg, 42.6% yield, 98% purity, TFA salt) as a white solid. MS (ESI) m / z 565.5 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.97 (br s, 2H), 8.72 - 8.60 84 Attorney Docket No.: 51728-013WO2 (m, 1H), 8.56 (s, 1H), 8.27 - 8.21 (m, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.81 - 7.73 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 5.28 (s, 2H), 4.41 (br d, J = 4.6 Hz, 2H), 3.40 (q, J = 6.0 Hz, 2H), 3.27 (s, 3H), 3.13 - 2.98 (m, 2H), 2.96 - 2.84 (m, 2H), 2.62 - 2.53 (m, 3H), 1.99 - 1.94 (m, 3H), 1.10 (d, J = 5.6 Hz, 3H). 5 Example 14: N-[2-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo- 7-(trifluoromethyl)isoindolin-5-yl]methylamino]ethyl]-N-prop-2-ynyl-prop-2-enamide 14 Synthesis of N-[2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]- 3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino]ethyl]-N-prop-2-ynyl-prop-2- enamide 14 10 To the solution of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3- oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (50 mg, 110 μmol, 1 eq) and N-(2- aminoethyl)-N-prop-2-ynyl-prop-2-enamide trifluoroacetate B-14-1(59 mg, 220 μmol, 2 eq) in DCM (3 mL) were added TEA (33 mg, 330 μmol, 46 μL, 3 eq), and AcOH (660 μg, 11.0 μmol, 15 0.6 μL, 0.1 eq) stirred at 20 °C for 15 h, then NaBH(OAc)3 (233 mg, 1.10 mmol, 10 eq) was added. The mixture was stirred at 20 °C for additional 1 hr. The mixture was diluted with sat. NaHCO3 (20 mL), then extracted with EA (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Waters Xbridge BEH C18100 * 30 mm * 10 um;20 mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 24%-52% B over 8.0 min). N-[2-[[2- [3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- (trifluoromethyl)isoindolin-5-yl]methylamino]ethyl]-N-prop-2-ynyl-prop-2-enamide 14 (12 mg, 18.5% yield, 100% purity) was obtained as a white solid. MS (ESI) m / z 591.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.03 (br d, J = 10.8 Hz, 2H), 7.97 (s, 1H), 7.70 (br d, J = 25 8.0 Hz, 1H), 7.47 - 7.38 (m, 1H), 7.12 (br d, J = 7.6 Hz, 1H), 6.85 - 6.69 (m, 1H), 6.10 (s, 1H), 5.78 - 5.62 (m, 1H), 5.19 (br s, 2H), 4.34 - 4.14 (m, 2H), 3.90 (br s, 2H), 3.61 - 3.42 (m, 2H), 3.21 (s, 3H), 3.17 - 3.09 (m, 1H), 2.95 - 2.79 (m, 2H), 2.75 - 2.64 (m, 2H), 2.64 - 2.52 (m, 3H), 1.09 (br d, J = 3.2 Hz, 3H). Example 15: (E)-4-(Methyl(prop-2-yn-1-yl)amino)-N-(3-(((2-(3-((1s,3s)-3-methyl-1-(4-30 methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5- yl)methyl) amino)propyl)but-2-enamide 15 Step 1: Synthesis of tert-butyl (E)-(3-(4-(methyl(prop-2-yn-1-yl)amino)but-2- enamido) propyl)carbamate B-15-1 35 To a solution of (E)-4-[methyl(prop-2-ynyl)amino]but-2-enoic acid B-12-3 (200 mg, 836 μmol, 1 eq) and tert-butyl N-(3-aminopropyl)carbamate (16 mg, 919 μmol, 161 μL, 1.1 eq) in 85 Attorney Docket No.: 51728-013WO2 DCM (2 mL) and DMF (1 mL) were added DIEA (324 mg, 2.51 mmol, 437 μL, 3 eq) and HATU (636 mg, 1.67 mmol, 2 eq). The mixture was stirred at 20 °C for 1 hr. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with DCM (3 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was 5 purified by prep-TLC (SiO2, EA) to give tert-butyl N-[3-[[(E)-4-[methyl(prop-2-ynyl)amino]but- 2-enoyl] amino] propyl]carbamate B-15-1 (276 mg, 73.7% yield, 69% purity) as a yellow oil. MS (ESI) m / z 310.1 [M+H]+. Step 2: Synthesis of (E)-N-(3-aminopropyl)-4-(methyl(prop-2-yn-1-yl)amino)but-2- enamide hydrochloride B-15-2 10 tert-Butyl N-[3-[[(E)-4-[methyl(prop-2-ynyl)amino]but-2-enoyl]amino]propyl] carbamate B-15-1 (100 mg, 323 μmol, 1 eq) in HCl / dioxane (4 M, 10.00 mL, 123.76 eq) was stirred at 20 °C for 1 hr under N2atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude (E)-N-(3-aminopropyl)-4-[methyl(prop-2-ynyl)amino]but-2- 15 enamide hydrochloride B-15-2 (80 mg) as a yellow oil. Step 3: Synthesis of (E)-4-(methyl(prop-2-yn-1-yl)amino)-N-(3-(((2-(3-((1s,3s)-3- methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl) isoindolin-5-yl) methyl)amino)propyl)but-2-enamide 15 20 To a solution of (E)-N-(3-aminopropyl)-4-[methyl(prop-2-ynyl)amino]but-2-enamide hydrochloride B-15-2 (78 mg, 319 μmol, 2.9 eq) and 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (50 mg, 110 μmol, 1 eq) in EtOH (3 mL) were added TEA (33 mg, 330 μmol, 46 μL, 3 eq) and Ti(i-PrO)4(125 mg, 440 μmol, 130 μL, 4 eq). The mixture was stirred at 20 °C for 16 hr, then NaBH3CN (139 mg, 25 2.20 mmol, 20 eq) was added at 20 °C. The mixture was stirred at 50 °C for additional 2 hr. Upon completion, the reaction mixture was quenched with water (10 mL) at 20 °C, then extracted with DCM (5 mL x 3). The combined organic layers were filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O(0.1%TFA)-ACN];gradient:10%-35% B over 8.0 min) to30 afford (E)-N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7- (trifluoromethyl)isoindolin-5-yl]methylamino]propyl]-4-[methyl(prop-2-ynyl)amino]but-2- enamide 15 (49.8 mg, 69.9% yield, 100% purity, TFA salt) as a white solid. MS (ESI) m / z 648.5 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.02 (br s, 2H), 8.57 (s, 1H), 8.48 (br t, J = 5.8 Hz, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.82 - 7.72 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.23 (d, 35 J = 8.0 Hz, 1H), 6.65 - 6.52 (m, 1H), 6.26 (d, J = 15.2 Hz, 1H), 5.28 (s, 2H), 4.41 (br t, J = 5.0 Hz, 2H), 4.07 (br s, 2H), 3.97 - 3.81 (m, 3H), 3.27 (s, 3H), 3.23 (q, J = 6.6 Hz, 2H), 3.00 (br s, 2H), 2.89 (br s, 2H), 2.76 (s, 3H), 2.63 - 2.53 (m, 3H), 1.89 - 1.76 (m, 2H), 1.10 (d, J = 5.6 Hz, 3H). Example 16: N-[2-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3- oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl-prop-2-ynyl-amino]ethyl]prop-2-enamide 16 86 Attorney Docket No.: 51728-013WO2 Step 1: Synthesis of tert-butyl N-[2-(prop-2-ynylamino)ethyl]carbamate B-16-1 To a solution of tert-butyl N-(2-aminoethyl)carbamate B-1-1 (3 g, 18.73 mmol, 2.95 mL, 1 eq) in MeCN (50 mL) were added K2CO3 (5.18 g, 37.5 mmol, 2 eq) and 3-bromoprop-1-yne 5 (2.23 g, 18.7 mmol, 1.61 mL, 1 eq), and the mixture was stirred at 60°C for 16hr. The mixture was concentrated under reduced pressure to give the crude. The crude was purified by flash silica gel chromatography (EA) to afford tert-butyl N-[2-(prop-2-ynylamino)ethyl]carbamate B-16-1 (1.05 g, 26.9% yield, 95% purity) as a light-yellow oil.1H NMR (400 MHz, DMSO-d6) δ 6.71 (br s, 1H), 3.28 (d, J = 2.4 Hz, 2H), 3.03 (t, J = 2.4 Hz, 1H), 2.98 (q, J = 6.4 Hz, 2H), 2.56 (br t, J = 6.4 Hz, 10 2H), 1.37 (s, 9H). Step 2: Synthesis of tert-butyl N-[2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl] phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl-prop-2-ynyl-amino] ethyl]carbamate B-16-2 15 To a solution of tert-butyl N-[2-(prop-2-ynylamino)ethyl]carbamate B-16-1 (95.5 mg, 482 μmol, 1.1 eq) in ACN (4 mL) was added [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl] methylmethanesulfonate Int-3- OMs (234 mg, 438 μmol, 1 eq) and K2CO3 (182 mg, 1.31 mmol, 3 eq). The mixture was stirred at 80 °C for 2hr. Upon completion, the reaction mixture cooled to room temperature and was 20 quenched by water (1 mL) , then extracted with EA (2 mL x 3). The combined organic layers were washed with brine (2 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, EA: MeOH = 5:1) to give tert-butyl N-[2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl] -3-oxo-7- (trifluoromethyl)isoindolin-5-yl]methyl-prop-2-ynyl-amino]ethyl]carbamate B-16-2 (180 mg, 25 54.9% yield, 85% purity) as a white solid. MS (ESI) m / z 637.5 [M+H]+. Step 3: 6-[[2-aminoethyl(prop-2-ynyl)amino]methyl]-2-[3-[3-methyl-1-(4-methyl- 1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl)isoindolin-1-one trifluoroacetate B- 16-3 87 Attorney Docket No.: 51728-013WO2 A solution of tert-butyl N-[2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl-prop-2-ynyl- amino]ethyl]carbamate B-16-2 (180 mg, 283 μmol, 1 eq) in TFA (0.5 mL) and DCM (1.5 mL) was stirred at 20 °C for 0.5 hr. Upon completion, the reaction mixture was concentrated under 5 reduced pressure to give crude 6-[[2-aminoethyl(prop-2-ynyl)amino]methyl]-2-[3-[3-methyl-1- (4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl] -4-(trifluoromethyl)isoindolin-1-one trifluoroacetate B-16-3 (180 mg) as a white solid. MS (ESI) m / z 537.4 [M+H]+. Step 4: N-[2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3- oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl-prop-2-ynyl-amino]ethyl] prop-2-enamide 16 10 To a solution of 6-[[2-aminoethyl(prop-2-ynyl)amino]methyl]-2-[3-[3-methyl-1-(4- methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl)isoindolin-1-one trifluoroacetate B-16-3(180 mg, 277 μmol, 1 eq) in DCM (4 mL) was added TEA (84 mg, 830 μmol, 116 μL, 3 eq) and prop-2-enoyl chloride (27.5 mg, 304 μmol, 24.7 μL, 1.1 eq) .The mixture was stirred at 15 0 °C for 0.5 hr. Upon completion, the reaction mixture was quenched with water (0.1 mL) at 20 °C, then concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 30%-65% B over 8.0 min) to afford N-[2-[[2-[3-[3-methyl-1-(4- methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl- 20 prop-2-ynyl-amino]ethyl]prop-2-enamide 16 (25 mg, 15% yield, 97.8% purity) as a white solid. MS (ESI) m / z 591.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.12 - 8.04 (m, 2H), 7.96 (d, J = 13.6 Hz, 2H), 7.68 (dd, J = 1.2, 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.26 - 6.16 (m, 1H), 6.10 - 5.99 (m, 1H), 5.55 (dd, J = 2.3, 10.1 Hz, 1H), 5.19 (s, 2H), 3.82 (s, 2H), 3.38 (br d, J = 2.0 Hz, 2H), 3.31 - 3.26 (m, 2H), 3.24 (t, J = 2.0 Hz, 1H), 3.22 25 (s, 3H), 2.86 (br d, J = 3.6 Hz, 2H), 2.61 (br t, J = 6.4 Hz, 2H), 2.56 (br d, J = 6.4 Hz, 3H), 1.09 (br d, J = 5.2 Hz, 3H). Example 17: N-[3-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo- 7-(trifluoromethyl)isoindolin-5-yl]methyl-prop-2-ynyl-amino]propyl]prop-2-enamide 17 Step 1: Synthesis of tert-butyl N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- 30 yl)cyclobutyl] phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl-prop-2-ynyl-amino] propyl]carbamate B-17-1 To a solution of tert-butyl N-[3-(prop-2-ynylamino)propyl]carbamate B-5-2 (35.7 mg, 168 μmol, 1.5 eq) in ACN (2 mL) were added K2CO3(46.5 mg, 337 μmol, 3 eq) and [2-[3-[3-methyl-35 1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5- 88 Attorney Docket No.: 51728-013WO2 yl]methyl methanesulfonate Int-3-OMs (60 mg, 112 μmol, 1 eq). The mixture was stirred at 80℃ for 16 h. Upon completion, the reaction mixture was quenched with H2O (10 mL) at 20oC, then extracted with EA 45 mL (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC 5 (SiO2, EA: MeOH = 5:1) to give tert-butyl N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl-prop-2-ynyl-amino] propyl]carbamate B-17-1 (80 mg, 98.6% yield, 90% purity) as a white solid. MS (ESI) m / z 651.4 [M+H]+. Step 2: Synthesis of 6-[[3-aminopropyl(prop-2-ynyl)amino]methyl]-2-[3-[3-methyl-1- 10 (4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl)isoindolin-1-one trifluoroacetate B-17-2 To a solution of tert-butyl N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl-prop-2-ynyl-amino]propyl]carbamate 15 B-17-1 (70 mg, 108 μmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL, 125 eq). The mixture was stirred at 25 ℃ for 0.5 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give 6-[[3-aminopropyl(prop-2-ynyl)amino]methyl]-2-[3- [3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl)isoindolin-1-one trifluoroacetate B-17-2 (60 mg) as a light-yellow oil. MS (ESI) m / z 551.3 [M+H]+. 20 Step 3: Synthesis of N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl-prop-2-ynyl-amino]propyl]prop-2- enamide 17 To a solution of 6-[[3-aminopropyl(prop-2-ynyl)amino]methyl]-2-[3-[3-methyl-1-(4- 25 methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl) isoindolin-1-one trifluoroacetate B-17-2 (60 mg, 102 μmol, 1 eq) in DCM (3 mL) were added TEA (31 mg, 307 μmol, 42.7 μL, 3 eq) and prop-2-enoyl chloride (9.25 mg, 102 μmol, 8.3 μL, 1 eq) at 0 ℃. The mixture was stirred at 25 ℃ for 0.5 hr. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH30C18100*25mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%-60% B over 8.0 min) to afford N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3- oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl-prop-2-ynyl-amino]propyl]prop-2-enamide 17 (14 mg, 22.7% yield, 100% purity) as a white solid. MS (ESI) m / z 605.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.12 - 8.03 (m, 2H), 7.97 (s, 1H), 7.92 (s, 1H), 7.68 (dd, J = 1.4, 8.2 Hz, 35 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.23 - 6.11 (m, 1H), 6.07 - 5.98 (m, 1H), 89 Attorney Docket No.: 51728-013WO2 5.54 (dd, J = 2.4, 10.0 Hz, 1H), 5.20 (s, 2H), 3.79 (s, 2H), 3.27 - 3.19 (m, 4H), 3.15 (q, J = 6.6 Hz, 2H), 2.91 - 2.79 (m, 2H), 2.61 - 2.51 (m, 7H), 1.62 (quin, J = 7.0 Hz, 2H), 1.09 (d, J = 5.2 Hz, 3H). Example 18: N-((3S,5S)-5-Ethynyl-1-((2-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol- 5 3-yl) cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)piperidin-3- yl)acrylamide 18 Step 1: Synthesis of tert-butyl (S)-3-(picolinamido)piperidine-1-carboxylate B-18-1 To a solution of tert-butyl (3S)-3-aminopiperidine-1-carboxylate B-2-1 (4 g, 20 mmol, 1 10 eq) and pyridine-2-carboxylic acid (2.70 g, 22 mmol, 1.1 eq) in DMF (10 mL) and DCM (10 mL) were added DIEA (5.16 g, 40 mmol, 6.96 mL, 2 eq) and HATU (9.11 g, 24 mmol, 1.2 eq). The mixture was stirred at 20 °C for 1 hr. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with DCM (10 mL x 2). The combined organic layers were concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: 15 Waters Xbridge BEH C18 250*70mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:30%-60% B over 15.0 min) to give tert-butyl (3S)-3-(pyridine-2-carbonylamino) piperidine-1-carboxylate B-18-1 (4.49 g, 72.9% yield, 99% purity) as a brown solid. Step 2: Synthesis of tert-butyl (3S,5S)-3-(picolinamido)-5-((triisopropylsilyl)ethynyl) piperidine-1-carboxylate B-18-2 20 A mixture of tert-butyl (3S)-3-(pyridine-2-carbonylamino)piperidine-1-carboxylate B-18- 1 (1.5 g, 4.91 mmol, 1 eq), 2-bromoethynyl(triisopropyl)silane (1.50 g, 5.74 mmol, 1.17 eq), Pd(OAc)2 (110 mg, 491 μmol, 0.1 eq) and AgOAc (1.64 g, 9.82 mmol, 503 μL, 2 eq) in toluene (30 mL) was degassed and purged with N2for 3 times, then the mixture was stirred at 130 °C for 25 18 hr under N2atmosphere. Upon completion, the reaction mixture cooled to room temperature, and was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Waters Xbridge BEH C18 250*70mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:80%-98% B over 30 20.0 min) to give tert-butyl (3S)-3-(pyridine-2-carbonylamino)-5-(2-triisopropylsilylethynyl) piperidine-1-carboxylate B-18-2 (2.7 g, 56.02% yield, 99% purity) as a yellow oil. MS (ESI) m / z 486.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.73 (br d, J = 8.4 Hz, 1H), 8.63 (d, J = 4.6 Hz, 1H), 8.07 - 7.96 (m, 2H), 7.61 (ddd, J = 1.6, 5.0, 7.0 Hz, 1H), 4.04 - 3.81 (m, 3H), 2.95 - 2.58 (m, 3H), 2.16 - 2.02 (m, 1H), 1.89 - 1.73 (m, 1H), 1.41 (s, 9H), 1.03 (d, J = 6.1 Hz, 22H). 35 Step 3: Synthesis of N-((3S,5S)-5-((triisopropylsilyl)ethynyl)piperidin-3- 90 Attorney Docket No.: 51728-013WO2 yl)picolinamide B-18-3 To a solution of tert-butyl (3S)-3-(pyridine-2-carbonylamino)-5-(2-triisopropyl 5 silylethynyl) piperidine-1-carboxylate B-18-2 (1 g, 2.06 mmol, 1 eq) in DCM (10 mL) was added TFA (5.07 g, 44.4 mmol, 3.3 mL, 21.6 eq). The mixture was stirred at 20 °C for 1 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to remove the solvent. The pH value of the residue was adjusted to 8 with aqueous NaHCO3 solution and extracted with DCM (3 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated10 under reduced pressure to give crude N-[(3S)-5-(2-triisopropylsilylethynyl)-3-piperidyl]pyridine- 2-carboxamide B-18-3 (888 mg) as a colorless oil. MS (ESI) m / z 386.3 [M+H]+. Step 4: Synthesis of N-((3S,5S)-1-(4-methoxybenzyl)-5-((triisopropylsilyl) ethynyl) piperidin-3-yl)picolin- amide B-18-4 15 To a solution of N-[(3S)-5-(2-triisopropylsilylethynyl)-3-piperidyl]pyridine-2- carboxamide B-18-3 (888 mg, 2.30 mmol, 1 eq) in DCM (20 mL) were added PMB-Cl (721 mg, 4.61 mmol, 625 μL, 2 eq) and TEA (466 mg, 4.61 mmol, 641 μL, 2 eq). The mixture was stirred at 40 °C for 5 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue obtained was purified by flash silica gel chromatography 20 (PE / EA = 3 / 1 to 0 / 1) to afford N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-triisopropylsilyl ethynyl)-3-piperidyl] pyridine-2-carboxamide B-18-4 (723 mg, 57.7% yield, 93% purity) as a white solid. MS (ESI) m / z 506.3 [M+H]+. Step 5: Synthesis of (3S,5S)-1-(4-methoxybenzyl)-5-((triisopropylsilyl) ethynyl) piperidin-3-amine 25 91 Attorney Docket No.: 51728-013WO2 To a solution of N-[(3S)-1-[(4-methoxyphenyl)methyl]-5-(2-triisopropyl silylethynyl)-3- piperidyl]pyridine-2- carboxamide B-18-4 (723 mg, 1.43 mmol, 1 eq) in i-PrOH (20 mL) was added NaOH (1.14 g, 28.6 mmol, 20 eq). The mixture was stirred at 100 °C for 16 hr. Upon completion, the reaction mixture was diluted with water (30 mL) and extracted with DCM (15 mL 5 x 3). The combined organic layers were dried overanhydrousNa2SO4, filtered and concentrated under reduced pressure to give (3S)-1-[(4-methoxyphenyl)methyl]-5-(2- triisopropylsilylethynyl)piperidin-3-amine B-18-5 (590 mg, 76.2% yield, 74% purity) as a yellow oil. MS (ESI) m / z 401.3 [M+H]+. Step 6: Synthesis of N-((3S,5S)-1-(4-methoxybenzyl)-5-((triisopropylsilyl)ethynyl) 10 piperidin-3-yl)acryla To a solution of (3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-triisopropyl silylethynyl) piperidin-3-amine B-18-5 (300 mg, 749 μmol, 1 eq) in DCM (3 mL) were added TEA (227 mg, 2.25 mmol, 313 μL, 3 eq) and prop-2-enoyl chloride (81.3 mg, 899 μmol, 73 μL, 1.2 eq) at 0 °C. 15 The mixture was stirred at 0 °C for 1 hr. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 3:1) to give N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2- triisopropylsilylethynyl)-3-piperidyl] prop-2-enamide B-18-6 (195 mg, 52.1% yield, 91% purity) as a white solid. MS (ESI) m / z 455.3 [M+H]+. 20 Step 7: Synthesis of N-((3S,5S)-5-((triisopropylsilyl)ethynyl)piperidin-3-yl) acrylamide B-18-7 To a solution of N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-triisopropyl silylethynyl)- 3-piperidyl]prop-2-enamide B-18-6 (195 mg, 429 μmol, 1 eq) in water (0.4 mL) and acetone (4 25 mL) was added CAN (1.18 g, 2.14 mmol, 1.07 mL, 5 eq). The mixture was stirred at 20 °C for 4 hr. Upon completion, the reaction mixture was quenched with saturated aqueous NaHCO3 solution (10 mL) and extracted with DCM (8 mL x 6). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, PE / EA = 3 / 1) to give N-[(3S,5S)-5-(2-triisopropylsilylethynyl)-3- 30 piperidyl] prop-2-enamide B-18-7 (76.6 mg, 39.5% yield, 74% purity) as a yellow oil. MS (ESI) m / z 335.2 [M+H]+. Step 8: Synthesis of N-((3S,5S)-5-ethynylpiperidin-3-yl)acrylamide B-18-8 92 Attorney Docket No.: 51728-013WO2 To a solution of N-[(3S,5S)-5-(2-triisopropylsilylethynyl)-3-piperidyl]prop-2-enamide B- 18-7 (76.6 mg, 229 μmol, 1 eq) in DMF (1 mL) was added CsF (408 mg, 2.68 mmol, 11.7 eq). The mixture was stirred at 40 °C for 1 hr. Upon completion, the reaction mixture was quenched 5 with water (3 mL), and extracted with DCM (5 mL x 6). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude N- [(3S,5S)-5-ethynyl-3-piperidyl]prop-2-enamide B-18-8 (48 mg) as a yellow oil. Step 9: Synthesis of N-((3S,5S)-5-ethynyl-1-((2-(3-(3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)piperidin- 10 3-yl) acrylamide 18 To a solution of N-[(3S,5S)-5-ethynyl-3-piperidyl]prop-2-enamide B-18-8 (48 mg, 269 μmol, 1 eq) and [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo-7- (trifluoromethyl)isoindolin-5-yl]methylmethanesulfonate Int-3-OMs (144 mg, 269 μmol, 1 eq) in 15 ACN (2 mL) was added K2CO3(111.66 mg, 807.94 μmol, 3 eq). The mixture was stirred at 80 °C for 1 hr. Upon completion, the reaction mixture was quenched by water (5 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O(10mM NH4HCO3)-20 ACN];gradient:40%-70% B over 8.0 min) to give N-[(3S,5S)-5-ethynyl-1-[[2-[3-[3-methyl-1-(4- methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo-7-(trifluoromethyl) isoindolin-5-yl]methyl]- 3-piperidyl]prop-2-enamide 18 (15.3 mg, 8.7% yield, 94% purity) as a white solid. MS (ESI) m / z 617.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.14 - 7.89 (m, 4H), 7.72 - 7.58 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.30 - 5.95 (m, 2H), 5.68 - 5.50 (m, 25 1H), 5.20 (s, 2H), 3.92 - 3.66 (m, 3H), 3.21 (s, 3H), 3.05 - 2.77 (m, 5H), 2.69 - 2.53 (m, 4H), 2.04 (br d, J = 12.4 Hz, 1H), 1.93 (br t, J = 11.0 Hz, 1H), 1.83 - 1.65 (m, 1H), 1.21 (q, J = 12.0 Hz, 1H), 1.09 (br d, J = 5.0 Hz, 3H). Example 19: N-[(3S,5R)-5-Ethyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl] phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]prop-2- 30 enamide 19 Step 1: Synthesis of tert-butyl N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2- triisopropylsilylethynyl)-3-piperidyl]carbamate B-19-1 93 Attorney Docket No.: 51728-013WO2 To a solution of (3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-triisopropyl silylethynyl)piperidin-3-amine B-18-5 (3 g, 7.49 mmol, 1 eq) and TEA (1.52 g, 15.0 mmol, 2.10 mL, 2 eq) in DCM (60 mL) was added Boc2O (2.45 g, 11.2 mmol, 2.60 mL, 1.5 eq) , and the 5 reaction mixture was stirred at 20 °C for 2 hr. The reaction mixture was diluted with H2O (5 mL), and extracted with DCM (25 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by MPLC (SiO2, Pe:EA = 100:1 to 20:1) to afford tert-Butyl N-[(3S,5S)-1-[(4- methoxyphenyl)methyl]-5-(2-triisopropylsilylethynyl)-3-piperidyl]carbamate (2.5 g, 58.0% yield, 10 87% purity) as a colorless oil. MS (ESI) m / z 501.4 [M+H]+. Step 2: Synthesis of N-[(3S,5S)-5-ethynyl-1-[(4-methoxyphenyl)methyl]-3-piperidyl] carbamate To a solution of tert-butyl N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-triisopropyl 15 silylethynyl)-3-piperidyl]carbamate B-19-1 (2.3 g, 4.59 mmol, 1 eq) in DMF (23 mL) was added CsF (8.37 g, 55.1 mmol, 12 eq), and the reaction mixture was stirred at 40 °C for 16 hr. The reaction mixture was diluted with H2O (15 mL), then extracted with EtOAc (50 mL x 2), washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated to give crude tert- butyl N-[(3S,5S)-5-ethynyl-1-[(4-methoxyphenyl)methyl]-3-piperidyl]carbamate B-19-2 (1.6 g)20as a yellow oil. MS (ESI) m / z 245.3 [M+H]+. Step 3: tert-butyl N-[(3S,5R)-5-ethyl-3-piperidyl]carbamate B-19-3 To a solution of tert-butyl N-[(3S,5S)-5-ethynyl-1-[(4-methoxyphenyl)methyl]-3-piperidyl] carbamate B-19-2 (1.6 g, 4.65 mmol, 1 eq) in EtOH (120 mL) and THF (40 mL) was added 10%25Pd / C (989 mg, 929 μmol, 0.2 eq) under N2 atmosphere. The suspension was degassed and purged with H2(9.36 mg, 4.65 mmol, 1 eq) 3 times. The mixture was stirred under H2(15 psi) at 20 °C for 16 hr. The reaction mixture was diluted with DCM (50 mL), filtrated through celite pad, and washed with DCM (50 mL x 2). The filtrate was concentrated to give crude tert-butyl N-[(3S,5R)- 5-ethyl-3-piperidyl]carbamate B-19-3 (1.2 g, 95.0% yield, 84% purity) as a white solid. MS (ESI) 30 m / z 229.3 [M+H]+. 94 Attorney Docket No.: 51728-013WO2 Step 4: Synthesis of tert-butyl ((3S,5R)-5-ethyl-1-((2-(3-(3-methyl-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl) isoindolin-5- yl)methyl)piperidin-3-yl) carbamate B-19-4 5 To a solution of [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3- oxo-7-(trifluoromethyl)isoindolin-5-yl]methylmethanesulfonate Int-3-OMs (0.47 g, 879 μmol, 1 eq) and tert-butyl N-[(3S,5R)-5-ethyl-3-piperidyl]carbamate (402 mg, 1.76 mmol, 2 eq) in ACN (10 mL) was added K2CO3(365 mg, 2.64 mmol, 502 μL, 3 eq), and the reaction mixture was stirred at 80°C for 1 hr. The reaction mixture was diluted with H2O (5 mL), then extracted with 10 DCM / MeOH (10 / 115 mL x 3), washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by MPLC (SiO2, DCM MeOH = 100:1 to 25:1) to afford tert-butyl((3S,5R)-5-ethyl-1-((2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)piperidin-3-yl)carbamate B- 19-4 (0.57 g, 84.6% yield, 87% purity) as a yellow solid. MS (ESI) m / z 667.4 [M+H]+. 15 Step 5: 6-(((3S,5R)-3-amino-5-ethylpiperidin-1-yl)methyl)-2-(3-(3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-(trifluoromethyl) isoindolin-1-one B-19-5 A solution of tert-butyl ((3S,5R)-5-ethyl-1-((2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol- 3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl) methyl)piperidin-3-yl) 20 carbamate B-19-4 (0.57 g, 855 μmol, 1 eq) in HCl / MeOH (4 M, 20 mL, 93.58 eq) was stirred at 20 °C for 4 hr. The reaction mixture was concentrated to afford crude 6-(((3S,5R)-3-amino-5- ethylpiperidin-1-yl)methyl)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-4-(trifluoromethyl)isoindolin-1-one B-19-5 (0.5 g, 97.0% yield, 94% purity, HCl salt) as a yellow solid. MS (ESI) m / z 567.4 [M+H]+. 25 Step 6: Synthesis of N-[(3S,5R)-5-ethyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol- 3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl] methyl]-3-piperidyl]prop- 2-enamide To a solution of 6-(((3S,5R)-3-amino-5-ethylpiperidin-1-yl)methyl)-2-(3-(3-methyl-1-(4- 30 methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-(trifluoromethyl) isoindolin-1-one B-19-5 (150 mg, 265 μmol, 1 eq, HCl salt) in DCM (3 mL) were added TEA (80.4 mg, 794 μmol, 111 μL, 95 Attorney Docket No.: 51728-013WO2 3 eq) and prop-2-enoyl chloride (36 mg, 397 μmol, 32.3 μL, 1.5 eq) at 0 °C, the reaction mixture was stirred at 0°C for 1 hr. The reaction mixture was diluted with H2O (5 mL), then extracted with DCM / MeOH (10:1, 15 mL x 4), washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by prep-HPLC (column: Waters Xbridge 5 BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:35%-65% B over 8.0 min) to afford N-[(3S,5R)-5-ethyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]prop-2- enamide 19 (42.1 mg, 25.3% yield, 98.9% purity) as a white solid. MS (ESI) m / z 621.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.54 - 7.49 10 (m, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.26 (d, J = 16.9 Hz, 1H), 6.10 - 5.98 (m, 1H), 5.63 (d, J = 10.3 Hz, 1H), 5.33 (br d, J = 8.4 Hz, 1H), 5.00 (s, 2H), 4.17 - 4.03 (m, 1H), 3.72 - 3.60 (m, 2H), 3.27 (s, 3H), 3.11 (br dd, J = 3.1, 9.8 Hz, 1H), 2.99 - 2.87 (m, 2H), 2.82 (br d, J = 7.2 Hz, 1H), 2.69 (br d, J = 6.3 Hz, 3H), 2.11 (br d, J = 11.9 Hz, 1H), 1.76 (t, J = 10.4 Hz, 1H), 1.62 (br s, 2H), 1.32 - 1.18 (m, 2H), 1.16 (d, J = 5.1 Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H), 0.84 - 15 0.73 (m, 1H). Example 20: N-[3-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo- 7-(trifluoromethyl)isoindolin-5-yl]methylamino]propyl]-4-prop-2-ynoxy-but-2-ynamide 20 Step 1: Synthesis of 4-prop-2-ynoxybut-2-ynoic acid B-20-2 20 A solution of 3-prop-2-ynoxyprop-1-yne B-20-1(1 g, 10.6 mmol, 1 eq) in THF (20 mL) under nitrogen was cooled to -78 °C. After n-BuLi (2.5 M, 3.40 mL, 0.8 eq) was added and stirred for 30 min, CO2was purged into the solution at 20 °C for 16 h. Upon completion, the reaction mixture was poured into aqueous NaHCO3(50 mL) slowly and washed with ethyl acetate (30 mL x 2). The aqueous layer was acidified with HCl (1N) to pH reached 1 and extracted with ethyl 25 acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-prop-2- ynoxybut-2-ynoic acid (700 mg, 47.7% yield) as a yellow oil. Step 2: Synthesis of tert-butyl N-[3-(4-prop-2-ynoxybut-2-ynoylamino) propyl] carbamate B-20-3 30 A mixture of 4-prop-2-ynoxybut-2-ynoic acid B-20-2 (160 mg, 1.16 mmol, 1 eq) and tert- butyl N-(3-aminopropyl)carbamate (404 mg, 2.32 mmol, 405 μL, 2 eq) in DCM (3 mL) were added T4P (1.67 g, 2.32 mmol, 50% purity, 2 eq) and DIEA (449 mg, 3.48 mmol, 605 μL, 3 eq). The mixture was stirred at 0 °C for 1 hr. Upon completion, the reaction mixture was poured into 35 water (10 mL) slowly and extracted with DCM (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was obtained purified by flash silica gel chromatography (PE:EA = 1:0 to 10:1） to give tert-butyl N-[3-(4-prop-2-ynoxybut-2-ynoylamino)propyl]carbamate B-20- 3 (190 mg, 55.7% yield) as a colorless oil. MS (ESI) m / z 295.3 [M+H]+. 96 Attorney Docket No.: 51728-013WO2 Step 3: Synthesis of N-(3-aminopropyl)-4-prop-2-ynoxy-but-2-ynamide trifluoroacetate B-20-4 A solution of tert-butyl N-[3-(4-prop-2-ynoxybut-2-ynoylamino)propyl] carbamate B-20- 5 3 (180 mg, 611 μmol, 1 eq) in TFA (0.5 mL) and DCM (1.5 mL) was stirred at 20 °C for 1 hr. Upon completion, the mixture was concentrated under reduced pressure to give crude N-(3- aminopropyl)-4-prop-2-ynoxy-but-2-ynamide trifluoroacetate (190 mg) as a yellow oil. MS (ESI) m / z 195.3 [M+H]+. Step 4: N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-10 oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino]propyl]-4-prop-2-ynoxy-but-2- ynamide 20 To a solution of N-(3-aminopropyl)-4-prop-2-ynoxy-but-2-ynamide trifluoroacetate B-20- 4 (163 mg, 528 μmol, 3 eq) and 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- 15 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (80 mg, 176 μmol, 1 eq) in EtOH (2 mL) were added TEA (71 mg, 704 μmol, 98 μL, 4 eq) and Ti(i-PrO)4 (200 mg, 704 μmol, 208 μL, 4 eq). The mixture was stirred at 20 °C for 2 hr, then NaBH3CN (111 mg, 1.76 mmol, 10 eq) was added at 20°C and stirred for additional 0.5hr. Upon completion, the reaction mixture was added aqueous NaHCO3 solution (10 mL) and extracted with ethyl acetate 20 (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*3 um;mobile phase: [H2O(0.1%TFA)-ACN]; gradient:10%-40% B over 8.0 min) to give N-[3-[[2-[3-[3-methyl-1-(4- methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoro- 25 methyl)isoindolin-5-yl]methylamino]propyl]-4-prop-2-ynoxy-but-2-ynamide 20 (52 mg, 46.7% yield) as white solid. MS (ESI) m / z 633.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.94 - 8.75 (m, 3H), 8.49 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 8.00 (s, 1H), 7.76 (br d, J = 9.3 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.21 (br d, J = 7.6 Hz, 1H), 5.27 (s, 2H), 4.43 - 4.36 (m, 4H), 4.24 (d, J = 2.4 Hz, 2H), 3.57 - 3.53 (m, 1H), 3.26 (s, 3H), 3.19 (q, J = 6.6 Hz, 2H), 2.99 (br d, J = 3.1 Hz, 2H), 2.89 30 (br d, J = 3.3 Hz, 2H), 2.62 - 2.53 (m, 3H), 1.80 (td, J = 7.0, 14.3 Hz, 2H), 1.10 (br d, J = 5.4 Hz, 3H). Example 21: (E)-4-(Dimethylamino)-N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]but-2 enamide 21 97 Attorney Docket No.: 51728-013WO2 Step 1: Synthesis of tert-butyl (3S)-3-[[(E)-4-(dimethylamino)but-2-enoyl]amino] piperidine-1- A mixture of tert-butyl (3S)-3-aminopiperidine-1-carboxylate B-2-1 (500 mg, 2.50 mmol, 5 1 eq) and (E)-4-(dimethylamino)but-2-enoic acid (827 mg, 4.99 mmol, 2 eq, HCl salt) in DMF (10 mL) were added HATU (2.85 g, 7.49 mmol, 3 eq) and DIEA (1.61 g, 12.5 mmol, 2.17 mL, 5 eq). The mixture was stirred at 20 °C for 16 hr. Upon completion, the residue was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC(column: Waters Xbridge BEH C18 250*70mm*10um;mobile phase: [H2O(10mM NH4HCO3)-10 ACN];gradient:15%-50% B over 16.0 min) to give tert-butyl (3S)-3-[[(E)-4-(dimethylamino)but- 2-enoyl]amino] piperidine-1-carboxylate B-21-1 (500 mg, 64.3% yield) as a brown solid. MS (ESI) m / z 312.2 [M+H]+. Step 2: Synthesis of (E)-4-(dimethylamino)-N-[(3S)-3-piperidyl]but-2-enamide trifluoroacetate B-21-2 15 A solution of tert-butyl (3S)-3-[[(E)-4-(dimethylamino)but-2-enoyl]amino] piperidine-1- carboxylate B-21-1 (75 mg, 240.83 μmol, 1 eq) in TFA (0.5 mL) and DCM (1.5 mL) was stirred at 20 °C for 1 hr. Upon completion, the mixture was concentrated under reduced pressure to give crude (E)-4-(dimethylamino)-N-[(3S)-3-piperidyl]but-2-enamide trifluoroacetate B-21-2 (80 mg) 20 as a yellow oil. MS (ESI) m / z 212.3 [M+H]+. Step 3: Synthesis of (E)-4-(dimethylamino)-N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl- 1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl) isoindolin-5-yl]methyl]-3- piperidyl]but-2-enamide 21 25 A mixture of (E)-4-(dimethylamino)-N-[(3S)-3-piperidyl]but-2-enamide frifluoroacetate B-21-2 (36.5 mg, 112 μmol, 1.2 eq) and [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl methanesulfonate Int-3- OMs (50 mg, 93.5 μmol, 1 eq) in ACN (1 mL) was added K2CO3(39 mg, 281 μmol, 3 eq). The mixture was stirred at 80°C for 2 hr. Upon completion, the residue was filtered and concentrated 30 under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*3 um; mobile phase: [H2O(0.1%TFA)-ACN];gradient:1%-30% B over 8.0 min) to afford (E)-4-(dimethylamino)-N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]but-2- enamide 21 (27.2 mg, 44.8% yield, 100% purity) as a white solid. MS (ESI) m / z 650.3 [M+H]+; 98 Attorney Docket No.: 51728-013WO2 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.24 - 8.20 (m, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.73 - 7.65 (m, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.65 - 6.55 (m, 1H), 6.27 (d, J = 15.5 Hz, 1H), 5.22 (s, 2H), 4.50 - 4.36 (m, 2H), 4.17 - 4.00 (m, 1H), 3.87 (d, J = 7.0 Hz, 2H), 3.37 - 3.19 (m, 5H), 3.09 (s, 1H), 2.99 - 2.82 (m, 3H), 2.79 (s, 6H), 2.66 - 2.58 (m, 3H), 1.97 5 - 1.86 (m, 2H), 1.80 - 1.67 (m, 1H), 1.55 - 1.42 (m, 1H), 1.12 (d, J = 5.7 Hz, 3H). Example 22: N-[2-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo- 7-(trifluoromethyl)isoindolin-5-yl]methylamino]ethyl]-N-propyl-prop-2-enamide 22 Step 1: Synthesis of tert-butyl N-[2-(propylamino)ethyl]carbamate B-22-1 10 To a solution of tert-butyl N-[2-(prop-2-ynylamino)ethyl]carbamate B-16-1 (200 mg, 1.01 mmol, 1 eq) in i-PrOH (2 mL) was added 10% Pd / C (200 mg, 188 μmol, 0.2 eq) under N2 atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 3hr. The reaction mixture was filtered and concentrated under reduced pressure to give crude tert-butyl N-[2-(propylamino)ethyl]carbamate B-22-1 (201 mg) as 15 a yellow oil. MS (ESI) m / z 203.3 [M+H]+. Step 2: Synthesis of tert-butyl N-[2-[prop-2-enoyl(propyl)amino]ethyl] carbamate B- 22-2 To a solution of tert-butyl N-[2-(propylamino)ethyl]carbamate B-22-1 (170 mg, 840 μmol, 20 1 eq) in DCM (2 mL) was added TEA (170 mg, 1.68 mmol, 234 μL, 2 eq) and prop-2-enoyl chloride (76 mg, 841 μmol, 68.3 μL, 1 eq). The mixture was stirred at 0 °C for 1hr. The reaction mixture was quenched with H2O (5 mL), and extracted with EA (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, PE: EA = 1:1) to 25 afford tert-butyl N-[2-[prop-2-enoyl(propyl)amino]ethyl]carbamate B-22-2 (130 mg, 59.1% yield, 98% purity) as a yellow oil. MS (ESI) m / z 157.3 [M+H-Boc]+. Step 3: Synthesis of N-(2-aminoethyl)-N-propyl-prop-2-enamide trifluoroacetate B- 22-3 30 To a solution of tert-butyl N-[2-[prop-2-enoyl(propyl)amino]ethyl]carbamate B-22-2 (120 mg, 468 μmol, 1 eq) in DCM (1 mL) was added TFA (921 mg, 8.08 mmol, 600 μL, 17 eq). The mixture was stirred at 20 °C for 1hr. The reaction mixture was concentrated under reduced 99 Attorney Docket No.: 51728-013WO2 pressure to give crude N-(2-aminoethyl)-N-propyl-prop-2-enamide trifluoroacetate B-22-3 (130 mg) as a yellow oil. MS (ESI) m / z 157.3 [M+H]+. Step 4: Synthesis of N-[2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino] ethyl]-N- 5 propyl-prop-2-enamide 22 To a solution of N-(2-aminoethyl)-N-propyl-prop-2-enamide trifluoroacetate B-22-3 (101 mg, 374 μmol, 2 eq) in EtOH (3 mL) were added TEA (38 mg, 374 μmol, 52 μL, 2 eq), 2-[3-[3- methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindoline- 10 5-carbaldehyde Int-2 (85 mg, 187 μmol, 1 eq) and Ti(i-PrO)4(160 mg, 561 μmol, 166 μL, 3 eq), and the mixture was stirred at 20°C for 1hr. Then NaBH3CN (118 mg, 1.87 mmol, 10 eq) was added and the mixture was stirred at 20°C for additional 1hr. The mixture was diluted with saturated aqueous NaHCO3 solution (10 mL) and DCM (30 mL) and filtered. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under 15 reduced pressure. The residue obtained was purified by prep-TLC (SiO2, DCM:MeOH = 10:1). Then by prep-HPLC (column: WePure Biotech XP tC18 150*40*7um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:30%-65% B over 8.0 min). N-[2-[[2-[3-[3-Methyl-1-(4- methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5- yl]methylamino]ethyl]-N-propyl-prop-2-enamide 22 (25.2 mg, 22.4% yield, 98.8% purity) was 20 obtained as a white solid. MS (ESI) m / z 595.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.03 (br d, J = 10.6 Hz, 2H), 7.97 (s, 1H), 7.70 (br d, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.12 (br d, J = 7.6 Hz, 1H), 6.74 (ddd, J = 10.4, 16.7, 19.2 Hz, 1H), 6.10 (td, J = 2.6, 16.6 Hz, 1H), 5.62 (dt, J = 2.4, 10.2 Hz, 1H), 5.19 (br s, 2H), 3.90 (br d, J = 3.2 Hz, 2H), 3.48 - 3.40 (m, 2H), 3.32 - 3.30 (m, 1H), 3.30 - 3.22 (m, 1H), 3.22 (s, 3H), 2.86 (br d, J = 3.4 Hz, 2H), 2.63 25 (br t, J = 6.6 Hz, 2H), 2.55 (br d, J = 6.6 Hz, 3H), 1.49 (dt, J = 7.6, 15.4 Hz, 2H), 1.09 (br d, J = 5.0 Hz, 3H), 0.82 (td, J = 7.4, 10.8 Hz, 3H);1H NMR (400 MHz, DMSO+D2O-d6) δ = 8.28 (s, 1H), 8.01 (br d, J = 12.4 Hz, 2H), 7.97 - 7.94 (m, 1H), 7.66 (br d, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.13 (br d, J = 7.8 Hz, 1H), 6.71 (dt, J = 10.4, 17.4 Hz, 1H), 6.12 - 6.02 (m, 1H), 5.62 (dt, J = 2.4, 10.6 Hz, 1H), 5.17 (br s, 2H), 3.87 (br d, J = 3.2 Hz, 2H), 3.46 - 3.37 (m, 2H), 3.36 - 30 3.23 (m, 2H), 3.21 (s, 3H), 2.85 (br d, J = 3.4 Hz, 2H), 2.68 - 2.59 (m, 2H), 2.53 (br d, J = 6.3 Hz, 3H), 1.56 - 1.41 (m, 2H), 1.07 (br d, J = 5.2 Hz, 3H), 0.80 (td, J = 7.4, 10.2 Hz, 3H). Example 23: N-[2-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo- 7-(trifluoromethyl)isoindolin-5-yl]methylamino]ethyl]-N-prop-2-ynyl-but-2-ynamide 23 Step 1: Synthesis of tert-butyl N-[2-[but-2-ynoyl(prop-2-ynyl)amino]ethyl] 35 carbamate B-23-1 100 Attorney Docket No.: 51728-013WO2 To a solution of but-2-ynoic acid (188 mg, 2.24 mmol, 1.2 eq) in DCM (10 mL) were added DIEA (482 mg, 3.73 mmol, 650 μL, 2 eq) and HATU (852 mg, 2.24 mmol, 1.2 eq), and the mixture was stirred at 0°C for 5 min. Then tert-butyl N-[2-(prop-2-ynylamino)ethyl]carbamate B- 5 16-1 (370 mg, 1.87 mmol, 1 eq) was added and the mixture was stirred at 20 °C for additional 1hr. The mixture was diluted with H2O (20 mL), then extracted with DCM (20mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude obtained was purified by prep-TLC (SiO2, PE:EA = 1:1) to afford tert-Butyl N-[2-[but-2-ynoyl(prop-2-ynyl)amino]ethyl]carbamate B-23-1 (380 mg, 73.2% 10 yield, 95% purity) as a light-yellow oil. MS (ESI) m / z 287.3 [M+H+Na]+. Step 2: Synthesis of N-(2-aminoethyl)-N-prop-2-ynyl-but-2-ynamide trifluoroacetate B-23-2 To a solution of tert-butyl N-[2-[but-2-ynoyl(prop-2-ynyl)amino]ethyl] carbamate B-23-1 15 (380 mg, 1.44 mmol, 1 eq) in DCM (3 mL) was added TFA (1 mL), and the solution was stirred at 20°C for 0.5hr. The mixture was concentrated under reduced pressure to give crude N-(2- aminoethyl)-N-prop-2-ynyl-but-2-ynamide trifluoroacetate B-23-2 (400 mg) as a light-yellow oil. MS (ESI) m / z 165.2 [M+H]+. Step 3: Synthesis of N-[2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-20 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino] ethyl]-N- prop-2-y To a solution of N-(2-aminoethyl)-N-prop-2-ynyl-but-2-ynamide trifluoroacetate B-23- 2(153 mg, 550 μmol, 2.5 eq) in EtOH (3 mL) were added TEA (55.7 mg, 550 μmol, 76.6 μL, 2.5 25 eq), 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl) isoindoline-5-carbaldehyde Int-2 (100 mg, 220 μmol, 1 eq) and Ti(i-PrO)4(188 mg, 660 μmol, 195 μL, 3 eq), and the mixture was stirred at 20 °C for 1hr. Then NaBH3CN (138 mg, 2.20 mmol, 10 eq) was added, and the mixture was stirred at 20°C for additional 1 hr. The mixture was diluted with saturated aqueous NaHCO3 solution (20 mL) and mixture of DCM and MeOH (10:1, 30 mL) 101 Attorney Docket No.: 51728-013WO2 and filtered. Aqueous solution was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude obtained was purified by prep-TLC (SiO2, DCM:MeOH = 10:1) to afford N- [2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- 5 (trifluoromethyl)isoindolin-5-yl] methylamino]ethyl]-N-prop-2-ynyl-but-2-ynamide 23 (120 mg, 81.4% yield, 90% purity) was obtained as a light-yellow solid. MS (ESI) m / z 603.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.08 - 7.94 (m, 3H), 7.70 (br d, J = 8.2 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.12 (br d, J = 7.6 Hz, 1H), 5.20 (br s, 2H), 4.43 (d, J = 2.4 Hz, 1H), 4.17 (d, J = 2.4 Hz, 1H), 3.90 (br d, J = 19.0 Hz, 2H), 3.68 (t, J = 6.6 Hz, 1H), 3.46 (t, J = 6.4 Hz, 1H), 10 3.21 (s, 3H), 3.19 (t, J = 2.4 Hz, 1H), 2.91 - 2.81 (m, 2H), 2.75 (br t, J = 6.2 Hz, 1H), 2.66 (br t, J = 6.2 Hz, 1H), 2.55 (br d, J = 6.8 Hz, 3H), 2.02 (d, J = 8.6 Hz, 3H), 1.09 (d, J = 5.2 Hz, 3H). Example 24: N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo- 7-(trifluoromethyl)isoindolin-5-yl]methylamino]propyl]-4-prop-2-ynoxy-but-2-ynamide 24 Step 1: Synthesis of octa-2,7-diynoic acid B-24-2 15 A solution of hepta-1,6-diyne B-24-1(1 g, 10.9 mmol, 1 eq) in THF (10 mL) under nitrogen was cooled to -78 °C. After n-BuLi (2.5 M, 3.47 mL, 0.8 eq) was added and the solution was stirred for 30 min, Then CO2 was purged into the solution at 20 °C for 16 h. Upon completion, the reaction mixture was poured into saturated aqueous NaHCO3 (50 mL) slowly and washed with 20 ethyl acetate (30 mL x 2). The aqueous layer was acidified with aqueous HCl solution(1N) until pH value was about 1, then extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude octa-2,7-diynoic acid B-24-2(1 g) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 13.41 (br s, 1H), 2.54 - 2.37 (m, 4H), 2.26 (dt, J = 2.6, 7.1 Hz, 1H), 1.79 25 - 1.64 (m, 2H). Step 2: Synthesis of tert-butyl N-[3-(octa-2,7-diynoylamino)propyl] carbamate B-24- 3 A mixture of octa-2,7-diynoic acid B-24-2 (200 mg, 1.47 mmol, 1 eq) and tert-butyl N-(3- 30 aminopropyl)carbamate (512 mg, 2.94 mmol, 513 μL, 2 eq) in DCM (5 mL) were added T4P (5.29 g, 7.34 mmol, 50% purity, 5 eq) and DIEA (569.57 mg, 4.41 mmol, 767.61 μL, 3 eq). The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was poured into water (10 mL) slowly and extracted with DCM (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. 35 The residue obtained was purified by flash silica chromatography (PE : EA = 1:0 to 10:1) to give tert-butyl N-[3-(octa-2,7-diynoylamino)propyl]carbamate B-24-3 (230 mg, 48.2% yield, 90% purity) as colorless oil. MS (ESI) m / z 293.2 [M+H]+. Step 3: Synthesis of N-(3-aminopropyl)octa-2,7-diynamide trifluoroacetate B-24-4 102 Attorney Docket No.: 51728-013WO2 A solution of tert-butyl N-[3-(octa-2,7-diynoylamino)propyl]carbamate B-24-3 (230 mg, 787 μmol, 1 eq) in TFA (0.5 mL) and DCM (1.5 mL) was stirred at 20 °C for 1h. Upon completion, the mixture was concentrated under reduced pressure to give crude N-(3-aminopropyl)octa-2,7- 5 diynamide trifluoroacetate B-24-4(250 mg) as a yellow oil. MS (ESI) m / z 193.2 [M+H]+. Step 4: Synthesis of N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino] propyl]-4- prop-2-ynoxy-but-2-ynamide 24 10 To a solution of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo- 7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (80 mg, 176 μmol, 1 eq) and N-(3- aminopropyl) octa-2,7-diynamide trifluoroacetate B-24-4 (216 mg, 704 μmol, 4 eq) in EtOH (5 mL) were added TEA (71 mg, 704 μmol, 98 μL, 4 eq) and Ti(i-PrO)4(200 mg, 704 μmol, 208 μL, 4 eq). The mixture was stirred at 20 °C for 2 h. Then NaBH3CN (110.62 mg, 1.76 mmol, 10 eq) 15 was added and the reaction solution was stirred at 20 °C for additional 0.5 h. Upon completion, The reaction mixture was added saturated aqueous NaHCO3 solution (10 mL) and extracted with ethyl acetate (5 mL) and filtered. Then the aqueous layer was extracted with ethyl acetate (5 mL x2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was 20 purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*3 um; mobile phase: [H2O(0.1%TFA)-ACN]; gradient:20%-50% B over 8.0 min) to afford N-[3-[[2-[3-[3-methyl-1-(4- methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoro methyl)isoindolin-5- yl]methylamino]propyl]-4-prop-2-ynoxy-but-2-ynamide 24 (52 mg, 47% yield, TFA salt) as a white solid. MS (ESI) m / z 631.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.89 (br s, 2H), 8.66 25 (t, J = 5.8 Hz, 1H), 8.62 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.77 (dd, J = 1.5, 8.2 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 5.28 (s, 2H), 4.40 (br t, J = 5.4 Hz, 2H), 3.28 (s, 3H), 3.15 (q, J = 6.5 Hz, 2H), 2.98 (br s, 2H), 2.93 - 2.84 (m, 3H), 2.62 - 2.54 (m, 3H), 2.43 (t, J = 7.0 Hz, 2H), 2.28 (dt, J = 2.7, 7.1 Hz, 2H), 1.83 - 1.73 (m, 2H), 1.66 (quin, J = 7.1 Hz, 2H), 1.10 (d, J = 5.6 Hz, 3H). 30 Example 25: N-((3S,5S)-5-ethynyl-1-((2-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol- 3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)piperidin-3-yl)but- 2-ynamide 25 Step 1: Synthesis of N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-triisopropylsilyl ethynyl)-3-piperidyl]but-2-ynamide B-25-1 103 Attorney Docket No.: 51728-013WO2 To a solution of (3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-triisopropylsilyl ethynyl) piperidin-3-amine B-18-5 (0.4 g, 998 μmol, 1 eq) and but-2-ynoyl chloride (87 mg, 849 μmol, 0.85 eq) in DCM (8 mL) were added TEA (303 mg, 2.99 mmol, 417 μL, 3 eq) and but-2-ynoyl 5 chloride (87 mg, 849 μmol, 0.85 eq) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with H2O (5 mL), and extracted with DCM (15 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude obtained was purified by prep-HPLC (column: WePure Biotech XP tC18150*40*7um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:75%-100% B over 10 8.0 min). N-[(3S,5S)-1-[(4-Methoxyphenyl)methyl]-5-(2-triisopropylsilylethynyl)-3-piperidyl] but-2-ynamide B-25-1 (125 mg, 25.5% yield, 95% purity) was obtained as a white solid. MS (ESI) m / z 467.2 [M+H]+. Step 2: Synthesis of N-[(3S,5S)-5-(2-triisopropylsilylethynyl)-3-piperidyl]but-2- ynamide B-25-2 15 To a solution of N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-triisopropyl silylethynyl)- 3-piperidyl]but-2-ynamide B-25-1 (110 mg, 236 μmol, 1 eq) in ACN (2 mL) and H2O (2 mL) was added CAN (646 mg, 1.18 mmol, 587 μL, 5 eq) at °C, and the reaction mixture was stirred at 20 20 °C for 16 hr. The reaction mixture was diluted with H2O (5 mL), and extracted with DCM (15 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated to give crude N-[(3S,5S)-5-(2-triisopropylsilylethynyl)-3- piperidyl]but-2-ynamide B-25-2 (120 mg) as a yellow solid. MS (ESI) m / z 347.3 [M+H]+. Step 3: Synthesis of N-[(3S,5S)-5-ethynyl-3-piperidyl]but-2-ynamide B-25-3 25 104 Attorney Docket No.: 51728-013WO2 To a solution of N-[(3S,5S)-5-(2-triisopropylsilylethynyl)-3-piperidyl]but-2-ynamide B- 25-2 (120 mg, 346 μmol, 1 eq) in DMF (2 mL) was added CsF (631 mg, 4.15 mmol, 12 eq), and the reaction mixture was stirred at 40 °C for 16 hr. The reaction mixture was diluted with H2O (5 mL), and then extracted with the mixture of DCM and MeOH (10:1, 50 mL x 5), dried over 5 anhydrous Na2SO4, filtered and concentrated to give crude N-[(3S,5S)-5-ethynyl-3-piperidyl]but- 2-ynamide B-25-3 (70 mg) as a brown solid. MS (ESI) m / z 191.3 [M+H]+. Step 4: Synthesis of N-[(3S,5S)-5-ethynyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4- triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl] but-2-ynamide 25 10 To a solution of [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3- oxo-7-(trifluoromethyl)isoindolin-5-yl]methylmethanesulfonate Int-3-OMs (0.12 g, 225 μmol, 1 eq) and N-[(3S,5S)-5-ethynyl-3-piperidyl]but-2-ynamide B-25-3 (42.7 mg, 225 μmol, 1 eq) in ACN (2 mL) was added K2CO3 (93 mg, 673 μmol, 3 eq), and the reaction mixture was stirred at 15 80 °C for 2 hr. The reaction mixture was filtered to give a crude product. The crude was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*70um;mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:33%-65% B over 8.0 min). N-[(3S,5S)-5-Ethynyl-1-[[2-[3-[3- methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5- yl] methyl]-3-piperidyl]but-2-ynamide 25 (30.5 mg, 21.6% yield, 100% purity) was obtained as a 20 white solid. MS (ESI) m / z 629.3 [M+H]+;1H NMR (400 MHz, CDCl3) δ 8.23 - 7.90 (m, 4H), 7.56 - 7.38 (m, 2H), 7.20 (br d, J = 7.1 Hz, 1H), 5.06 - 4.91 (m, 2H), 4.28 - 4.13 (m, 1H), 3.83 (br d, J = 8.8 Hz, 2H), 3.29 (s, 3H), 3.07 - 2.36 (m, 11H), 2.34 - 1.55 (m, 6H), 1.16 (br d, J = 5.0 Hz, 3H). Example 26: N-[(3S)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]- 25 3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]pyrrolidin-3-yl]prop-2-enamide 26 Step 1: Synthesis of tert-butyl (3S)-3-(prop-2-enoylamino)pyrrolidine-1-carboxylate B-26-2 To a solution of tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate B-26-1 (0.1 g, 537 μmol, 30 1 eq) in DCM (2 mL) was added TEA (163 mg, 1.61 mmol, 224 μL, 3 eq) and prop-2-enoyl chloride (49 mg, 537 μmol, 44 μL, 1 eq). The mixture was stirred at 0 °C for 0.5 h. Upon completion, the reaction mixture was quenched with H2O (3 mL) at 20 °C, and extracted with DCM 9 mL (3 mL x 3). The combined organic layers were washed with brine 3 mL, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was35 purified by prep-TLC (SiO2, EA) to give tert-butyl (3S)-3-(prop-2-enoylamino)pyrrolidine-1- 105 Attorney Docket No.: 51728-013WO2 carboxylate (90 mg, 69.8% yield) as a colorless oil. MS (ESI) m / z 263.1 [M+Na]+. Step 2: Synthesis of N-[(3S)-pyrrolidin-3-yl]prop-2-enamide trifluoroacetate B-26-3 A solution of tert-butyl (3S)-3-(prop-2-enoylamino)pyrrolidine-1-carboxylate B-26-2 5 (0.03 g, 125 μmol, 1 eq) in DCM (1 mL) and TFA (0.3 mL) was stirred at 20 °C for 0.5 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude N-[(3S)- pyrrolidin-3-yl]prop-2-enamide trifluoroacetate B-26-3(18 mg) as a white solid. MS (ESI) m / z 141.3 [M+H]+. Step 3: Synthesis of N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-10 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]pyrrolidin-3- yl]prop-2-enamide 26 To a solution of N-[(3S)-pyrrolidin-3-yl]prop-2-enamide trifluoroacetate B-26-3 (18 mg, 128 μmol, 1 eq) and [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- 15 (trifluoromethyl)isoindolin-5-yl]methyl methanesulfonate Int-3-OMs (76 mg, 141 μmol, 1.1 eq) in ACN (1 mL) was added K2CO3 (53 mg, 385 μmol, 3 eq). The mixture was stirred at 80 °C for 1 hr. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18100 * 40 mm * 3 um; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 5%-40% B over 8.0 min) to afford N-20 [(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo-7-(trifluoro- methyl)isoindolin-5-yl]methyl]pyrrolidin-3-yl]prop-2-enamide 26 (25 mg, 33.7% yield, 100% purity) as a white solid. MS (ESI) m / z 579.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 10.38 - 10.05 (m, 1H), 8.63 - 8.37 (m, 2H), 8.28 (s, 1H), 8.22 (br s, 1H), 8.00 (s, 1H), 7.74 (br d, J = 8.0 Hz, 1H), 7.55 - 7.43 (m, 1H), 7.22 (br d, J = 7.2 Hz, 1H), 6.27 - 6.05 (m, 2H), 5.72 - 5.61 (m, 1H), 25 5.33 - 5.24 (m, 2H), 4.67 - 4.56 (m, 2H), 4.45 - 4.30 (m, 2H), 3.71 - 3.51 (m, 3H), 3.26 (s, 3H), 2.97 - 2.81 (m, 2H), 2.57 (q, J = 7.6 Hz, 3H), 2.28 - 1.85 (m, 2H), 1.15 - 1.07 (m, 3H). Example 27: N-[(3S)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]- 3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]azepan-3-yl]prop-2-enamide 27 Step 1: Synthesis of tert-butyl (3S)-3-(prop-2-enoylamino)azepane-1-carboxylate B- 30 27-2 106 Attorney Docket No.: 51728-013WO2 To a solution of tert-butyl (3S)-3-aminoazepane-1-carboxylate B-27-1 (200 mg, 933 μmol, 1 eq) in DCM (2 mL) were added TEA (283 mg, 2.80 mmol, 390 μL, 3 eq) and prop-2-enoyl chloride (101 mg, 1.12 mmol, 91 μL, 1.2 eq) at 0 °C. The mixture was stirred at 20 °C for 1 hr. 5 Upon completion, the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, PE : EA = 1 : 1) to give tert-butyl (3S)-3-(prop-2-enoyl amino)azepane-1-carboxylate B-27-2 (190 mg, 74.4% yield, 98% purity) as a yellow oil. MS (ESI) m / z 213.2 [M+H]+. Step 2: Synthesis of N-[(3S)-azepan-3-yl]prop-2-enamide trifluoroacetate B-27-3 10 To a solution of tert-butyl (3S)-3-(prop-2-enoylamino)azepane-1-carboxylate B-27-2 (100 mg, 373 μmol, 1 eq) in DCM (2 mL) was added TFA (4.61 g, 40.4 mmol, 3.00 mL, 108 eq). The mixture was stirred at 20 °C for 1 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude N-[(3S)-azepan-3-yl]prop-2-enamide trifluoroacetate B-27- 15 3 (60 mg) as a yellow oil. MS (ESI) m / z 169.2 [M+H]+. Step 3: Synthesis of N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]azepan-3-yl]prop-2- enamide 27 20 To a solution of N-[(3S)-azepan-3-yl]prop-2-enamide trifluoroacetate B-27-3 (40 mg, 142 μmol, 1.2 eq) in ACN (1 mL) were added K2CO3 (49 mg, 354 μmol, 3 eq) and [2-[3-[3-methyl-1- (4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl methanesulfonate Int-3-OMs (63 mg, 118 μmol, 1 eq). The mixture was stirred at 80 °C for 2 hr. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The 25 residue obtained was purified by prep-HPLC (column: Phenomenex Luna C1875 * 30 mm * 3 um; mobile phase: [H2O (0.1%TFA)-ACN]; gradient:10%-40% B over 8.0 min) to afford N-[(3S)- 1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- (trifluoromethyl)isoindolin-5-yl]methyl]azepan-3-yl]prop-2-enamide 27 (40 mg, 55.5% yield, 99.5% purity) as a white solid. MS (ESI) m / z 607.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 107 Attorney Docket No.: 51728-013WO2 10.09 - 9.73 (m, 1H), 8.56 (s, 1H), 8.39 - 8.19 (m, 3H), 7.99 (br s, 1H), 7.75 (br d, J = 8.5 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.21 - 6.05 (m, 2H), 5.68 - 5.55 (m, 1H), 5.27 (br d, J = 8.2 Hz, 2H), 4.80 - 4.48 (m, 3H), 4.26 - 4.11 (m, 1H), 3.54 - 3.11 (m, 7H), 2.99 - 2.80 (m, 2H), 2.63 - 2.55 (m, 2H), 2.00 - 1.48 (m, 6H), 1.10 (d, J = 5.6 Hz, 3H). 5 Example 28: (E)-N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]azepan-3-yl]-4- [methyl(prop-2-ynyl)amino]but-2-enamide 28 Step 1: Synthesis of tert-butyl (3S)-3-[[(E)-4-[methyl(prop-2-ynyl)amino] but-2- enoyl]amino]azepane-1-carboxylate B-28-1 10 To a solution of tert-butyl (3S)-3-aminoazepane-1-carboxylate B-27-1(200 mg, 933 μmol, 1 eq) in DMF (5 mL) were added HATU (710 mg, 1.87 mmol, 2 eq), DIEA (362 mg, 2.80 mmol, 488 μL, 3 eq) and (E)-4-[methyl(prop-2-ynyl)amino]but-2-enoic acid B-12-3 (429 mg, 2.80 mmol, 3 eq). The mixture was stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was 15 quenched with H2O (5 mL), and extracted with EA (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by prep-TLC (SiO2, DCM : MeOH = 10 : 1) to give tert-butyl (3S)-3-[[(E)- 4-[methyl (prop-2-ynyl)amino]but-2-enoyl]amino]azepane-1-carboxylate B-28-1 (280 mg, 72.1% yield, 84% purity) as a yellow oil. MS (ESI) m / z 350.3 [M+H]+. 20 Step 2: Synthesis of (E)-N-[(3S)-azepan-3-yl]-4-[methyl(prop-2-ynyl)amino]but-2- enamide trifluoroacetate B-28-2 To a solution of tert-butyl (3S)-3-[[(E)-4-[methyl(prop-2-ynyl)amino]but-2- enoyl]amino]azepane-1-carboxylate B-28-1 (100 mg, 286 μmol, 1 eq) in DCM (2 mL) was added 25 TFA (4.61 g, 40.4 mmol, 3.00 mL, 141 eq). The mixture was stirred at 20 °C for 1 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude (E)-N- [(3S)-azepan-3-yl]-4-[methyl(prop-2-ynyl)amino]but-2-enamide trifluoroacetate B-28-2 (60 mg) as a yellow oil. MS (ESI) m / z 250.3[M+H]+. Step 3: Synthesis of (E)-N-[(3S)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-30 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl] azepan-3-yl]-4- [methyl (prop-2-ynyl)amino]but-2-enamide 28 108 Attorney Docket No.: 51728-013WO2 To a solution of (E)-N-[(3S)-azepan-3-yl]-4-[methyl(prop-2-ynyl)amino]but-2-enamide trifluoroacetate B-28-2 (55 mg, 151 μmol, 1.2 eq) in ACN (1 mL) were added K2CO3(52 mg, 378 μmol, 3 eq) and [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- 5 (trifluoromethyl)isoindolin-5-yl]methylmethane sulfonate Int-3-OMs (67 mg, 126 μmol, 1 eq). The mixture was stirred at 80 °C for 2 hr. Upon completion, the reaction mixture was filtered and concentrated. The residue obtained was purified by prep-HPLC (column: Phenomenex Luna C18 75 * 30 mm *3 um; mobile phase: [H2O (0.1%TFA)-ACN]; gradient:5%-35% B over 8.0 min) to afford (E)-N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo-10 7-(trifluoromethyl)isoindolin-5-yl]methyl]azepan-3-yl]-4-[methyl (prop-2-ynyl)amino]but-2- enamide 28 (46 mg, 52.8% yield, 99.6% purity) as a white solid. MS (ESI) m / z 688.3[M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.68 - 9.78 (m, 1H), 8.59 (s, 2H), 8.28 (br s, 2H), 7.99 (s, 1H), 7.74 (br d, J = 8.1 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.25 (br d, J = 7.7 Hz, 1H), 6.68 - 6.52 (m, 1H), 6.24 (br d, J = 15.1 Hz, 1H), 5.27 (br s, 2H), 4.81 - 4.49 (m, 2H), 4.34 - 4.12 (m, 1H), 4.06 15 (br s, 2H), 3.94 - 3.79 (m, 3H), 3.56 - 3.14 (m, 6H), 2.89 (br d, J = 3.7 Hz, 2H), 2.76 (s, 3H), 2.64 - 2.52 (m, 3H), 1.94 - 1.55 (m, 6H), 1.10 (d, J = 5.4 Hz, 3H). Example 29: N-[(3S)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]- 3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]-4-[(1-methyltriazol-4 yl)methoxy] butanamide 29 20 Step 1: Synthesis of tert-butyl (3S)-3-(but-2-ynoylamino)azepane-1-carboxylate B- 29-1 To a solution of tert-butyl (3S)-3-aminoazepane-1-carboxylate B-27-1 (200 mg, 933 μmol, 1 eq) in DCM (2 mL) were added TEA (189 mg, 1.87 mmol, 260 μL, 2 eq), and but-2-ynoyl 25 chloride (105 mg, 1.03 mmol, 1.1 eq) at 0 ℃. The mixture was stirred at 25 ℃ for 1 hr. Upon completion, the reaction mixture was quenched with H2O (10 mL) at 0 ℃, and extracted with DCM 45 mL (15 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, EA) to give tert-butyl (3S)-3-(but-2-ynoylamino)azepane-1- 30 carboxylate B-29-1 (130 mg, 48.2% yield, 97% purity) as a colorless oil. MS (ESI) m / z 225.2 [M+H-tBu]+;1H NMR (400 MHz, DMSO-d6) δ 8.37 (br d, J = 8.1 Hz, 1H), 3.91 (br dd, J = 3.8, 7.5 Hz, 1H), 3.69 - 3.41 (m, 2H), 3.11 - 2.82 (m, 2H), 1.94 (s, 3H), 1.66 (br d, J = 7.1 Hz, 2H), 1.56 - 1.47 (m, 1H), 1.39 (s, 11H), 1.32 - 1.22 (m, 1H). Step 2: Synthesis of N-[(3S)-azepan-3-yl]but-2-ynamide trifluoroacetate B-29-2 109 Attorney Docket No.: 51728-013WO2 To a solution of tert-butyl (3S)-3-(but-2-ynoylamino)azepane-1-carboxylate B-29-1 (40 mg, 143 μmol, 1 eq) in DCM (0.9 mL) was added TFA (461 mg, 4.04 mmol, 0.3 mL, 28 eq). The mixture was stirred at 25 ℃ for 1 hr. Upon completion, the reaction mixture was concentrated 5 under reduced pressure to give crude N-[(3S)-azepan-3-yl]but-2-ynamide trifluoroacetate B-29-2 (42 mg) as a yellow oil. MS (ESI) m / z 181.3 [M+H]+. Step 3: Synthesis of N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]azepan-3-yl]but-2- ynamide 29 10 To a solution of N-[(3S)-azepan-3-yl]but-2-ynamide trifluoroacetate B-29-2 (40 mg, 136 μmol, 1.25 eq, TFA) in ACN (3 mL) were added K2CO3(45 mg, 326 μmol, 3 eq) and [2-[3-[3- methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5- yl]methyl methanesulfonate Int-3-OMs (58 mg, 109 μmol, 1 eq). The mixture was stirred at 80 ℃ 15 for 16 hr. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:15%-45% B over 8.0 min) to afford N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- (trifluoromethyl)isoindolin-5-yl]methyl]azepan-3-yl]but-2-ynamide 29 (35 mg, 42.8% yield, 97.2% 20 purity, TFA salt) as a white solid. MS (ESI) m / z 619.4 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.08 - 9.76 (m, 1H), 8.82 - 8.65 (m, 1H), 8.62 (s, 1H), 8.26 (br d, J = 19.3 Hz, 2H), 8.01 (br s, 1H), 7.75 (br d, J = 8.1 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 5.28 (s, 2H), 4.73 - 4.57 (m, 2H), 3.45 - 3.13 (m, 8H), 2.99 - 2.85 (m, 2H), 2.64 - 2.55 (m, 3H), 1.94 (s, 3H), 1.90 - 1.50 (m, 6H), 1.10 (d, J = 5.6 Hz, 3H). 25 Example 30: (E)-N-((3S,5R)-5-Ethyl-1-((2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)piperidin-3-yl)-4- (methyl (prop-2-yn-1-yl)amino)but-2-enamide 30 Step 1: Synthesis of (E)-N-((3S,5R)-5-ethyl-1-((2-(3-(3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)piperidin- 30 3-yl)-4-(methyl (prop-2-yn-1-yl)amino)but-2-enamide 30 110 Attorney Docket No.: 51728-013WO2 To a solution of 6-[[(3S,5R)-3-amino-5-ethyl-1-piperidyl]methyl]-2-[3-[3-methyl-1-(4- methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl) isoindolin-1-one B-19-5 (150.00 mg, 265 μmol, 1 eq, HCl salt) and (E)-4-[methyl(prop-2-ynyl)amino]but-2-enoic acid B- 5 12-3 (100 mg, 653 μmol, 2.47 eq) in DCM (3 mL) were DIEA (102.64 mg, 794.13 μmol, 138.32 μL, 3 eq) and HATU (201 mg, 529 μmol, 2 eq), and the reaction mixture was stirred at 20 °C for 1 hr. The reaction mixture was diluted with H2O (5 mL), and extracted with the mixture of DCM and MeOH (10:1, 15 mL x 4), washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by prep-HPLC (column: Waters Xbridge 10 BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:45%-75% B over 8.0 min) to afford (E)-N-[(3S,5R)-5-ethyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl) isoindolin-5-yl]methyl]-3-piperidyl]-4-[methyl (prop-2-ynyl) amino]but-2-enamide 30 (17 mg, 8.7% yield, 94.6% purity) as a white solid. MS (ESI) m / z 702.4 [M+H]+;1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.02 (s, 1H), 7.97 (s, 1H), 15 7.86 (s, 1H), 7.52 (br d, J = 8.3 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 6.77 (td, J = 6.1, 15.3 Hz, 1H), 5.93 (d, J = 15.3 Hz, 1H), 5.23 (br d, J = 8.3 Hz, 1H), 5.00 (s, 2H), 4.15 - 4.02 (m, 1H), 3.71 - 3.60 (m, 2H), 3.33 (d, J = 2.3 Hz, 2H), 3.27 (s, 3H), 3.18 (d, J = 5.3 Hz, 2H), 3.10 (br dd, J = 4.1, 10.8 Hz, 1H), 2.93 (br d, J = 3.8 Hz, 2H), 2.82 (br d, J = 8.2 Hz, 1H), 2.75 - 2.64 (m, 3H), 2.33 (s, 3H), 2.24 (t, J = 2.3 Hz, 1H), 2.14 - 2.05 (m, 1H), 1.74 (t, J = 10.3 20 Hz, 1H), 1.64 (br d, J = 5.8 Hz, 2H), 1.30 - 1.18 (m, 2H), 1.16 (d, J = 5.3 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H), 0.81 - 0.71 (m, 1H). Example 31: N-[[(3R)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]- 3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]methyl]prop-2-enamide 31 Step 1: Synthesis of tert-butyl (3R)-3-[(prop-2-enoylamino)methyl] piperidine-1- 25 carboxylate A solution of tert-butyl (3R)-3-(aminomethyl)piperidine-1-carboxylate B-31-1 (300 mg, 1.40 mmol, 1 eq) in DCM (5 mL) was added TEA (425 mg, 4.20 mmol, 585 μL, 3 eq). The mixture was cooled at 0 °C, then prop-2-enoyl chloride (127 mg, 1.40 mmol, 114 μL, 1 eq) in DCM (0.5 30 mL) was added. The mixture was stirred at 0 °C for 1 hr. Upon completion, the reaction mixture was quenched with water (10 mL) at 20 °C and diluted with DCM (20 mL). Organic layer was separated and the aqueous layer was extracted with DCM (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, EA) to give tert-butyl (3R)-3-[(prop-2-enoylamino) 35 methyl] piperidine-1-carboxylate B-31-2 (210 mg, 53.7% yield, 96% purity) as a yellow oil. MS (ESI) m / z 168.9 [M+H-Boc]+. Step 2: Synthesis of N-[[(3S)-3-piperidyl]methyl]prop-2-enamide trifluoroacetate B- 111 Attorney Docket No.: 51728-013WO2 31-3 A solution of tert-butyl (3R)-3-[(prop-2-enoylamino)methyl]piperidine-1-carboxylate B- 31-2 (30 mg, 112 μmol, 1 eq) in DCM (0.5 mL) was added TFA (307 mg, 2.69 mmol, 0.2 mL, 24 5 eq), and the mixture was stirred at 0 °C for 0.5 hr. Upon completion, the reaction solution was concentrated under reduced pressure to give crude N-[[(3S)-3-piperidyl]methyl]prop-2-enamide trifluoroacetate B-31-3 (30 mg) as a yellow oil. MS (ESI) m / z 168.9 [M+H]+. Step 3: Synthesis of N-[[(3R)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]methyl] 10 prop-2-enamide 31 A solution of N-[[(3S)-3-piperidyl]methyl]prop-2-enamide trifluoroacetate B-31-3 (30 mg, 106μmol, 1 eq, TFA) in ACN (1 mL) were added [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl methanesulfonate Int-3- 15 OMs (57 mg, 106 μmol, 1 eq) and K2CO3(44 mg, 319 μmol, 3 eq), and the mixture was stirred at 80 °C for 2 hr. Upon completion, the reaction was cooled to room temperature, quenched with H2O (0.1 mL), filtered and concentrated. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*3 um; mobile phase: [H2O(0.1%TFA)-ACN]; gradient:5%-40% B over 8.0 min) to afford N-[[(3R)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4- 20 triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl] methyl]prop-2-enamide 31 (25 mg, 36.3% yield, 93.6% purity) as a white solid. MS (ESI) m / z 607.2 [M+H]+;1H NMR (400 MHz, DMSO-d6, 273K) δ 9.71 - 9.50 (m, 1H), 8.58 (s, 1H), 8.27 (br t, J = 6.0 Hz, 1H), 8.24 - 8.15 (m, 2H), 8.01 (s, 1H), 7.77 - 7.71 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.23 (br d, J = 7.3 Hz, 1H), 6.26 - 6.15 (m, 1H), 6.12 - 6.04 (m, 1H), 5.64 - 5.57 (m, 1H), 25 5.33 - 5.25 (m, 2H), 4.64 - 4.46 (m, 2H), 3.39 - 3.30 (m, 2H), 3.28 (s, 3H), 3.08 (br t, J = 6.3 Hz, 2H), 2.96 - 2.83 (m, 3H), 2.76 - 2.54 (m, 4H), 1.98 - 1.56 (m, 4H), 1.20 - 1.03 (m, 4H);1H NMR (400 MHz, DMSO-d6, 273+80K) δ 8.37 (s, 1H), 8.24 (s, 1H), 8.15 (s, 1H), 8.06 - 7.95 (m, 2H), 7.71 (br d, J = 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.21 (br d, J = 7.6 Hz, 1H), 6.25 - 6.13 (m, 1H), 6.11 - 6.01 (m, 1H), 5.62 - 5.51 (m, 1H), 5.30 - 5.19 (m, 2H), 4.54 (br d, J = 7.4 Hz, 2H), 30 3.40 - 3.28 (m, 2H), 3.26 (s, 3H), 3.16 - 3.09 (m, 2H), 2.95 - 2.86 (m, 3H), 2.67 - 2.58 (m, 3H), 2.12 - 1.95 (m, 1H), 1.92 - 1.61 (m, 3H), 1.39 - 1.08 (m, 5H). Example 32: (E)-N-[(3S)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]pyrrolidin-3-yl]-4- [methyl(prop-2-ynyl)amino] but-2-enamide 32 35 Step 1: Synthesis of tert-butyl (3S)-3-[[(E)-4-[methyl(prop-2-ynyl)amino]but-2-enoyl] 112 Attorney Docket No.: 51728-013WO2 amino]pyrrolidine-1-carboxylate B-32-1 To a solution of (E)-4-[methyl(prop-2-ynyl)amino]but-2-enoic acid B-11-3 (206 mg, 1.34 mmol, 2.5 eq) in DCM (3 mL) were added TEA (163 mg, 1.61 mmol, 224 μL, 3 eq) and T4P (580 5 mg, 805 μmol, 50% purity, 1.5 eq), and the mixture was stirred at 20 °C for 0.5 hr. tert-Butyl (3S)- 3-aminopyrrolidine-1-carboxylate B-26-1 (100 mg, 537 μmol, 1 eq) was then added and the reaction was stirred for 0.5 hr. Upon completion, the reaction mixture was quenched with H2O (3 mL) at 20 °C, and extracted with DCM 9 mL (3 mL x 3). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced10 pressure. The residue obtained was purified by prep-TLC (SiO2, EA: MeOH = 10:1) to give tert- butyl (3S)-3-[[(E)-4-[methyl(prop-2-ynyl)amino]but-2-enoyl]amino]pyrrolidine-1-carboxylate B-32-1 (200 mg, 58% yield) as a white solid. MS (ESI) m / z 322.3 [M+H]+. Step 2: Synthesis of (E)-4-[methyl(prop-2-ynyl)amino]-N-[(3S)-pyrrolidin-3-yl]but-2- enamide trifluoroacetate B-32-2 15 A solution of tert-butyl (3S)-3-[[(E)-4-[methyl(prop-2-ynyl)amino]but-2-enoyl]amino] pyrrolidine-1-carboxylate B-32-1 (90 mg, 280 μmol, 1 eq) in DCM (0.9 mL) and TFA (0.3 mL) was stirred at 20 °C for 1 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude (E)-4-[methyl(prop-2-ynyl)amino]-N-[(3S)-pyrrolidin-3-yl]but-2- 20 enamide trifluoroacetate B-32-2 (187 mg) as a colorless oil. MS (ESI) m / z 222.3 [M+H]+. Step 3: Synthesis of (E)-N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl] pyrrolidin-3-yl]-4- [methyl (prop-2-ynyl)amino]but-2-enamide 32 25 To a solution of (E)-4-[methyl(prop-2-ynyl)amino]-N-[(3S)-pyrrolidin-3-yl]but-2- enamide trifluoroacetate B-32-2 (70 mg, 208.76 μmol, 1.5 eq) in EtOH (2 mL) were added 2-[3- [3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- (trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (63 mg, 139 μmol, 1 eq), TEA (42 mg, 418 μmol, 58 μL, 3 eq), Ti(i-PrO)4 (59 mg, 209 μmol, 62 μL, 1.5 eq) and AcOH (42 mg, 696 μmol, 30 40 μL, 5 eq). The mixture was stirred at 20 °C for 50 min, then NaBH3CN (87.46 mg, 1.39 mmol, 10 eq) was added. The solution was stirred at 20 °C for 10 min. Upon completion, the reaction mixture was quenched with H2O (2 mL) at 20 °C, filtered and concentrated under reduced pressure. 113 Attorney Docket No.: 51728-013WO2 The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18100 * 40 mm * 3 um; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 5%-35% B over 8.0 min) to afford (E)- N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- (trifluoromethyl)isoindolin-5-yl]methyl]pyrrolidin-3-yl]-4-[methyl(prop-2-ynyl) amino]but-2- 5 enamide 32 (25 mg, 27.1% yield, 99.5% purity, TFA salt) as a white solid. MS (ESI) m / z 660.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.67 - 10.23 (m, 1H), 8.86 - 8.58 (m, 1H), 8.49 (s, 1H), 8.27 (br s, 1H), 8.22 (br s, 1H), 8.00 (s, 1H), 7.73 (dd, J = 1.6, 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 6.68 - 6.52 (m, 1H), 6.30 - 6.17 (m, 1H), 5.27 (s, 2H), 4.64 (br s, 2H), 4.53 - 4.28 (m, 2H), 4.02 (br s, 2H), 3.85 (br s, 3H), 3.69 - 3.47 (m, 2H), 3.26 (s, 3H), 2.93 10 - 2.84 (m, 2H), 2.73 (br s, 3H), 2.57 (q, J = 7.6 Hz, 3H), 2.46 - 2.38 (m, 1H), 2.27 - 1.87 (m, 2H), 1.10 (d, J = 5.6 Hz, 3H). Example 33: N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3- oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]pyrrolidin-3-yl]but-2-ynamide 33 Step 1: Synthesis of tert-butyl (3S)-3-(but-2-ynoylamino)pyrrolidine-1-carboxylate 15 B-33-1 To a solution of tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate B-26-1 (200 mg, 1.07 mmol, 1 eq) in DCM (2 mL) at 0 ℃ was added TEA (217 mg, 2.15 mmol, 299 μL, 2 eq) and but- 2-ynoyl chloride (99 mg, 967 μmol, 0.9 eq). The mixture was stirred at 0 ℃ for 1 hr. Upon 20 completion, the reaction mixture was quenched with H2O (5 mL), and extracted with DCM 15 mL (5 mL x 3). The combined organic layers were dried on anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, EA) to give tert-butyl (3S)-3-(but-2-ynoylamino)pyrrolidine-1-carboxylate B-33-1 (156 mg, 57.6% yield) as a yellow solid. MS (ESI) m / z 275.2 [M+Na]+. 25 Step 2: Synthesis of N-[(3S)-pyrrolidin-3-yl]but-2-ynamide trifluoroacetate B-33-2 To a solution of tert-butyl (3S)-3-(but-2-ynoylamino)pyrrolidine-1-carboxylate B-33-1 (30 mg, 119 μmol, 1 eq) in DCM (1 mL) was added TFA (460 mg, 4.04 mmol, 0.3 mL, 34 eq). The mixture was stirred at 20 ℃ for 1 hr. Upon completion, the reaction mixture was concentrated30 under reduced pressure to give crude N-[(3S)-pyrrolidin-3-yl]but-2-ynamide trifluoroacetate B- 33-2 (31 mg) as a yellow oil. MS (ESI) m / z 153.2 [M+H]+. Step 3: Synthesis of N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl] pyrrolidin-3-yl]but- 2-ynamide 33 114 Attorney Docket No.: 51728-013WO2 To a solution of N-[(3S)-pyrrolidin-3-yl]but-2-ynamide trifluoroacetate B-33-2 (31 mg, 116 μmol, 1.07 eq) in ACN (1 mL) were added K2CO3(45 mg, 326 μmol, 3 eq) and [2-[3-[3- methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5- 5 yl]methyl methanesulfonate Int-3-OMs (58 mg, 109 μmol, 1 eq). The mixture was stirred at 80 ℃ for 16 hr. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%-60% B over 8.0 min) to afford N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3- 10 oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]pyrrolidin-3-yl]but-2-ynamide 33 (18 mg, 27.3% yield, 97.3% purity) as a pink solid. MS (ESI) m / z 591.3 [M+H]+;1H NMR (400 MHz, DMSO- d6) δ = 8.71 (d, J = 6.9 Hz, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.68 (dd, J = 1.3, 8.2 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 5.19 (s, 2H), 4.21 - 4.07 (m, 1H), 3.86 - 3.64 (m, 2H), 3.22 (s, 3H), 2.92 - 2.82 (m, 2H), 2.73 - 2.55 (m, 5H), 2.41 (br s, 1H), 15 2.38 - 2.31 (m, 1H), 2.15 - 2.01 (m, 1H), 1.94 (s, 3H), 1.70 - 1.59 (m, 1H), 1.09 (d, J = 5.4 Hz, 3H). Example 34: (E)-N-[(3S,5S)-5-Ethynyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]-4-[methyl (prop-2-ynyl)amino]but-2-enamide 34 20 Step 1: Synthesis of (E)-N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2- triisopropylsilylethynyl)-3-piperidyl]-4-[methyl(prop-2-ynyl)amino]but-2-enamide B-34-1 To a solution of (E)-4-[methyl(prop-2-ynyl)amino]but-2-enoic acid B-11-3 (344 mg, 2.25 mmol, 3 eq) in DCM (8 mL) were added DIEA (194 mg, 1.50 mmol, 261 μL, 2 eq) and HATU25 (342 mg, 898 μmol, 1.2 eq), and the mixture was stirred at 20 °C for 5 mins. Then (3S,5S)-1-[(4- methoxyphenyl)methyl]-5-(2-triisopropylsilylethynyl) piperidin-3-amine B-18-5 (300 mg, 749 μmol, 1 eq) was added, and the mixture was stirred at 20 °C for 1hr. The mixture was diluted with water (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The30 crude obtained was purified by prep-TLC (SiO2, PE:EA = 1:1). (E)-N-[(3S,5S)-1-[(4- Methoxyphenyl)methyl]-5-(2-triisopropylsilylethynyl)-3-piperidyl]-4-[methyl(prop-2-ynyl) amino]but-2-enamide B-34-1 (550 mg, crude) was obtained as a light-yellow oil. MS (ESI) m / z 536.5 [M+H]+. Step 2: Synthesis of (E)-4-[methyl(prop-2-ynyl)amino]-N-[(3S,5S)-5-(2- 35 triisopropylsilyl ethynyl)-3-piperidyl]but-2-enamide B-34-2 115 Attorney Docket No.: 51728-013WO2 To a solution of (E)-N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-triisopropyl silyl ethynyl)-3-piperidyl]-4-[methyl(prop-2-ynyl)amino]but-2-enamide B-34-1 (500 mg, 933 μmol, 1 eq) in MeCN (10 mL) and H2O (1 mL) was added CAN (2.56 g, 4.67 mmol, 5 eq), and the mixture 5 was stirred at 20 °C for 16 hr. The mixture was diluted with saturated aqueous NaHCO3solution (60 mL) and EA (30mL) and filtered. Aqueous layer was extracted with the mixture of DCM and MeOH (10 / 1, 30 mL x 4). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude (E)-4-[methyl(prop-2-ynyl)amino]- N-[(3S,5S)-5-(2-triisopropylsilylethynyl)-3-piperidyl]but-2-enamide B-34-2(350 mg) as a light-10yellow oil. MS (ESI) m / z 416.4 [M+H]+. Step 3: Synthesis of (E)-N-[(3S,5S)-5-ethynyl-3-piperidyl]-4-[methyl(prop-2-ynyl) amino] but-2-enamide B-34-3 To a solution of (E)-4-[methyl(prop-2-ynyl)amino]-N-[(3S,5S)-5-(2-triisopropylsilyl 15 ethynyl) -3-piperidyl]but-2-enamide B-34-2 (350 mg, 842 μmol, 1 eq) in DMF (5 mL) was added CsF (1.28 g, 8.42 mmol, 10 eq), and the mixture was stirred at 40 °C for 16 hr. The mixture was diluted with saturated aqueous NaHCO3 solution (60 mL) and EA (30 mL) and filtered. The aqueous layer was extracted with the mixture of DCM and MeOH (10 / 1, 30 mL x 4). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under20 reduced pressure to give crude (E)-N-[(3S,5S)-5-ethynyl-3-piperidyl]-4-[methyl(prop-2- ynyl)amino]but-2-enamide B-34-3 (210 mg) as a light-yellow oil. MS (ESI) m / z 260.2 [M+H]+. Step 4: Synthesis of (E)-N-[(3S,5S)-5-ethynyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4- triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3- piperidyl]-4-[methyl (prop-2-ynyl)amino]but-2-enamide 34 25 To a solution of [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl] phenyl]-3- oxo-7-(trifluoromethyl)isoindolin-5-yl]methylmethanesulfonate Int-3-OMs (320 mg, 599 μmol, 1 eq) and (E)-N-[(3S,5S)-5-ethynyl-3-piperidyl]-4-[methyl(prop-2-ynyl)amino]but-2-enamide (311 mg, 838 μmol, 1.4 eq) in MeCN (10 mL) was added K2CO3(331 mg, 2.39 mmol, 4 eq), and 30 the mixture was stirred at 50 °C for 3hr. Upon completion, the mixture was filtered to give the crude. The crude was purified by prep-TLC(SiO2, MeOH=10:1). Then purified by prep- 116 Attorney Docket No.: 51728-013WO2 HPLC(column: Waters Xbridge BEH C18 100 * 30mm * 10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:35%-65% B over 8.0 min) to afford (E)-N-[(3S,5S)-5-ethynyl-1-[[2- [3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl) isoindolin-5-yl]methyl]-3-piperidyl]-4-[methyl(prop-2-ynyl)amino]but-2-enamide 34 (26.6 mg, 5 6.4% yield, 100% purity) as a white solid. MS (ESI) m / z 698.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.96 - 7.91 (m, 2H), 7.67 (br d, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.49 (m, 1H), 5.98 (d, J = 15.6 Hz, 1H), 5.20 (s, 2H), 3.84 - 3.69 (m, 3H), 3.26 (d, J = 2.0 Hz, 2H), 3.22 (s, 3H), 3.15 (t, J = 2.0 Hz, 1H), 3.08 (br d, J = 6.0 Hz, 2H), 2.98 - 2.80 (m, 5H), 2.56 (m, 4H), 2.17 (s, 3H), 2.09 - 1.99 (m, 1H), 10 1.92 (s, 1H), 1.74 (s, 1H), 1.19 (br d, J = 12.4 Hz, 1H), 1.09 (br d, J = 5.2 Hz, 3H). Example 35: N-[(3S,5R)-5-(1-Isopropyltriazol-4-yl)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4- triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3- piperidyl]prop-2-enamide 35 Step 1: Synthesis of tert-butyl N-[(3S,5R)-5-(1-isopropyltriazol-4-yl)-1-[(4- 15 methoxyphenyl)methyl]-3-piperidyl]carbamate B-35-1 A mixture of tert-butyl N-[(3S,5S)-5-ethynyl-1-[(4-methoxyphenyl)methyl]-3-piperidyl] carbamate B-19-2 (500 mg, 1.45 mmol, 1 eq) and 2-azidopropane (124 mg, 1.45 mmol, 1 eq) in DMF (5 mL) were added CuSO4·5H2O (435 mg, 1.74 mmol, 1.2 eq) and sodium ascorbate (690 20 mg, 3.48 mmol, 2.4 eq). The mixture was stirred at 20°C for 1hr. Upon completion, the solution was poured into water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (5 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (EA, Rf = 0.45）to give tert-butyl N-[(3S,5R)-5-(1-isopropyltriazol-4-yl)-1-[(4-methoxyphenyl)methyl]-3- 25 piperidyl]carbamate B-35-1 (550 mg, 70.6% yield, 80% purity) as a yellow oil. MS (ESI) m / z 430.3 [M+H]+. Step 2: Synthesis of (3S,5R)-5-(1-isopropyltriazol-4-yl)-1-[(4-methoxyphenyl)methyl] piperidin-3-amine trifluoroacetate B-35-2 30 A solution of tert-butyl N-[(3S,5R)-5-(1-isopropyltriazol-4-yl)-1-[(4- methoxyphenyl)methyl]-3-piperidyl]carbamate B-35-1 (550 mg, 1.28 mmol, 1 eq) in TFA (2 mL) and DCM (10 mL) was stirred at 25°C for 1hr. Upon completion, the mixture was concentrated 117 Attorney Docket No.: 51728-013WO2 under reduced pressure to give (3S,5R)-5-(1-isopropyltriazol-4-yl)-1-[(4-methoxyphenyl)methyl] piperidin-3-amine trifluoroacetae B-35-2 (570 mg, crude) as a yellow oil. MS (ESI) m / z 330.2 [M+H]+. Step 3: Synthesis of N-[(3S,5R)-5-(1-isopropyltriazol-4-yl)-1-[(4-methoxyphenyl) 5 methyl] -3-piperidyl]prop-2-enamide B-35-3 A solution of (3S,5R)-5-(1-isopropyltriazol-4-yl)-1-[(4-methoxyphenyl)methyl] piperidin- 3-amine trifluoroacetate B-35-2 (550 mg, 1.24 mmol, 1 eq) in DCM (5 mL) was added TEA (627 mg, 6.20 mmol, 863 μL, 5 eq) followed by prop-2-enoyl chloride (112 mg, 1.24 mmol, 101 μL, 1 10 eq) at 0°C and stirred at 0°C for 1hr. Upon completion, the reaction mixture was poured into water (10 mL) slowly and extracted with DCM (5 mL x 2). The combined organic layers were washed with brine (3 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N-[(3S,5R)-5-(1-isopropyltriazol-4-yl)-1-[(4-methoxyphenyl)methyl]-3- piperidyl] prop-2-enamide B-35-3 (450 mg, 75.7% yield, 80% purity) as a yellow oil. MS (ESI) 15 m / z 384.3 [M+H]+. Step 4: Synthesis of 4-[methyl(prop-2-ynyl)amino]-N-[(3S)-3-piperidyl] butanamide B-35-4 A solution of N-[(3S,5R)-5-(1-isopropyltriazol-4-yl)-1-[(4-methoxyphenyl) methyl]-3- 20 piperidyl] prop-2-enamide B-35-3 (450 mg, 1.17 mmol, 1 eq) in ACN (10 mL) and H2O (1 mL) was added CAN (6.43 g, 11.7 mmol, 10 eq). The mixture was stirred at 20 °C for 16 hr. Upon completion, the solution was filtered and concentrated under reduced pressure. The crude product obtained was purified by prep – HPLC (column: Phenomenex luna C18250*50mm*15um;mobile phase: [H2O(0.1% TFA)-ACN]; gradient:1%-25% B over 10.0 min) to give N-[(3S,5R)-5-(1- 25 isopropyltriazol-4-yl)-3-piperidyl]prop-2-enamide B-35-4 (60 mg, 19.4% yield) as a brown oil. MS (ESI) m / z 264.1 [M+H]+. Step 5: Synthesis of N-[(3S,5R)-5-(1-isopropyltriazol-4-yl)-1-[[2-[3-[3-methyl-1-(4- methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5- yl]methyl]-3-piperidyl] prop-2-enamide 35 118 Attorney Docket No.: 51728-013WO2 A mixture of N-[(3S,5R)-5-(1-isopropyltriazol-4-yl)-3-piperidyl]prop-2-enamide B-35-4 (30 mg, 114 μmol, 1 eq) and [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]- 3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl methanesulfonate Int-3-OMs (102 mg, 114 5 μmol, 1 eq) in ACN (2 mL) was added K2CO3(79 mg, 570 μmol, 5 eq). The mixture was stirred at 80 °C for 2 hr. The reaction mixture solution was cooled to room temperature, saturated aqueous NaHCO3solution (10 mL) and ethyl acetate (5 mL) were added and filtered. Then aqueous solution was extracted with ethyl acetate(5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced 10 pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*3 um; mobile phase: [H2O (0.1%TFA)-ACN];gradient:10%-45% B over 8.0 min) to afford N-[(3S,5R)-5-(1-isopropyltriazol-4-yl)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl] phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]prop-2- enamide 35 (26.02 mg, 31.9% yield, 98% purity) as a white solid. MS (ESI) m / z 702.3 [M+H]+; 151H NMR (400 MHz, DMSO-d6) δ 8.60 - 8.53 (m, 1H), 8.41 (br d, J = 7.4 Hz, 1H), 8.25 (br d, J = 13.8 Hz, 2H), 8.09 (s, 1H), 8.01 (s, 1H), 7.73 (br d, J = 8.1 Hz, 1H), 7.54 - 7.43 (m, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.27 - 6.08 (m, 2H), 5.70 - 5.61 (m, 1H), 5.27 (s, 2H), 4.81 - 4.75 (m, 1H), 4.61 (br s, 2H), 4.23 (br s, 2H), 3.62 - 3.55 (m, 1H), 3.51 (s, 1H), 3.27 (s, 3H), 3.12 - 3.01 (m, 1H), 2.89 (br d, J = 3.5 Hz, 2H), 2.79 (br d, J = 3.3 Hz, 1H), 2.61 - 2.55 (m, 3H), 2.23 (br d, J = 11.6 20 Hz, 1H), 1.76 - 1.60 (m, 1H), 1.46 (d, J = 6.6 Hz, 6H), 1.13 - 1.07 (m, 3H);1H NMR (400 MHz, DMSO-d6+ D2O) δ 8.69 - 8.58 (m, 1H), 8.18 (br d, J = 13.3 Hz, 2H), 8.03 - 7.93 (m, 2H), 7.62 (br d, J = 8.4 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.24 (br d, J = 8.0 Hz, 1H), 6.27 - 6.04 (m, 2H), 5.71 - 5.64 (m, 1H), 5.21 (br s, 2H), 4.73 (td, J = 6.7, 13.4 Hz, 1H), 4.58 (br s, 2H), 4.30 - 4.11 (m, 2H), 3.60 (br d, J = 9.6 Hz, 1H), 3.42 (s, 1H), 3.30 (s, 3H), 3.16 - 3.06 (m, 1H), 2.92 - 2.80 (m, 3H), 25 2.56 - 2.52 (m, 3H), 2.21 (br d, J = 12.1 Hz, 1H), 1.78 - 1.61 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H), 1.05 (br d, J = 4.9 Hz, 3H). Example 36: N-((1H-1,2,3-Triazol-4-yl)methyl)-N-(2-(((2-(3-(3-methyl-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5- yl)methyl)amino)ethyl) acrylamide 36 30 Step 1: Synthesis of tert-butyl N-[2-[prop-2-enoyl(1H-triazol-4-ylmethyl)amino]ethyl] carbamate B-36-2 To a solution of tert-butyl N-[2-[prop-2-enoyl(prop-2-ynyl)amino]ethyl] carbamate B-36- 119 Attorney Docket No.: 51728-013WO2 1 (0.5 g, 1.98 mmol, 1 eq), CuSO4·5H2O (990 mg, 3.96 mmol, 2 eq) and sodium-ascorbate (1.18 g, 5.95 mmol, 3 eq) in DMF (10 mL) was added NaN3 (155 mg, 2.38 mmol, 1.2 eq) under N2. The reaction mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched with saturated aqueous NH4Cl solution (20 mL), added EDTA (1 g) and stirred at room temperature for 0.5 hr. 5 The solution was extracted with EtOAc (20 mL x 3), washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 um; mobile phase: [H2O(0.2% FA)-ACN]; gradient: 5%-45% B over 8.0 min). tert-Butyl N-[2-[prop-2-enoyl(1H- triazol-4-ylmethyl)amino]ethyl]carbamate B-36-2 (150 mg, 25.6% yield, 100% purity) was 10 obtained as an aquamarine solid. MS (ESI) m / z 296.1 [M+H]+. Step 2: Synthesis of N-(2-aminoethyl)-N-(1H-triazol-4-ylmethyl)prop-2-enamide B- 36-3 The solution of tert-butyl N-[2-[prop-2-enoyl(1H-triazol-4-ylmethyl)amino] ethyl] 15 carbamate B-36-2 (0.14 g, 474 μmol, 1 eq) in DCM (1.5 mL) and TFA (0.5 mL) was stirred at 20 °C for 16 hr. The reaction mixture was concentrated to give crude N-(2-aminoethyl)-N-(1H- triazol-4-ylmethyl)prop-2-enamide trifluoroacetate B-36-3 (0.14 g) as an aquamarine solid. MS (ESI) m / z 196.2 [M+H]+. Step 3: Synthesis of N-[2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] 20 phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino]ethyl]-N-(1H-triazol-4-yl methyl To a solution of N-(2-aminoethyl)-N-(1H-triazol-4-ylmethyl)prop-2-enamide trifluroacetate B-36-3 (86 mg, 440 μmol, 2.5 eq) in EtOH (2 mL) were added TEA (36 mg, 35225 μmol, 49 μL, 2 eq), 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7- (trifluoromethyl) isoindoline-5-carbaldehyde Int-2 (80 mg, 176μmol, 1 eq), Ti(i-PrO)4(150 mg, 528 μmol, 156 μL, 3 eq), and the mixture was stirred at 20°C for 1hr. Then NaBH3CN (111 mg, 1.76 mmol, 10 eq) was added and the mixture was stirred at 20°C for 1hr. The reaction mixture was quenched with H2O (10 mL), extracted with the mixture of DCM and MeOH (10:1, 25 mL x303), washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*15um;mobile phase: [H2O(0.1% TFA)-ACN]; gradient:25%-45% B over 10.0 min) to afford N-[2-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7- (trifluoromethyl)isoindolin-5-yl]methylamino]ethyl]-N-(1H-triazol-4-ylmethyl)prop-2-enamide 120 Attorney Docket No.: 51728-013WO2 36 (23.2 mg, 17% yield, 96.3% purity, TFA salt) as a white solid. MS (ESI) m / z 634.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.14 - 8.88 (m, 2H), 8.64 (br s, 1H), 8.29 - 8.13 (m, 2H), 8.00 (s, 1H), 7.78 (br d, J = 8.0 Hz, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.22 (br d, J = 7.6 Hz, 1H), 6.96 - 6.70 (m, 1H), 6.29 - 6.16 (m, 1H), 5.83 - 5.71 (m, 1H), 5.28 (s, 2H), 4.75 (s, 2H), 4.44 (br s, 2H), 5 3.76 - 3.67 (m, 2H), 3.32 - 3.17 (m, 5H), 2.97 - 2.84 (m, 2H), 2.58 (br d, J = 8.0 Hz, 3H), 1.10 (br d, J = 5.5 Hz, 3H);1H NMR (400 MHz, DMSO-d6, 273K+80K) δ 8.93 (br s, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.97 (t, J = 1.7 Hz, 1H), 7.78 (br s, 1H), 7.73 (dd, J = 1.5, 8.0 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 6.89 - 6.76 (m, 1H), 6.20 (dd, J = 2.2, 16.6 Hz, 1H), 5.75 (dd, J = 2.2, 10.4 Hz, 1H), 5.23 (s, 2H), 4.73 (br s, 2H), 4.46 (s, 2H), 3.75 (br t, J = 6.6 10 Hz, 2H), 3.28 - 3.22 (m, 5H), 2.94 - 2.88 (m, 2H), 2.65 - 2.58 (m, 3H), 1.12 (d, J = 5.8 Hz, 3H). Example 37: N-(2-(((2-(3-(3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl) - 3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)amino)ethyl)-N-((1-methyl-1H-1,2,3- triazol-4-yl)methyl)acrylamide 37 15 Step 1: Synthesis of tert-butyl N-[2-[(1-methyltriazol-4-yl)methyl-prop-2-enoyl- amino] ethyl]carbamate B-37-1 To a solution of MeI (422 mg, 2.97 mmol, 185 μL, 1.5 eq) in DMF (8 mL) and H2O (2 mL) were added NaN3(193 mg, 2.97 mmol, 1.5 eq), CuSO4·5H2O (198 mg, 793 μmol, 0.4 eq), sodium 20 ascorbate (314 mg, 1.59 mmol, 0.8 eq) and Na2CO3(840 mg, 7.93 mmol, 4 eq). The reaction solution was stirred for 10 min and tert-butyl N-[2-[prop-2-enoyl(prop-2-ynyl)amino]ethyl] carbamate B-36-1 (0.5 g, 1.98 mmol, 1 eq) was added. The reaction mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched with saturated aqueous NH4Cl solution (20 mL), added EDTA (1 g) and stirred at room temperature for 0.5 hr. The solution was extracted with25EtOAc (20 mL x 3), washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7um; mobile phase: [H2O(0.05% NH3H2O+10mM NH4HCO3)-ACN]; gradient:15%-45% B over 8.0 min). tert-Butyl N-[2-[(1-methyltriazol-4-yl) methyl-prop-2-enoyl-amino]ethyl]carbamate B-37-1 (320 mg, 52.2% yield, 100% purity) was 30 obtained as a white solid. MS (ESI) m / z 310.0 [M+H]+. Step 2: Synthesis of N-(2-aminoethyl)-N-[(1-methyltriazol-4-yl)methyl] prop-2- enamide trifluoroacetate B-37-2 The solution of tert-butyl N-[2-[(1-methyltriazol-4-yl)methyl-prop-2-enoyl-amino]ethyl] 35 carbamate B-37-1 (150 mg, 484.87 μmol, 1 eq) in DCM (1.5 mL) and TFA (0.5 mL) was stirred at 20 °C for 16 hr. The reaction mixture was concentrated to give crude N-(2-aminoethyl)-N-[(1- 121 Attorney Docket No.: 51728-013WO2 methyltriazol-4-yl)methyl]prop-2-enamide trifluoroacetate B-37-2 (0.15 g) as a colorless oil. MS (ESI) m / z 210.2 [M+H]+. Step 3: Synthesis of N-[2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino] ethyl]-N-[(1- 5 methyltriazol-4-yl)methyl] prop-2-enamide 37 To a solution of N-(2-aminoethyl)-N-[(1-methyltriazol-4-yl)methyl]prop-2-enamide trifluoroacetate B-37-2 (92 mg, 440 μmol, 2.5 eq) in EtOH (2 mL) were added TEA (36 mg, 352 μmol, 49 μL, 2 eq), 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- 10 (trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (80 mg, 176 μmol, 1 eq) and Ti(i-PrO)4 (150mg, 528 μmol, 156 μL, 3 eq), and the mixture was stirred at 20 °C for 1hr. Then NaBH3CN (111 mg, 1.76 mmol, 10 eq) was added the mixture was stirred at 20°C for 1hr. The reaction mixture was quenched with H2O (10 mL), extracted with the mixture of DCM and MeOH (10:1, 25 mL x 3), washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated 15 under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18250*50mm*15um;mobile phase: [H2O(0.1% TFA)-ACN]; gradient:25%-45% B over 10.0 min). to give N-[2-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3- oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino] ethyl]-N-[(1-methyltriazol-4- yl)methyl]prop-2-enamide 37 (31 mg, 22.6% yield, 97.7% purity, TFA salt) as a white solid . MS 20 (ESI) m / z 648.3 [M+H]+;1H NMR (400 MHz, DMSO-d6, 273K) δ 9.19 - 8.90 (m, 2H), 8.60 (s, 1H), 8.28 - 8.16 (m, 2H), 8.02 (d, J = 10.9 Hz, 2H), 7.77 (br d, J = 8.1 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.96 - 6.70 (m, 1H), 6.22 (dd, J = 1.9, 16.6 Hz, 1H), 5.81 - 5.71 (m, 1H), 5.28 (s, 2H), 4.71 - 4.57 (m, 2H), 4.45 (br s, 2H), 4.04 - 4.00 (m, 3H), 3.80 - 3.68 (m, 2H), 3.33 - 3.19 (m, 5H), 2.96 - 2.83 (m, 2H), 2.63 - 2.55 (m, 3H), 1.10 (d, J = 5.6 Hz, 3H);25 1HNMR (400 MHz, DMSO-d6, 273K + 80K) δ 9.08 - 8.85 (m, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.96 (br d, J = 1.8 Hz, 2H), 7.73 (dd, J = 1.6, 8.2 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.89 - 6.76 (m, 1H), 6.20 (dd, J = 2.3, 16.7 Hz, 1H), 5.74 (dd, J = 2.2, 10.4 Hz, 1H), 5.23 (s, 2H), 4.68 (br s, 2H), 4.46 (s, 2H), 4.03 (s, 3H), 3.77 (br t, J = 6.4 Hz, 2H), 3.26 (s, 5H), 2.96 - 2.83 (m, 2H), 2.65 - 2.58 (m, 3H), 1.12 (d, J = 5.7 Hz, 3H). 30 Example 38: N-((3S,5S)-5-Ethynyl-1-((2-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol- 3-yl) cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)piperidin-3- yl)octa-2,7-diynamide 38 Step 1: Synthesis of N-((3S,5S)-1-(4-methoxybenzyl)-5-((triisopropylsilyl) ethynyl) piperid 35 122 Attorney Docket No.: 51728-013WO2 To a solution of (3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-triisopropyl silylethynyl) piperidin-3-amine B-18-5(1 g, 2.50 mmol, 1 eq) and octa-2,7-diynoic acid (204 mg, 1.50 mmol, 0.6 eq) in DCM (20 mL) was added DIEA (968 mg, 7.49 mmol, 1.30 mL, 3 eq) followed by dropwise addition of T4P (8.99 g, 12.5 mmol, 50% purity, 5 eq) at 0 °C. The reaction mixture was 5 stirred at 20 °C for 1 hr. The reaction mixture was diluted with H2O (15 mL), extracted with DCM (50 mL x 2), washed with saturated aqueous NaHCO3solution (50 mL), brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Welch Xtimate C18 180*70mm#10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 68%-98% B over 16.0 min) to afford N-[(3S,5S)-1-10 [(4-methoxyphenyl)methyl]-5-(2-triisopropylsilylethynyl)-3-piperidyl] octa-2,7-diynamide B-38- 1 (0.25 g, 18.3% yield, 95% purity) as a colorless oil. MS (ESI) m / z 519.2 [M+H]+;1H NMR (400 MHz, CDCl3) δ 7.23 (br d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 4.15 (br s, 1H), 3.81 (s, 3H), 3.59 - 3.37 (m, 2H), 2.95 - 2.55 (m, 3H), 2.43 (t, J = 7.1 Hz, 2H), 2.32 (dt, J = 2.6, 6.9 Hz, 2H), 2.14 - 2.04 (m, 1H), 1.99 (t, J = 2.6 Hz, 1H), 1.85 - 1.73 (m, 2H), 1.65 - 1.45 (m, 2H), 1.15 - 0.99 15 (m, 22H). Step 2: Synthesis of N-[(3S,5S)-5-(2-triisopropylsilylethynyl)-3-piperidyl] octa-2,7- diynamide To a solution of N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-triisopropyl silylethynyl)- 20 3-piperidyl]octa-2,7-diynamide B-38-1 (0.25 g, 482 μmol, 1 eq) in ACN (1.25 mL) and H2O (1.25 mL) was added CAN (1.32 g, 2.41 mmol, 1.20 mL, 5 eq), and the reaction mixture was stirred at 20 °C for 1 hr. The reaction mixture was diluted with H2O (5 mL), extracted with EtOAc (15 mL x 2), washed with brine (5 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was suspended in PE (30 mL). The precipitate was25 collected by filtration and washed with PE (10 mL x 3) to afford crude N-[(3S,5S)-5-(2- triisopropylsilylethynyl)-3-piperidyl]octa-2,7-diynamide B-38-2 (0.2 g, 83.3% yield, 80% purity) as a light-yellow solid. MS (ESI) m / z 399.3 [M+H]+. 38-3 30 To a solution of N-[(3S,5S)-5-(2-triisopropylsilylethynyl)-3-piperidyl]octa-2,7-diynamide B-38-2 (180 mg, 452 μmol, 1 eq) in DMF (2 mL) was added CsF (823 mg, 5.42 mmol, 12 eq), and the reaction mixture was stirred at 45 °C for 1 hr. The reaction mixture was diluted with H2O (5 mL), extracted with the mixture of DCM and MeOH (10:1, 15 mL x 2), washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give crude N-[(3S,5S)-5-ethynyl- 123 Attorney Docket No.: 51728-013WO2 3-piperidyl]octa-2,7-diynamide B-38-3 (0.1 g) as a brown oil. MS (ESI) m / z 243.2 [M+H]+. Step 4: Synthesis of N-[(3S,5S)-5-ethynyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4- triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3- piperidyl]octa-2,7-diynamide 38 5 To a solution of [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3- oxo-7-(trifluoromethyl)isoindolin-5-yl]methylmethanesulfonate Int-3-OMs (100 mg, 187 μmol, 1 eq) and N-[(3S,5S)-5-ethynyl-3-piperidyl]octa-2,7-diynamide B-38-3 (45 mg, 187 μmol, 1 eq) in ACN (2 mL) was added K2CO3(78 mg, 561 μmol, 3 eq), and the reaction mixture was stirred 10 at 80 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: WePure Biotech XPt C18150*40*7um; mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:45%-75% B over 8.0 min) to afford N- [(3S,5S)-5-ethynyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo- 7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]octa-2,7-diynamide 38 (37.7 mg, 28.3%15 yield, 95.5% purity) as a white solid. MS (ESI) m / z 681.3 [M+H]+;1H NMR (400 MHz, DMSO- d6) δ 8.47 (d, J = 8.0 Hz, 1H), 8.29 (s, 1H), 8.07 (t, J = 1.8 Hz, 1H), 7.95 (d, J = 19.3 Hz, 2H), 7.67 (dd, J = 1.4, 8.2 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 5.20 (s, 2H), 3.82 - 3.69 (m, 3H), 3.22 (s, 3H), 2.99 - 2.79 (m, 6H), 2.63 - 2.53 (m, 4H), 2.40 (t, J = 7.1 Hz, 2H), 2.26 (dt, J = 2.6, 7.1 Hz, 2H), 1.98 (br d, J = 12.0 Hz, 1H), 1.89 (br t, J = 11.0 Hz, 1H), 1.76 (t, J 20 = 10.7 Hz, 1H), 1.69 - 1.60 (m, 2H), 1.21 (q, J = 12.5 Hz, 1H), 1.09 (d, J = 5.4 Hz, 3H). Example 39: (E)-N-[(3S)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]-4- [methyl-[(1-methyltriazol-4-yl) methyl]amino]but-2-enamide 39 Step 1: Synthesis of tert-butyl N-methyl-N-[(1-methyltriazol-4-yl)methyl] carbamate 25 B-39-2 To a solution of MeI (923 mg, 6.50 mmol, 405 μL, 1.1 eq) in DMF (8 mL) and H2O (2 mL) were added NaN3 (461 mg, 7.09 mmol, 1.2 eq), Na2CO3 (1.88 g, 17.7 mmol, 3 eq), sodium ascorbate (937 mg, 4.73 mmol, 0.8 eq), CuSO4·5H2O (590 mg, 2.36 mmol, 0.4 eq) and tert-butyl 30 N-methyl-N-prop-2-ynyl-carbamate (1 g, 5.91 mmol, 1 eq). The reaction mixture was stirred at 25°C for 16 hr. Upon completion, the solution was added saturated aqueous NaHCO3solution (20ml) until pH value was larger than 9. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude tert-butyl N-methyl-N- 35 [(1-methyltriazol-4-yl)methyl]carbamate B-39-2 (1.1 g, 82.3% yield) as a yellow oil. MS (ESI) m / z 227.3 [M+H]+. Step 2: Synthesis of N-methyl-1-(1-methyltriazol-4-yl)methanamine hydrochloride B-39-3 124 Attorney Docket No.: 51728-013WO2 A solution of tert-butyl N-methyl-N-[(1-methyltriazol-4-yl)methyl]carbamate B-39-2 (500 mg, 2.21 mmol, 1 eq) in HCl / dioxane (4 M, 10.00 mL) was stirred at 20°C for 1hr. Upon completion, the mixture was concentrated under reduced pressure to give crude N-methyl-1-(1- 5 methyltriazol-4-yl)methanamine hydrochloride B-39-3 (400 mg) as a yellow oil. MS (ESI) m / z 127.3 [M+H]+. Step 3: Synthesis of (E)-4-bromobut-2-enoic acid B-39-5 To a solution of Methyl (E)-4-bromobut-2-enoate B-39-4 (1 g, 5.59 mmol, 657 μL, 1 eq) 10 in THF (5 mL) were added LiOH·H2O (352 mg, 8.38 mmol, 1.5 eq) and H2O (5 mL) at 0° C, and the solution was stirred for 2 hr. Upon completion, the reaction mixture was poured into H2O (20 mL) slowly and washed with ethyl acetate (10 mL x 2). Then the aqueous solution was acidified with HCl aqueous solution (1N) until pH value was around 1 and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10mL), dried over anhydrous15 sodium sulfate, filtered and concentrated under reduced pressure to give crude (E)-4-bromobut-2- enoic acid B-39-5 (500 mg) as a brown oil.1H NMR (400 MHz, DMSO-d6) δ 6.86 - 6.81 (m, 1H), 6.06 (d, J = 15.3 Hz, 1H), 4.26 (d, J = 7.5 Hz, 2H). Step 4: Synthesis of tert-butyl (3S)-3-[[(E)-4-bromobut-2-enoyl]amino] piperidine-1- carboxylate B-39-6 20 A solution of (E)-4-bromobut-2-enoic acid B-39-5 (500 mg, 3.03 mmol, 1 eq) and tert- butyl (3S)-3-aminopiperidine-1-carboxylate B-2-1 (607 mg, 3.03 mmol, 1 eq) in DCM (10 mL) was added DIEA (1.18 g, 9.09 mmol, 1.58 mL, 3 eq) followed by T4P (3.28 g, 4.55 mmol, 50% purity, 1.5 eq) at 0°C and stirred for 1hr. Upon completion, the reaction mixture was poured into 25 water (20 mL) slowly and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by flash silica gel chromatography (PE:EA = 10:1 to 1:1) to give tert-butyl (3S)-3-[[(E)-4-bromobut-2-enoyl]amino]piperidine-1-carboxylate B-39-6 (650 mg, 1.68 mmol, 55.6% yield, 90% purity) as a brown oil. MS (ESI) m / z 347.1 [M+H]+. 30 Step 5: Synthesis of tert-butyl (3S)-3-[[(E)-4-[methyl-[(1-methyltriazol-4-yl)methyl] amino]but-2-enoyl]amino]piperidine-1-carboxylate B-39-7 125 Attorney Docket No.: 51728-013WO2 A mixture of tert-butyl (3S)-3-[[(E)-4-bromobut-2-enoyl]amino]piperidine-1-carboxylate B-39-6 (500 mg, 1.44 mmol, 1 eq) and N-methyl-1-(1-methyltriazol-4-yl) methanamine hydrochloride B-39-3 (351 mg, 2.16 mmol, 1.5 eq) in ACN (10 mL) was added K2CO3 (995 mg, 7.20 mmol, 5 eq). The mixture was stirred at 20°C for 16 hr. Upon completion, the reaction mixture 5 was poured into water (20 mL) slowly and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (EA, Rf=0.45）to give tert-butyl (3S)-3-[[(E)-4-[methyl-[(1-methyltriazol-4-yl)methyl]amino]but-2- enoyl]amino] piperidine-1-carboxylate B-39-7 (250 mg, 42.0% yield, 95% purity) as a brown oil. 10 MS (ESI) m / z 393.3 [M+H]+. Step 6: Synthesis of (E)-4-[methyl-[(1-methyltriazol-4-yl)methyl]amino]-N-[(3S)-3- piperidyl] but-2-enamide trifluoroacetate B-39-8 H H N B-39-7 B-39-8 A solution of tert-butyl (3S)-3-[[(E)-4-[methyl-[(1-methyltriazol-4-yl)methyl] amino]but- 15 2-enoyl]amino]piperidine-1-carboxylate B-39-7 (50 mg, 127 μmol, 1 eq) in TFA (0.5 mL) and DCM (2 mL) was stirred at 20°C for 1 hr. Upon completion, the mixture was concentrated under reduced pressure to give crude (E)-4-[methyl-[(1-methyltriazol-4-yl)methyl]amino]-N-[(3S)-3- piperidyl] but-2-enamide trifluoroacetate B-39-8 (50 mg) as a yellow oil. MS (ESI) m / z 293.3 [M+H]+. 20 Step 7: Synthesis of (E)-N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]-4-[methyl [(1-methyl triazol-4-yl)methyl]amino]but-2-enamide 39 A m 3-piperidyl]25 but-2-enamide trifluoroacetate B-39-8 (50 mg, 123 μmol, 1 eq) and [2-[3-[3-methyl-1-(4-methyl- 1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl) isoindolin-5-yl]methyl methanesulfonate Int-3-OMs (110 mg, 123 μmol, 1 eq) in ACN (3 mL) were added K2CO3(85 mg, 615 μmol, 5 eq). The mixture was stirred at 80°C for 2 hr. Upon completion, the reaction mixture was added saturated aqueous NaHCO3 solution (10 mL), extracted with ethyl acetate (5 30 mL) and filtered Aqueous solution was extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC(column: Phenomenex luna C18 100*40mm*3 um; mobile phase: [H2O(0.1%TFA)-ACN]; gradient:5%- 35% B over 8.0 min) to afford (E)-N-[(3S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-35 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]-4-[methyl- [(1-methyltriazol-4-yl)methyl]amino]but-2-enamide 39 (28 mg, 30.9% yield, 99% purity, TFA salt) as a white solid. MS (ESI) m / z 731.4 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.45 - 9.88 (m, 2H), 8.52 (br s, 1H), 8.24 - 8.17 (m, 3H), 8.00 (s, 1H), 7.72 (br d, J = 8.0 Hz, 1H), 7.47 (t, J = 8.0 126 Attorney Docket No.: 51728-013WO2 Hz, 1H), 7.23 (br d, J = 7.6 Hz, 1H), 6.72 - 6.57 (m, 1H), 6.25 (br d, J = 15.5 Hz, 1H), 5.28 (br s, 2H), 4.59 (br s, 2H), 4.41 (br s, 2H), 4.09 (s, 3H), 3.91 (br d, J = 3.4 Hz, 2H), 3.44 - 3.34 (m, 2H), 3.25 (s, 3H), 2.96 - 2.80 (m, 4H), 2.69 (s, 3H), 2.57 (br d, J = 7.3 Hz, 3H), 2.44 (br s, 1H), 1.95 - 1.86 (m, 2H), 1.74 - 1.62 (m, 1H), 1.48 - 1.36 (m, 1H), 1.09 (br d, J = 5.4 Hz, 3H). 5 Example 40: N-[(3S,5R)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-5-(1H-triazol-4-yl)- 3-piperidyl]prop-2-enamide 40 Step 1: Synthesis of N-[(3S,5R)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-5-(1H-triazol-4-yl)-3- 10 piperidyl]prop-2-enamide 40 To a solution of N-[(3S,5S)-5-ethynyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]prop-2- enamide 18 (50 mg, 81.1 μmol, 1 eq) in DMF (1 mL) were added CuSO4·5H2O (24.3 mg, 97.3 15 μmol, 1.2 eq), sodium ascorbate (39 mg, 195 μmol, 2.4 eq) and NaN3 (10 mg, 154 μmol, 1.90 eq). The mixture was stirred at 20 °C for 16 hr. After completion, the mixture was diluted with saturated aqueous NaHCO3 solution (10 mL) and EDTA (500 mg), extracted with DCM (50 mL x 5), dried over anhydrous Na2SO4, filter and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: 3_Phenomenex Luna C1875 * 30 mm * 3um; mobile phase:20 [H2O(0.1% TFA)-ACN]; gradient:5%-35% B over 8.0 min). N-[(3S,5R)-1-[[2-[3-[3-Methyl-1-(4- methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoro methyl)isoindolin-5-yl]methyl]- 5-(1H-triazol-4-yl)-3-piperidyl]prop-2-enamide 40 (5 mg, 9.1% yield, 97.6% purity, TFA salt) was obtained as a white solid. MS (ESI) m / z 660.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.65 - 8.52 (m, 1H), 8.46 - 8.36 (m, 1H), 8.24 (br d, J = 15.2 Hz, 2H), 8.01 (s, 1H), 7.88 - 7.75 (m, 1H), 25 7.73 (br d, J = 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.21 (br d, J = 7.2 Hz, 1H), 6.29 - 6.07 (m, 2H), 5.66 (m, 1H), 5.34 - 5.23 (s, 2H), 4.71 - 4.53 (s, 2H), 4.27 - 4.18 (s, 1H), 3.62 - 3.47 (m, 2H), 3.38 - 3.21 (m, 4H), 3.16 - 3.01 (m, 1H), 2.94 - 2.83 (m, 2H), 2.81 - 2.70 (m, 1H), 2.64 - 2.54 (m, 3H), 2.29 - 2.17 (m, 1H), 1.75 - 1.59 (m, 1H), 1.10 (br d, J = 5.2 Hz, 3H). Example 41: N-[(3S,5R)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-30 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-5-(1-methyltriazol- 4-yl)-3-piperidyl]prop-2-enamide 41 Step 1: Synthesis of tert-butyl N-[(3S,5R)-1-[(4-methoxyphenyl)methyl]-5-(1- methyltriazol-4-yl)-3-piperidyl]carbamate B-41-1 127 Attorney Docket No.: 51728-013WO2 The solution of MeI (247 mg, 1.74 mmol, 108 μL, 1.2 eq) in DMF (10 mL) and H2O (2 mL) were added NaN3 (142 mg, 2.18 mmol, 1.5 eq), tert-butyl N-[(3S,5S)-5-ethynyl-1-[(4- methoxyphenyl)methyl]-3-piperidyl]carbamate B-19-2 (500 mg, 1.45 mmol, 1 eq), CuSO4·5H2O (145 mg, 581 μmol, 0.4 eq), Na2CO3 (615.42 mg, 5.81 mmol, 4 eq) and sodium ascorbate (230.06 5 mg, 1.16 mmol, 0.8 eq) subsequently. The mixture was stirred at 20 °C for 2 hr. Upon completion, the reaction mixture was quenched with H2O (20 mL), extracted with DCM (15 mL x 2), washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by flash silica gel chromatography (PE:EA = 10:1 to 1:10) to give tert-butyl N- [(3S,5R)-1-[(4-methoxyphenyl)methyl]-5-(1-methyltriazol-4-yl)-3-piperidyl] carbamate B-41-1 10 (520 mg, 89.2% yield) as a white solid. MS (ESI) m / z 402.3 [M+H]+;1H NMR (400 MHz, CDCl3) δ 7.26 - 7.14 (m, 3H), 6.85 (d, J = 8.6 Hz, 2H), 4.40 (br d, J = 5.5 Hz, 1H), 4.04 (s, 3H), 3.80 (s, 3H), 3.62 - 3.45 (m, 2H), 3.19 - 2.97 (m, 3H), 2.32 (br d, J = 11.7 Hz, 1H), 2.14 - 1.97 (m, 1H), 1.79 (br d, J = 8.6 Hz, 1H), 1.60 (br d, J = 11.4 Hz, 1H), 1.43 (s, 9H). Step 2: Synthesis of (3S,5R)-1-[(4-methoxyphenyl)methyl]-5-(1-methyltriazol-4-yl) 15 piperidin-3-amine hydrochloride B-41-2 The solution of tert-butyl N-[(3S,5R)-1-[(4-methoxyphenyl)methyl]-5-(1-methyltriazol-4- yl)-3-piperidyl]carbamate B-41-1 (0.4 g, 996 μmol, 1 eq) in HCl / MeOH (4 M, 8.00 mL, 32 eq) was stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was concentrated under20 reduced pressure to give crude (3S,5R)-1-[(4-methoxyphenyl)methyl]-5-(1-methyltriazol-4- yl)piperidin-3-amine hydrochloride B-41-2 (0.38 g) as a yellow solid. MS (ESI) m / z 302.2 [M+H]+Step 3: Synthesis of N-[(3S,5R)-1-[(4-methoxyphenyl)methyl]-5-(1-methyltriazol-4- yl)-3-piperidyl]prop-2-enamide B-41-3 25 The solution of (3S,5R)-1-[(4-methoxyphenyl)methyl]-5-(1-methyltriazol-4-yl)piperidin- 3-amine hydrochloride B-41-2 (0.38 g, 1.26 mmol, 1 eq) in DCM (10 mL) was added TEA (383 mg, 3.78 mmol, 527 μL, 3 eq) followed by the addition of prop-2-enoyl chloride (125.53 mg, 1.39 mmol, 112.68 μL, 1.1 eq) in DCM (0.5 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hr. Upon30 completion, the reaction mixture was concentrated under the reduced pressure to give crude N- [(3S,5R)-1-[(4-methoxyphenyl)methyl]-5-(1-methyltriazol-4-yl)-3-piperidyl]prop-2-enamide B- 41-3 (0.4 g) as a yellow oil. MS (ESI) m / z 356.3 [M+H]+. Step 4: Synthesis of N-[(3S,5R)-5-(1-methyltriazol-4-yl)-3-piperidyl]prop-2-enamide B-41-4 128 Attorney Docket No.: 51728-013WO2 The solution of N-[(3S,5R)-1-[(4-methoxyphenyl)methyl]-5-(1-methyltriazol-4-yl)-3- piperidyl] prop-2-enamide B-41-3 (400 mg, 1.13 mmol, 1 eq) in ACN (4.5 mL) and H2O (0.5 mL) was added CAN (4.94 g, 9.00 mmol, 8 eq) and stirred at 25 °C for 12 hr. Upon completion, the 5 reaction mixture was quenched with saturated aqueous NaHCO3solution (10 mL) and extracted with DCM (15 mL x 6). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18250 * 50 mm * 15 um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient:1%-10% B over 10.0 min) to give N-[(3S,5R)-5-(1-methyltriazol-4-yl)-3-piperidyl]prop-102-enamide B-41-4 (38 mg, 14.4% yield) as a white solid. MS (ESI) m / z 236.2 [M+H]+. Step 5: Synthesis of N-[(3S,5R)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-5-(1-methyltriazol-4- yl)-3-piperidyl] prop-2-enamide 41 15 The solution of N-[(3S,5R)-5-(1-methyltriazol-4-yl)-3-piperidyl]prop-2-enamide B-41-4 (30 mg, 128 μmol, 1 eq) and [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]- 3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl methanesulfonate Int-3-OMs (114 mg, 128 μmol, 1 eq) in ACN (3 mL) was added K2CO3(88 mg, 638 μmol, 5 eq). The reaction solution was stirred at 80 °C for 1 hr. Upon completion, the reaction mixture was added saturated aqueous 20 NaHCO3solution (10 mL), extracted with ethyl acetate (5 mL) and filtered. Aqueous solution was extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex Luna C1875 * 30 mm * 3 um; mobile phase: [H2O(0.1%TFA)-ACN]; gradient:15%-40% B over 8.0 min) and the residue 25 was purified by prep-SFC(Column: DAICEL CHIRALCEL OD(250 mm *30 mm,10 um); mobile phase: [CO2-MeOH];B%:45%, isocratic elution mode) to afford N-[(3S,5R)-1-[[2-[3-[3-methyl- 1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5- yl]methyl]-5-(1-methyltriazol-4-yl)-3-piperidyl]prop-2-enamide 41 (29 mg, 28.3% yield, 98% purity, TFA salt) as a white solid. MS (ESI) m / z 674.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 30 8.29 (s, 1H), 8.11 - 8.04 (m, 2H), 8.01 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.67 (br d, J = 8.3 Hz, 129 Attorney Docket No.: 51728-013WO2 1H), 7.43 (s, 1H), 7.12 (br d, J = 7.8 Hz, 1H), 6.16 (d, J = 10.0 Hz, 1H), 6.08 (d, J = 2.0 Hz, 1H), 5.61 - 5.52 (m, 1H), 5.20 (s, 2H), 3.97 (s, 4H), 3.80 (s, 2H), 3.21 (s, 3H), 3.09 - 2.96 (m, 3H), 2.86 (br d, J = 2.3 Hz, 2H), 2.56 (br d, J = 6.3 Hz, 3H), 2.11 (br d, J = 12.5 Hz, 1H), 1.98 (s, 1H), 1.84 (s, 1H), 1.39 (q, J = 12.3 Hz, 1H), 1.09 (br d, J = 4.9 Hz, 3H). 5 Example 42: (E)-N-[5-Methyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl] phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]-4-[methyl (prop-2- ynyl)amino]but-2-enamide 42 Step 1: Synthesis of methyl cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl- piperidine-3-carboxylate B-42-2-cis 10 A solution of methyl 5-methylpiperidine-3-carboxylate hydrochloride B-42-1 (5 g, 25.8 mmol, 1 eq, CAS:1044591-98-1) in DMF (100 mL) were added Cs2CO3(25.2 g, 77.5 mmol, 3 eq) and PMB-Cl (4.85 g, 31 mmol, 4.20 mL, 1.2 eq). The mixture was stirred at 20 °C for 16 hr. Upon completion. The reaction mixture was filtered and concentrated under reduced pressure to give a 15 crude product of B-42-2. The residue was purified by prep-HPLC (column: Welch Xtimate C18 250 * 70 mm * 10 um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:40%-75% B over 17.0 min) to give methyl cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-piperidine-3- carboxylate (1.2 g, 4.33 mmol,16.76% yield) B-42-2-cis as a yellow oil. MS (ESI) m / z 278.2 [M+H]+;1HNMR (400 MHz, DMSO-d6) δ 7.18 (d, J = 8.6 Hz, 2H), 6.91 - 6.84 (m, 2H), 3.73 (s, 20 3H), 3.56 (s, 3H), 3.47 - 3.34 (m, 2H), 3.01 - 2.92 (m, 1H), 2.74 (br dd, J = 1.3, 9.2 Hz, 1H), 2.57 - 2.50 (m, 1H), 1.90 (br d, J = 12.8 Hz, 1H), 1.78 (t, J = 11.2 Hz, 1H), 1.59 (ddd, J = 3.9, 7.1, 11.0 Hz, 1H), 1.52 - 1.41 (m, 1H), 0.98 - 0.85 (m, 1H), 0.81 (d, J = 6.6 Hz, 3H). Step 2: Synthesis of cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-piperidine-3- carboxylic acid B-42-3-cis 25 A mixture of racemic methyl cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-piperidine- 3-carboxylate B-42-2-cis (0.5 g, 1.80 mmol, 1 eq) in THF (6 mL) and H2O (1.2 mL) was added LiOH·H2O (378 mg, 9.01 mmol, 5 eq), and the mixture was stirred at 50 °C for 16 hr. Upon completion, the reaction mixture was diluted with H2O (10 mL) and washed with EA mL (10 mL). 30 The aqueous phase was acidified until pH was between 4 and 5, then extracted with EA mL (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude cis-(3,5)-1-[(4-methoxy phenyl)methyl]-5-methyl-piperidine-3-carboxylic acid B-42-3-cis (600 mg, crude) as a white solid. MS (ESI) m / z 264.1 [M+H]+. 35 Step 3: Synthesis of tert-butyl N-[cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-3- piperidyl] carbamate B-42-4-cis 130 Attorney Docket No.: 51728-013WO2 The solution of cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-piperidine-3-carboxylic acid B-43-2-cis (550 mg, 2.09 mmol, 1 eq) in t-BuOH (10 mL) were added Et3N (317 mg, 3.13 mmol, 436 μL, 1.5 eq), DPPA (862 mg, 3.13 mmol, 676 μL, 1.5 eq), and the mixture was stirred 5 at 80 °C for 3 hr. Upon completion, the reaction mixture was quenched with H2O (10 mL), and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Waters Xbridge BEH C18250 * 50 mm * 10 um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:40%-60% B over 10.0 min) to give tert- 10 butyl N-[cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-3-piperidyl]carbamate B-42-4-cis (350 mg, 41.6% yield, 83% purity) as a white solid. MS (ESI) m / z 335.2 [M+H]+. Step 4: Synthesis of cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-piperidin-3- amine hydrochloride B-42-5-cis 15 The solution of tert-butyl N-[cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-3-piperidyl] carbamate B-42-4-cis (350 mg, 1.05 mmol, 1 eq) in HCl / MeOH (4 M, 5 mL, 19.1 eq) was stirred at 20 °C for 1 hr. Upon compeltion, the reaction mixture was concentrated under reduced pressure to give crude cis-(3,5)-1-[(4-methoxy phenyl)methyl]-5-methyl-piperidin-3-amine hydrochloride B-42-5-cis (250 mg) as a yellow solid. MS (ESI) m / z 235.3 [M+H]+. 20 Step 5: Synthesis of (E)-N-[cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-3- piperidyl] -4-[methyl(prop-2-ynyl)amino]but-2-enamide B-42-6-cis A mixture of (E)-4-[methyl(prop-2-ynyl)amino]but-2-enoic acid B-12-3 (119 mg, 779 μmol, 2 eq) and cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-piperidin-3-amine 25 hydrochloride B-42-5-cis (110 mg, 390 μmol, 1 eq) in DCM (5 mL) were added T4P (561 mg, 779 μmol, 50% purity, 2 eq) and Et3N (118 mg, 1.17 mmol, 163 μL, 3 eq), and the mixture was stirred at 20 °C for 1 hr. Upon completion, the reaction mixture was quenched with H2O (5 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was 30 purified by prep-TLC (SiO2, DCM: MeOH =20:1) to give (E)-N-[cis-(3,5)-1-[(4-methoxyphenyl) methyl]-5-methyl-3-piperidyl]-4-[methyl(prop-2-ynyl)amino]but-2-enamide B-42-6-cis (90 mg, 60% yield, 96% purity) as a yellow solid. MS (ESI) m / z 370.3 [M+H]+. Step 6: Synthesis of (E)-N-[cis-(3,5)-5-methyl-3-piperidyl]-4-[methyl(prop-2- ynyl)amino] but-2-enamide B-42-7-cis 131 Attorney Docket No.: 51728-013WO2 The solution of (E)-N-[cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-3-piperidyl]-4- [methyl (prop-2-ynyl)amino]but-2-enamide B-42-6-cis (80 mg, 217 μmol, 1 eq) in ACN (1.8 mL) and H2O (0.2 mL) was added CAN (950 mg, 1.73 mmol, 8 eq), and the mixture was stirred at 5 20 °C for 4 hr. Upon completion, the reaction mixture was added H2O (5 mL) and saturated aqueous NaHCO3 solution until pH = 8. The solution was extracted with DCM (10 mL x 5), washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude (E)-N-[cis-(3,5)-5-methyl-3-piperidyl]-4-[methyl(prop-2-ynyl)amino]but- 2-enamide B-42-7-cis (60 mg) as a yellow solid. MS (ESI) m / z 250.3 [M+H]+. 10 Step 7: Synthesis of (E)-N-[5-methyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]-4-[methyl (prop-2-ynyl)amino]but-2-enamide 42 The solution of [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo- 15 7-(trifluoromethyl)isoindolin-5-yl]methylmethanesulfonate Int-3-OMs (118 mg, 221 μmol, 1 eq) and (E)-N-[cis-(3,5)-5-methyl-3-piperidyl]-4-[methyl(prop-2-ynyl)amino]but-2-enamide B-42-7- cis (55 mg, 221 μmol, 1 eq) in ACN (2 mL) was added K2CO3 (92 mg, 662 μmol, 3 eq), and the mixture was stirred at 80 °C for 1 hr. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column:20 Phenomenex Luna C1875 * 30 mm * 3 um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient:5%- 35% B over 8.0 min) to give (E)-N-[5-methyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]-4-[methyl (prop-2-ynyl)amino]but-2-enamide 42 (46.1 mg, 30.4% yield, 99.89% purity) as a white solid. MS (ESI) m / z 688.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.60 - 9.90 (m, 1H), 8.62 (s, 25 1H), 8.53 (br d, J = 7.0 Hz, 1H), 8.23 (br d, J = 13.8 Hz, 2H), 8.02 (s, 1H), 7.74 (dd, J = 1.4, 8.1 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.67 - 6.52 (m, 1H), 6.24 (d, J = 15.4 Hz, 1H), 5.28 (s, 2H), 4.62 - 4.54 (m, 2H), 4.06 (br s, 3H), 3.90 (br s, 1H), 3.88 (br d, J = 2.1 Hz, 2H), 3.47 - 3.39 (m, 1H), 3.34 - 3.22 (m, 4H), 2.94 - 2.84 (m, 2H), 2.76 (s, 3H), 2.72 - 2.61 (m, 2H), 2.58 (br d, J = 7.9 Hz, 2H), 1.91 (br d, J = 11.1 Hz, 2H), 1.16 (br d, J = 12.3 Hz, 1H), 1.10 30 (d, J = 5.6 Hz, 3H), 0.93 (br d, J = 6.4 Hz, 3H). Example 43: N-[5-Methyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]prop-2- enamide 43 Step 1: Synthesis of N-[cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-3-piperidyl] 35 prop-2-enamide B-43-1-cis 132 Attorney Docket No.: 51728-013WO2 To a solution of cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-piperidin-3-amine hydrochloride B-42-5-cis (120 mg, 512 μmol, 1 eq) in DCM (3 mL) at 0 °C were added TEA (156 mg, 1.54 mmol, 214 μL, 3 eq) and prop-2-enoyl chloride (47 mg, 512 μmol, 41.6 μL, 1 eq). The 5 mixture was stirred at 0 °C for 1 hr. Upon completion, the reaction mixture was quenched with H2O (3 mL) at 20 °C, and extracted with DCM 9 mL (3 mL x 3). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, EA: MeOH = 5:1) to give N-[cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-3-piperidyl]prop-2-enamide B-43-1-cis10(70 mg, 47.4% yield) as a white solid. MS (ESI) m / z 289.2 [M+H]+;1H NMR (400 MHz, DMSO- d6) δ 7.92 (br d, J = 7.6 Hz, 1H), 7.18 (br d, J = 8.4 Hz, 2H), 6.87 (br d, J = 8.4 Hz, 2H), 6.22 - 6.10 (m, 1H), 6.08 - 5.99 (m, 1H), 5.55 (dd, J = 2.4, 10.0 Hz, 1H), 3.73 (s, 4H), 3.45 - 3.35 (m, 2H), 2.89 - 2.81 (m, 1H), 2.72 (br d, J = 9.2 Hz, 1H), 1.79 (br d, J = 12.4 Hz, 1H), 1.70 - 1.38 (m, 3H), 0.84 - 0.72 (m, 4H). 15 Step 2: Synthesis of N-[cis-(3,5)-5-methyl-3-piperidyl]prop-2-enamide B-43-2-cis To a solution of N-[cis-(3,5)-1-[(4-methoxyphenyl)methyl]-5-methyl-3-piperidyl]prop-2- enamide B-43-1-cis (60 mg, 208 μmol, 1 eq) in ACN (1 mL) and H2O (0.2 mL) was added CAN (570 mg, 1.04 mmol, 5 eq). The mixture was stirred at 20 °C for 1 hr. Upon completion, the 20 reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with DCM (3 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude N-[cis-(3,5)-5-methyl-3- piperidyl]prop-2-enamide B-43-2-cis (60 mg) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 6.39 - 6.23 (m, 1H), 6.17 - 5.98 (m, 1H), 5.80 - 5.58 (m, 1H), 3.38 - 3.28 (m, 1H), 3.06 - 2.95 (m, 1H), 25 2.25 - 2.03 (m, 2H), 1.91 - 1.77 (m, 3H), 1.74 - 1.63 (m, 1H), 1.34 - 1.23 (m, 1H), 1.17 - 1.02 (m, 1H), 0.99 - 0.85 (m, 3H). Step 3: Synthesis of N-[5-methyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]prop-2- enamide 43 30 133 Attorney Docket No.: 51728-013WO2 To a solution of N-[cis-(3,5)-5-methyl-3-piperidyl]prop-2-enamide B-43-2-cis (25 mg, 149 μmol, 1 eq) in ACN were added K2CO3 (82.15 mg, 594.40 μmol, 4 eq) and [2-[3-[3-methyl-1-(4- methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoro methyl)isoindolin-5-yl]methyl methanesulfonate Int-3-OMs (87 mg, 164 μmol, 1.1 eq). The mixture was stirred at 80 °C for 1 5 hr. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%-70% B over 8.0 min) to afford N-[5-methyl-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-3-piperidyl]prop-2-enamide 43 (2.5 10 mg, 4.12 μmol, 2.8% yield) as a white solid. MS (ESI) m / z 607.5 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.07 (s, 1H), 7.99 - 7.91 (m, 3H), 7.67 (dd, J = 1.5, 8.1 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.21 - 6.11 (m, 1H), 6.07 - 5.99 (m, 1H), 5.59 - 5.51 (m, 1H), 5.20 (s, 2H), 3.86 - 3.77 (m, 1H), 3.76 - 3.67 (m, 2H), 3.21 (s, 3H), 2.93 - 2.81 (m, 3H), 2.77 (br d, J = 8.6 Hz, 1H), 2.62 - 2.52 (m, 3H), 1.82 (br d, J = 12.4 Hz, 1H), 1.75 - 1.63 (m, 2H), 15 1.60 - 1.52 (m, 1H), 1.09 (d, J = 5.4 Hz, 3H), 0.87 - 0.76 (m, 4H). Example 44: N-((3S,5S)-5-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-((2-(3-(3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl) methyl) piperidin-3-yl)acrylamide 44 Step 1: Synthesis of tert-butyl ((3S,5S)-5-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-(4- 20 methoxybenzyl)piperidin-3-yl)carbamate B-44-1 To a solution of tert-butyl N-[(3S,5S)-5-ethynyl-1-[(4-methoxyphenyl)methyl]-3-piperidyl] carbamate B-19-2 (1 g, 2.90 mmol, 1 eq) in THF (30 mL) was added LDA (2 M, 3.63 mL, 2.5 eq) at -78°C under N2, the mixture was stirred at -78°C for 0.5hr. Then acetone (337 mg, 5.81 mmol, 25 427 μL, 2 eq) was added at -78°C, and the resulting mixture was stirred at -78°C for 1hr. The reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL) and water (10 mL ) at 0 °C, and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, PE: EA = 1:1, Rf=0.24) to give tert-butyl30 N-[(3S,5S)-5-(3-hydroxy-3-methyl-but-1-ynyl)-1-[(4-methoxyphenyl)methyl]-3- piperidyl]carbamate B-44-1 (500 mg, 42.8% yield) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 7.22 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 3.78 (s, 3H), 3.58 - 3.41 (m, 3H), 2.96 - 2.79 (m, 2H), 2.57 (br t, J = 10.7 Hz, 1H), 2.07 (br d, J = 12.5 Hz, 1H), 1.92 - 1.72 (m, 2H), 1.41 (s, 15H), 1.22 - 1.13 (m, 1H). 35 Step 2: Synthesis of 4-((3S,5S)-5-amino-1-(4-methoxybenzyl)piperidin-3-yl)-2-methyl but-3-yn-2-ol hydrochloride B-44-2 134 Attorney Docket No.: 51728-013WO2 The solution of tert-butyl N-[(3S,5S)-5-(3-hydroxy-3-methyl-but-1-ynyl)-1-[(4-methoxy phenyl)methyl]-3-piperidyl]carbamate B-44-1 (490 mg, 1.22 mmol, 1 eq) in HCl / EtOAc (1M, 4 mL) was stirred at 25°C for 0.5hr. The reaction mixture was concentrated under reduced pressure 5 to give the crude product which was triturated with DCM (2 mL) for 10 min.4-[(3S,5S)-5-Amino- 1-[(4-methoxyphenyl)methyl]-3-piperidyl]-2-methyl-but-3-yn-2-ol hydrochloride B-44-2 (390 mg, 94.5% yield) was obtained as a white solid. 1H NMR (400 MHz, Methanol-d4) δ 7.53 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 4.49 - 4.32 (m, 2H), 3.83 (s, 3H), 3.74 - 3.64 (m, 1H), 3.59 (br d, J = 11.4 Hz, 2H), 3.25 - 3.12 (m, 1H), 3.09 - 2.97 (m, 2H), 2.44 (br d, J = 12.7 Hz, 1H), 10 1.73 (q, J = 12.0 Hz, 1H), 1.43 (s, 6H). Step 3: Synthesis of N-((3S,5S)-5-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-(4- methoxybenzyl)piperidin-3-yl)acrylamide B-44-3 To a solution of 4-[(3S,5S)-5-amino-1-[(4-methoxyphenyl)methyl]-3-piperidyl] -2- 15 methyl-but-3-yn-2-ol hydrochloride B-44-2 (390 mg, 1.15 mmol, 1 eq) in DCM (6 mL) at 0°C were added TEA (349 mg, 3.45 mmol, 481 μL, 3 eq) and prop-2-enoyl chloride (104 mg, 1.15 mmol, 93.5 μL, 1 eq). The mixture was stirred at 0°C for 5 min. The reaction mixture was quenched with H2O (3 mL) and extracted with DCM (4 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under20 reduced pressure to give crude N-[(3S,5S)-5-(3-hydroxy-3-methyl-but-1-ynyl)-1-[(4- methoxyphenyl)methyl]-3-piperidyl]prop-2-enamide B-44-3 (410 mg) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.98 (br d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 6.20 - 6.01 (m, 2H), 5.57 (dd, J = 2.4, 9.9 Hz, 1H), 5.14 (s, 1H), 3.73 (s, 4H), 3.44 (br d, J = 7.0 Hz, 2H), 2.90 - 2.77 (m, 2H), 2.03 - 1.92 (m, 1H), 1.74 (br t, J = 11.1 Hz, 1H), 1.64 (br t, J = 25 10.6 Hz, 1H), 1.30 (s, 6H), 1.27 - 1.22 (m, 1H). Step 4: Synthesis of N-((3S,5S)-5-(3-hydroxy-3-methylbut-1-yn-1-yl) piperidin-3-yl) acrylamide B-44-4 135 Attorney Docket No.: 51728-013WO2 To a solution of N-[(3S,5S)-5-(3-hydroxy-3-methyl-but-1-ynyl)-1-[(4-methoxyphenyl) methyl]-3-piperidyl]prop-2-enamide B-44-3 (410 mg, 1.15 mmol, 1 eq) in ACN (6 mL) and H2O (6 mL) was added CAN (3.15 g, 5.75 mmol, 2.87 mL, 5 eq) and stirred at 25°C for 12hr. The 5 reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um;mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:5%-35% B over 9.0 min) to afford N-[(3S,5S)-5-(3-hydroxy-3- methyl-but-1-ynyl)-3-piperidyl]prop-2-enamide B-44-4 (90 mg, 33.1% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.07 - 7.85 (m, 1H), 6.23 - 5.99 (m, 2H), 5.63 - 5.51 (m, 1H), 10 5.23 - 5.08 (m, 1H), 4.12 - 3.97 (m, 1H), 3.64 - 3.52 (m, 1H), 2.92 (br d, J = 11.5 Hz, 2H), 2.42 - 2.31 (m, 1H), 2.26 - 1.98 (m, 3H), 1.32 (s, 6H), 1.27 - 1.22 (m, 1H). Step 5: Synthesis of N-((3S,5S)-5-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-((2-(3-(3- methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7- (trifluoromethyl)isoindolin-5-yl) methyl)piperidin-3-yl)acrylamide 44 15 To a solution of N-[(3S,5S)-5-(3-hydroxy-3-methyl-but-1-ynyl)-3-piperidyl] prop-2- enamide B-44-4 (30 mg, 127 μmol, 1 eq) in ACN (1 mL) were added [2-[3-[3-methyl-1-(4-methyl- 1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl) isoindolin-5-yl]methylmethane- sulfonate Int-3-OMs (68 mg, 127 μmol, 1 eq) and K2CO3(53 mg, 381 μmol, 3 eq) at 25°C, and 20 the mixture was stirred at 80°C for 1hr. The reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: WePure Biotech XP tC18150*40*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 30%-60% B over 8.0 min) to afford N-[(3S,5S)-5-(3-hydroxy-3-methyl-but-1-ynyl)-1-[[2-[3-[3-methyl-1-(4-methyl -1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl] methyl]-3- 25 piperidyl]prop-2-enamide 44 (25.2 mg, 29.2% yield, 99.3% purity) as a white solid. MS (ESI) m / z 675.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ = 8.29 (s, 1H), 8.07 (s, 1H), 8.01 - 7.96 (m, 2H), 7.93 (s, 1H), 7.67 (dd, J = 1.2, 8.1 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.20 - 6.11 (m, 1H), 6.09 - 6.01 (m, 1H), 5.60 - 5.54 (m, 1H), 5.20 (s, 2H), 5.14 (s, 1H), 3.86 - 3.73 (m, 3H), 3.21 (s, 3H), 2.96 - 2.81 (m, 4H), 2.59 - 2.54 (m, 4H), 2.01 (br d, J = 12.3 Hz, 1H), 30 1.88 (br t, J = 11.0 Hz, 1H), 1.77 (br t, J = 10.5 Hz, 1H), 1.30 (s, 6H), 1.24 - 1.14 (m, 1H), 1.09 (br d, J = 5.1 Hz, 3H). Example 45: N-[(3S,5S)-1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3- 136 Attorney Docket No.: 51728-013WO2 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-5-(2- phenylethynyl)-3-piperidyl]prop-2-enamide 45 yl)methyl]-5-(2- 5 To a solution of tert-butyl N-[(3S,5S)-5-ethynyl-1-[(4-methoxyphenyl)methyl]-3-piperidyl] carbamate B-19-2 (0.6 g, 1.74 mmol, 1 eq) and iodobenzene (569 mg, 2.79 mmol, 311 μL, 1.6 eq) in THF (12 mL) and i-Pr2NH (6 mL) were added CuI (66 mg, 348 μmol, 0.2 eq) and Pd(PPh3)2Cl2(122 mg, 174 μmol, 0.1 eq) under N2, the reaction mixture was stirred at 20 °C for 4 hr. The 10 reaction mixture was diluted with H2O (15 mL), and extracted with EtOAc (50 mL x 2), washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under the reduced pressure. The crude obtained was purified by MPLC (SiO2, PE:EA = 20:1 to 8:1). tert-butyl N- [(3S,5S)-1-[(4-Methoxyphenyl)methyl]-5-(2-phenylethynyl)-3-piperidyl]carbamate B-45-1 (0.36 g, 48.1% yield, 98% purity) was obtained as a brown solid. MS (ESI) m / z 421.3 [M+H]+. 15 Step 2: Synthesis of (3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-pheny lethynyl) piperidin-3-amine hydrochloride B-45-2 A solution of tert-butyl N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-phenyl ethynyl)-3- piperidyl]carbamate (0.3 g, 713 μmol, 1 eq) in HCl / MeOH (4 M, 12 mL, 67 eq) , was stirred at 20 20°C for 2 hr. The reaction mixture was concentrated under the reduced pressure to afford crude (3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-phenyl ethynyl)piperidin-3-amine B-45-2 (0.23 g, 95.6% yield, 95% purity) as a yellow solid. MS (ESI) m / z 321.2 [M+H]+. Step 3: Synthesis of N-((3S,5S)-1-(4-methoxybenzyl)-5-(phenylethynyl) piperidin-3- yl) acrylamide B-45-3 137 Attorney Docket No.: 51728-013WO2 To a solution of (3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-phenylethynyl) piperidin-3- amine hydrochloride B-45-2 (0.22 g, 687 μmol, 1 eq) in DCM (4 mL) was added TEA (208 mg, 2.06 mmol, 287 μL, 3 eq) at 0 °C, and the mixture solution was stirred at 0 °C for 10 min under 5 N2. Then prop-2-enoyl chloride (75 mg, 824 μmol, 67 μL, 1.2 eq) was added at 0 °C, and the resulting solution was stirred at 0 °C for 1 h under N2. The reaction mixture was quenched with water (4 mL) at 0°C, and extracted with DCM (5 mL x 2). The combined organic layers were washed with brine (4 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-phenylethynyl)- 10 3-piperidyl]prop-2-enamide B-45-3 (257 mg, 100% yield) as a yellow oil. MS (ESI) m / z 375.1 [M+H]+. Step 4: Synthesis of N-((3S,5S)-5-(phenylethynyl)piperidin-3-yl) acrylamide B-45-4 To a solution of N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-(2-phenyl ethynyl)-3- 15 piperidyl]prop-2-enamide B-45-3 (257 mg, 686 μmol, 1 eq) in ACN (2 mL) and H2O (2 mL) was added CAN (1.88 g, 3.43 mmol, 5 eq) at 25 °C, and the solution was stirred at 25 °C for 12 hr under N2. The reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: WePure Biotech XPt C18150*40*7um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:25%-55% B over 8.0 min) to afford N-[(3S,5S)- 20 5-(2-phenylethynyl)-3-piperidyl]prop-2-enamide B-45-4 (65 mg, 37.2% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 7.8 Hz, 1H), 7.42 - 7.28 (m, 5H), 6.23 - 6.14 (m, 1H), 6.11 - 6.04 (m, 1H), 5.58 (dd, J = 2.4, 9.9 Hz, 1H), 4.14 - 3.60 (m, 1H), 3.17 (d, J = 4.5 Hz, 1H), 3.12 - 2.92 (m, 2H), 2.71 - 2.61 (m, 1H), 2.42 - 2.31 (m, 1H), 2.22 - 2.11 (m, 2H), 1.41 (q, J = 12.0 Hz, 1H) 25 Step 5: Synthesis of N-((3S,5S)-1-((2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)-5-(phenylethynyl) piperidin-3-yl)acrylamide 45 138 Attorney Docket No.: 51728-013WO2 To a solution of N-[(3S,5S)-5-(2-phenylethynyl)-3-piperidyl]prop-2-enamide B-45-4 (35 mg, 138 μmol, 1 eq) in ACN (1 mL) were added K2CO3(57 mg, 413 μmol, 3 eq) and -[3-[3- methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5- 5 yl]methyl methanesulfonate Int-3-OMs (73.56 mg, 137.62 μmol, 1 eq) at 0 °C, and the solution was stirred at 80 °C for 2 hr under N2. The reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:45%-85% B over 8.0 min) to afford N-[(3S,5S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-10 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-5-(2-phenyl ethynyl)-3- piperidyl]prop-2-enamide 45 (27 mg, 27.8% yield, 98.12% purity) as a white solid. MS (ESI) m / z 693.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.11 - 7.92 (m, 4H), 7.73 - 7.60 (m, 1H), 7.51 - 7.25 (m, 6H), 7.12 (d, J = 7.4 Hz, 1H), 6.24 - 5.99 (m, 2H), 5.58 (d, J = 9.4 Hz, 1H), 5.20 (s, 2H), 3.92 - 3.75 (m, 3H), 3.21 (s, 3H), 3.04 (d, J = 8.4 Hz, 1H), 2.98 - 2.82 (m, 4H), 15 2.55 (s, 3H), 2.21 - 1.98 (m, 2H), 1.84 (t, J = 10.0 Hz, 1H), 1.39 - 1.27 (m, 1H), 1.09 (s, 3H);1H NMR (400 MHz, METHANOL-d4) δ 8.30 (s, 1H), 8.08 (s, 2H), 7.98 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.39 - 7.14 (m, 6H), 6.19 (d, J = 5.8 Hz, 2H), 5.63 (t, J = 5.8 Hz, 1H), 5.15 (s, 2H), 4.03 (s, 1H), 3.88 - 3.72 (m, 2H), 3.33 (s, 3H), 3.11 - 2.85 (m, 5H), 2.75 - 2.54 (m, 3H), 2.32 - 2.12 (m, 2H), 1.99 (t, J = 10.1 Hz, 1H), 1.44 (q, J = 11.8 Hz, 1H), 1.16 (d, J = 5.9 20 Hz, 3H). Example 46: N-((3S,5S)-1-((2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl) phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)-5-(prop-1-yn-1-yl)piperidin-3-yl) acrylamide 46 Step 1: Synthesis of tert-butyl (tert-butoxycarbonyl)((3S,5S)-5-ethynyl-1-(4- 25 methoxybenzyl)piperidin-3-yl)carbamate B-46-1 To a solution of tert-butyl N-[(3S,5S)-5-ethynyl-1-[(4-methoxyphenyl)methyl]-3-piperidyl] carbamate B-19-2 (1 g, 2.90 mmol, 1 eq) in toluene (10 mL) were added DMAP (355 mg, 2.90 mmol, 1 eq), TEA (588 mg, 5.81 mmol, 808 μL, 2 eq) and (Boc)2O (1.90 g, 8.71 mmol, 3 eq) at 30 25°C, and the solution was stirred at 110 °C for 12 hr under N2. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by flash silica gel chromatography (PE / EA = 5 / 1 to 3 / 1, Rf = 0.54) to give tert-butyl N-tert-butoxycarbonyl-N- [(3S,5S)-5-ethynyl-1-[(4-methoxyphenyl)methyl]-3-piperidyl]carbamate B-46-1 (1.1 g, 85.2% yield) as a yellow oil.1H NMR (400 MHz, Methanol-d4) δ 7.22 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 139 Attorney Docket No.: 51728-013WO2 8.6 Hz, 2H), 4.11 (tt, J = 4.0, 11.6 Hz, 1H), 3.78 (s, 3H), 3.60 - 3.49 (m, 2H), 3.02 - 2.92 (m, 1H), 2.82 - 2.75 (m, 1H), 2.64 - 2.53 (m, 1H), 2.48 - 2.37 (m, 2H), 2.04 - 1.83 (m, 3H), 1.47 (s, 18H). Step 2: Synthesis of tert-butyl (tert-butoxycarbonyl)((3S,5S)-1-(4-methoxybenzyl)-5- (prop-1-yn-1-yl)piperidin-3-yl)carbamate B-46-2 5 To a solution of tert-butyl N-tert-butoxycarbonyl-N-[(3S,5S)-5-ethynyl-1-[(4-methoxy phenyl)methyl]-3-piperidyl]carbamate B-46-1 (990 mg, 2.23 mmol, 1 eq) in THF (10 mL) was added LiHMDS (1 M, 3.34 mL, 1.5 eq) at -78°C under N2, and the mixture solution was stirred at -78 °C for 30 min under N2. Then CH3I (948 mg, 6.68 mmol, 416 μL, 3 eq) was added at -78 °C 10 under N2, and the resulting solution was stirred at -10 °C for additional 3 hr under N2. The reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL) at 0°C, and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: WePure Biotech XPt C18150*40*7um; mobile phase:15 [H2O(10mM NH4HCO3)-ACN]; gradient:65%-95% B over 8.0 min) to give tert-butyl N-tert- butoxycarbonyl-N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-prop-1-ynyl-3-piperidyl]carbamate B-46-2 (900 mg, 88.13% yield) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 7.45 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 4.47 - 4.26 (m, 3H), 3.84 (s, 3H), 3.56 - 3.37 (m, 3H), 2.90 - 2.75 (m, 2H), 2.21 - 2.02 (m, 2H), 1.78 (s, 3H), 1.54 - 1.42 (m, 16H). 20 Step 3: Synthesis of (3S,5S)-1-(4-methoxybenzyl)-5-(prop-1-yn-1-yl)piperidin-3- amine hydrochloride B-46-3 The solution of tert-butyl N-tert-butoxycarbonyl-N-[(3S,5S)-1-[(4-methoxy phenyl)methyl] -5-prop-1-ynyl-3-piperidyl]carbamate B-46-2 (600 mg, 1.31 mmol, 1 eq) in HCl / EtOAc (1M, 6 25 mL) was stirred at 25 °C for 2 hr under N2. The reaction mixture was concentrated under reduced pressure to give crude (3S,5S)-1-[(4-methoxyphenyl)methyl]-5-prop-1-ynyl-piperidin-3-amine hydrochloride B-46-3 (385 mg, 99.8% yield) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 7.53 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 4.52 - 4.31 (m, 2H), 3.84 (s, 3H), 3.72 - 3.53 (m, 3H), 3.03 (quin, J = 11.9 Hz, 3H), 2.41 (d, J = 12.6 Hz, 1H), 1.79 (d, J = 2.0 Hz, 3H), 1.70 30 (q, J = 12.1 Hz, 1H). Step 4: Synthesis of N-((3S,5S)-1-(4-methoxybenzyl)-5-(prop-1-yn-1-yl)piperidin-3-yl) acrylamide B-46-4 140 Attorney Docket No.: 51728-013WO2 To a solution of (3S,5S)-1-[(4-methoxyphenyl)methyl]-5-prop-1-ynyl-piperidin -3-amine hydrochloride B-46-3 (385 mg, 1.31 mmol, 1 eq) in DCM (5 mL) was added TEA (396 mg, 3.92 mmol, 545 μL, 3 eq) at 0 °C, and the mixture solution was stirred at 0 °C for 10 min under N2. 5 Then prop-2-enoyl chloride (142 mg, 1.57 mmol, 127 μL, 1.2 eq) was added at 0 °C, and the resulting solution was stirred at 0 °C for 1 hr under N2. The reaction mixture was quenched with H2O (5 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (4 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-prop-1-ynyl-3-piperidyl]prop-2-enamide B- 10 46-4 (407 mg, crude) as a yellow oil.1H NMR (400 MHz, Methanol-d4) δ 7.23 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 6.19 (d, J = 5.9 Hz, 2H), 5.64 (t, J = 6.0 Hz, 1H), 3.99 - 3.87 (m, 1H), 3.78 (s, 3H), 3.54 (s, 2H), 3.21 (q, J = 7.4 Hz, 1H), 3.03 - 2.90 (m, 2H), 2.65 - 2.47 (m, 1H), 2.11 (d, J = 12.5 Hz, 1H), 1.96 - 1.87 (m, 1H), 1.81 (t, J = 10.8 Hz, 1H), 1.73 (d, J = 2.0 Hz, 3H). Step 5: Synthesis of N-((3S,5S)-5-(prop-1-yn-1-yl)piperidin-3-yl) acrylamide B-46-5 15 To a solution of N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-prop-1-ynyl-3-piperidyl] prop-2-enamide B-46-4 (407 mg, 1.30 mmol, 1 eq) in ACN (2 mL) and H2O (2 mL) was added CAN (3.57 g, 6.51 mmol, 5 eq) at 25 °C, and the solution was stirred at 25 °C for 12 hr under N2. The reaction mixture was filtered and concentrated under the reduced pressure. The residue 20 obtained was purified by prep-HPLC (column: WePure Biotech XPt C18150*40*7um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:5%-35% B over 8.0 min) to give crude N- [(3S,5S)-5-prop-1-ynyl-3-piperidyl] prop-2-enamide B-46-5 (80 mg, 31.9% yield) as a yellow solid.1H NMR (400 MHz, Methanol-d4) δ 6.27 - 6.16 (m, 2H), 5.66 (dd, J = 4.6, 7.3 Hz, 1H), 3.89 - 3.77 (m, 1H), 3.19 - 2.90 (m, 3H), 2.58 - 2.44 (m, 2H), 2.25 - 2.03 (m, 2H), 1.75 (d, J = 1.8 Hz, 25 3H). Step 6: Synthesis of N-((3S,5S)-1-((2-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)-5-(prop-1- yn-1-yl)piperidin-3-yl)acrylamide 46 141 Attorney Docket No.: 51728-013WO2 To a solution of N-[(3S,5S)-5-prop-1-ynyl-3-piperidyl]prop-2-enamide B-46-5 (32 mg, 166 μmol, 1 eq) in ACN (1 mL) were added K2CO3 (69 mg, 499 μmol, 3 eq) and [2-[3-[3-methyl- 1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5- 5 yl]methyl methanesulfonate Int-3-OMs (89 mg, 166 μmol, 1 eq) at 0 °C, and the solution was stirred at 80°C for 2 hr under N2. The reaction mixture was filtered and concentrated. The residue obtained was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um; mobile phase: [H2O(0.1%TFA)-ACN]; gradient:20%-40% B over 8.0 min) to afford N-[(3S,5S)-1-[[2- [3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- 10 (trifluoromethyl)isoindolin-5-yl] methyl]-5-prop-1-ynyl-3-piperidyl]prop-2-enamide 46 (26 mg, 24.7% yield, 99.7% purity) as a white solid. MS (ESI) m / z 631.3 [M+H]+;1H NMR (400 MHz, DMSO - d6) δ 10.78 - 9.39 (m, 1H), 8.54 (s, 1H), 8.30 (d, J = 4.5 Hz, 1H), 8.18 (d, J = 16.0 Hz, 2H), 8.03 (s, 1H), 7.76 - 7.68 (m, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 6.25 - 6.05 (m, 2H), 5.68 - 5.61 (m, 1H), 5.26 (s, 2H), 4.64 - 4.21 (m, 2H), 4.01 (d, J = 4.0 Hz, 1H), 3.27 15 (s, 3H), 2.93 - 2.74 (m, 4H), 2.57 (q, J = 7.4 Hz, 6H), 2.09 (d, J = 12.5 Hz, 1H), 1.76 (s, 3H), 1.45 (d, J = 8.8 Hz, 1H), 1.10 (d, J = 5.4 Hz, 3H). Example 47: N-((3S,5S)-1-((2-(3-(3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)-5-(pyridine-2- ylethynyl)piperidin-3-yl) acrylamide 47 20 Step 1: Synthesis of tert-butyl ((3S,5S)-1-(4-methoxybenzyl)-5-(pyridin-2-ylethynyl) piperidin-3-yl)carbamate B-47-1 To a solution of tert-butyl N-[(3S,5S)-5-ethynyl-1-[(4-methoxyphenyl)methyl]-3-piperidyl] carbamate B-19-2 (550 mg, 1.60 mmol, 1 eq) and 2-iodopyridine (524 mg, 2.55 mmol, 272 μL, 25 1.6 eq) in THF (10 mL) and i-Pr2NH (5 mL) were added CuI (60.8 mg, 319 μmol, 0.2 eq) and Pd(PPh3)2Cl2 (112 mg, 160 μmol, 0.1 eq) under N2 , and the reaction mixture was stirred at 25 °C for 2 hr. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash silica30 gel chromatography (PE / EA = 100 / 1 to 50 / 50, Rf=0.38) to give tert-butyl N-[(3S,5S)-1-[(4- methoxyphenyl)methyl]-5-[2-(2-pyridyl)ethynyl]-3-piperidyl]carbamate B-47-1 (600 mg, 89.1% yield) as a yellow solid. MS (ESI) m / z 422.2 [M+H]+. 142 Attorney Docket No.: 51728-013WO2 Step 2: Synthesis of (3S,5S)-1-(4-methoxybenzyl)-5-(pyridin-2-ylethynyl)piperidin-3- amine hydrochloride B-47-2 A mixture of tert-butyl N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-[2-(2- 5 pyridyl)ethynyl]-3-piperidyl]carbamate B-47-1 (600 mg, 1.42 mmol, 1 eq) in HCl / EtOAc (6 mL) was stirred at 25°C for 1hr. The reaction mixture was concentrated under reduced pressure to give crude (3S,5S)-1-[(4-methoxyphenyl)methyl]-5-[2-(2-pyridyl)ethynyl]piperidin-3-amine hydrochloride B-47-2 (500 mg, 98.2% yield) as a yellow solid. MS (ESI) m / z 322.2 [M+H]+. Step 3: Synthesis of N-((3S,5S)-1-(4-methoxybenzyl)-5-(pyridin-2-ylethynyl) 10 piperidin-3-yl) acrylamide B-47-3 To a solution of (3S,5S)-1-[(4-methoxyphenyl)methyl]-5-[2-(2-pyridyl)ethynyl] piperidin- 3-amine hydrochloride B-47-2 (500 mg, 1.40 mmol, 1 eq) in DCM (5 mL) were added TEA (424 mg, 4.19 mmol, 583 μL, 3 eq) and prop-2-enoyl chloride (139 mg, 1.54 mmol, 125 μL, 1.1 eq) at 15 0°C. The mixture was stirred at 0°C for 1hr. The reaction mixture was concentrated under reduced pressure to give crude N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-[2-(2-pyridyl)ethynyl]-3- piperidyl]prop-2-enamide B-47-3 (500 mg) as a yellow solid. MS (ESI) m / z 376.3 [M+H]+. Step 4: Synthesis of N-((3S,5S)-5-(pyridin-2-ylethynyl)piperidin-3-yl)acrylamide B- 47-4 20 143 Attorney Docket No.: 51728-013WO2 To a solution of N-[(3S,5S)-1-[(4-methoxyphenyl)methyl]-5-[2-(2-pyridyl) ethynyl]-3- piperidyl]prop-2-enamide B-47-3 (500 mg, 1.33 mmol, 1 eq) in ACN (5 mL) and H2O (5 mL) was added CAN (3.65 g, 6.66 mmol, 5 eq) and the reaction solution was stirred at 25°C for 12hr . The reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was 5 purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:10%-40% B over 8.0 min) to give N-[(3S,5S)-5-[2-(2- pyridyl)ethynyl]-3-piperidyl]prop-2-enamide B-47-4 (80 mg, 18.8% yield, 80% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.51 (br d, J = 4.4 Hz, 1H), 7.98 (br d, J = 8.1 Hz, 1H), 7.76 (dt, J = 1.9, 7.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.37 - 7.31 (m, 1H), 6.24 - 6.14 (m, 10 1H), 6.10 - 6.04 (m, 1H), 5.61 - 5.54 (m, 1H), 3.65 (ddd, J = 3.6, 7.5, 11.6 Hz, 1H), 3.12 - 3.06 (m, 1H), 2.95 (br dd, J = 4.2, 12.3 Hz, 1H), 2.74 - 2.69 (m, 1H), 2.40 (br d, J = 12.0 Hz, 1H), 2.18 (ddd, J = 4.8, 6.3, 11.1 Hz, 2H), 1.42 (q, J = 12.1 Hz, 1H). Step 5: Synthesis of N-((3S,5S)-1-((2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)-5-(pyridin-2-ylethynyl) 15 piperidin-3-yl) acrylamide 47 To a solution of N-[(3S,5S)-5-[2-(2-pyridyl)ethynyl]-3-piperidyl]prop-2-enamide B-47-4 (45 mg, 141 μmol, 1 eq) in ACN (0.2 mL) were added [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol- 3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl) isoindolin-5-yl]methyl methanesulfonate Int-203-OMs (75 mg, 141 μmol, 1 eq) and K2CO3 (58 mg, 423 μmol, 3 eq) at 25°C, and the mixture was stirred at 80°C for 1hr. The reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%-60% B over 8.0 min) to afford N-[(3S,5S)-1-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-25 3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]-5-[2-(2-pyridyl)ethynyl]-3-piperidyl]prop-2- enamide 47 (23.1 mg, 23.6% yield, 99.9% purity) as a yellow solid. MS (ESI) m / z 694.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.53 - 8.47 (m, 1H), 8.29 (s, 1H), 8.10 - 8.05 (m, 2H), 8.02 (s, 1H), 7.97 (s, 1H), 7.76 (dt, J = 1.8, 7.8 Hz, 1H), 7.70 - 7.64 (m, 1H), 7.44 (td, J = 4.0, 7.8 Hz, 2H), 7.34 (ddd, J = 1.1, 4.9, 7.6 Hz, 1H), 7.11 (br d, J = 7.8 Hz, 1H), 6.22 - 6.12 (m, 1H), 6.10 - 6.02 30 (m, 1H), 5.62 - 5.55 (m, 1H), 5.20 (s, 2H), 3.96 - 3.79 (m, 3H), 3.21 (s, 3H), 3.05 (br d, J = 10.0 Hz, 1H), 2.98 - 2.81 (m, 4H), 2.55 (br d, J = 6.4 Hz, 3H), 2.16 (br d, J = 12.1 Hz, 1H), 2.06 (br t, J = 10.9 Hz, 1H), 1.84 (br t, J = 10.6 Hz, 1H), 1.34 (q, J = 12.3 Hz, 1H), 1.09 (br d, J = 5.1 Hz, 3H). Example 48: N-[3-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3- 35 oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino]propyl]pent-2-ynamide 48 Step 1: Synthesis of tert-butyl N-[3-(pent-2-ynoylamino)propyl]carbamate B-48-2 144 Attorney Docket No.: 51728-013WO2 To a solution of pent-2-ynoic acid B-48-1 (100 mg, 1.02 mmol, 1 eq) in DCM (5 mL) were added DIEA (395 mg, 3.06 mmol, 533 μL, 3 eq), tert-butyl N-(3-aminopropyl)carbamate B-4-1 (178 mg, 1.02 mmol, 178 μL, 1 eq) and T4P (1.47 g, 2.04 mmol, 50% purity, 2 eq). The mixture 5 was stirred at 0 °C for 1 hr. Upon completion, the reaction mixture was quenched with H2O (10 mL), and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, EA) to give tert-butyl N-[3-(pent-2-ynoylamino)propyl] carbamate B-48-2 (170 mg, 59% yield, 90% purity) as a yellow oil. 10 Step 2: Synthesis of N-(3-aminopropyl)pent-2-ynamide trifluoroacetate B-48-3 To a solution of tert-butyl N-[3-(pent-2-ynoylamino)propyl]carbamate B-48-2 (100 mg, 393 μmol, 1 eq) in DCM (2 mL) was added TFA (512 mg, 4.49 mmol, 333 μL, 11.4 eq). The mixture was stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was concentrated 15 under reduced pressure to give N-(3-aminopropyl)pent-2-ynamide trifluoroacetate B-48-3 (110 mg) as a yellow oil. MS (ESI) m / z 155.2 [M+H]+. Step 3: Synthesis of N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino] propyl]pent- 2-ynamide 48 20 To a solution of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo- 7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (80 mg, 176 μmol, 1 eq) and N-(3- aminopropyl) pent-2-ynamide trifluoroacetate B-48-3 (94 mg, 352 μmol, 2 eq) in DCM (3 mL) were added Ti(iPrO)4(100 mg, 352 μmol, 104 μL, 2 eq), TEA (36 mg, 352 μmol, 49 μL, 2 eq) 25 and HOAc (1.06 mg, 17.6 μmol, 1 μL, 0.1 eq). The mixture was stirred at 20 °C for 1 hr, then NaBH3CN (111 mg, 1.76 mmol, 10 eq) was added. The mixture was stirred at 20 °C for 0.5 hr. Upon completion, the reaction mixture was quenched with H2O (3 mL), and then extracted with EA (5 mL x 3), filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18 250 * 50 mm * 15 um; mobile phase:30 [H2O (0.1% TFA) - ACN]; gradient: 20%-50% B over 10.0 min) to afford N-[3-[[2-[3-[3-methyl- 145 Attorney Docket No.: 51728-013WO2 1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl) isoindolin-5-yl] methylamino]propyl]pent-2-ynamide 48 (52.3 mg, 50% yield, 99.9% purity, TFA salt) as a white solid. MS (ESI) m / z 593.3 [M+H]+;1H NMR (400 MHz, DMSO-d6 +D2O) δ 8.73 (s, 1H), 8.26 - 8.10 (m, 2H), 8.00 (s, 1H), 7.78 - 7.67 (m, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 5 5.25 (s, 2H), 4.36 (s, 2H), 3.31 (s, 3H), 3.14 (t, J = 6.6 Hz, 2H), 3.04 - 2.84 (m, 4H), 2.61 - 2.52 (m, 3H), 2.31 (q, J = 7.4 Hz, 2H), 1.85 - 1.69 (m, 2H), 1.18 - 1.02 (m, 6H). Example 49: 3-Cyclopropyl-N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino]propyl]prop-2-ynamide 49 Step 1: Synthesis of tert-butyl N-[3-(3-cyclopropylprop-2-ynoylamino) propyl] 10 carbamate B-49-2 To a solution of 3-cyclopropylprop-2-ynoic acid B-49-1(100 mg, 908 μmol, 1 eq) in DCM (5 mL) were added DIEA (352 mg, 2.72 mmol, 475 μL, 3 eq), tert-butyl N-(3-aminopropyl) carbamate (158 mg, 908 μmol, 159 μL, 1 eq) and T4P (1.31 g, 1.82 mmol, 50% purity, 2 eq). The 15 mixture was stirred at 0 °C for 1 hr. Upon completion, the reaction mixture was quenched with H2O (10 mL), and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over anhhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, EA) to give tert-butyl N-[3-(3- cyclopropylprop-2-ynoylamino)propyl]carbamate B-49-2 (150 mg, 55.8% yield, 90% purity) as a 20 yellow oil. Step 2: Synthesis of N-(3-aminopropyl)-3-cyclopropyl-prop-2-ynamide trifluoroacetate B-49-3 To a solution of tert-butyl N-[3-(3-cyclopropylprop-2-ynoylamino)propyl] carbamate B- 25 49-2 (100 mg, 375 μmol, 1 eq) in DCM (2 mL) was added TFA (512 mg, 4.49 mmol, 333 μL, 12 eq). The mixture was stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude N-(3-aminopropyl)-3-cyclopropyl-prop-2- ynamide trifluoroacetate B-49-3 (130 mg) as a yellow oil. MS (ESI) m / z 167.2 [M+H]+. Step 3: Synthesis of 3-cyclopropyl-N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-30 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl] methylamino]propyl]prop- 2-ynamide 49 146 Attorney Docket No.: 51728-013WO2 To a solution of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo- 7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (100 mg, 220 μmol, 1 eq) and N-(3- aminopropyl)-3-cyclopropyl-prop-2-ynamide trifluoroacetate B-49-3 (123 mg, 440 μmol, 2 eq) in 5 EtOH (3 mL) were added Ti(i-PrO)4 (188 mg, 660 μmol, 195 μL, 3 eq), TEA (44.5 mg, 440 μmol, 61 μL, 2 eq) and HOAc (1.32 mg, 22.0 μmol, 1.3 μL, 0.1 eq). The mixture was stirred at 25 °C for 1 hr, then NaBH3CN (69 mg, 1.10 mmol, 5 eq) was added, and the mixture was stirred at 25 °C for 0.5 hr. Upon completion, the reaction mixture was quenched with H2O (3 mL), and extracted with EA (5 mL x 3), filtered and concentrated under reduced pressure. The residue obtained was 10 purified by prep-HPLC (column: Phenomenex luna C18 250 * 50 mm * 15 um; mobile phase: [H2O (0.1% TFA) - ACN]; gradient:20%-50% B over 10.0 min) to afford 3-cyclopropyl-N-[3- [[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl] -3-oxo-7- (trifluoromethyl)isoindolin-5-yl]methylamino]propyl]prop-2-ynamide 49 (52.3 mg, 39.2% yield, 99.9% purity, TFA salt) as a white solid. MS (ESI) m / z 605.3 [M+H]+;1H NMR (400 MHz, 15 DMSO-d6+D2O) δ 8.73 (s, 1H), 8.26 - 8.10 (m, 2H), 7.99 (s, 1H), 7.71 (dd, J = 1.4, 8.2 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 5.24 (s, 2H), 4.34 (s, 2H), 3.31 (s, 3H), 3.12 (t, J = 6.8 Hz, 2H), 2.99 - 2.84 (m, 4H), 2.61 - 2.52 (m, 3H), 1.85 - 1.64 (m, 2H), 1.49 - 1.33 (m, 1H), 1.07 (d, J = 5.4 Hz, 3H), 0.94 - 0.83 (m, 2H), 0.76 - 0.63 (m, 2H). Example 50: N-Methyl-N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-20 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino]propyl]but-2- ynamide 50 Step 1: Synthesis of tert-butyl N-[3-[but-2-ynoyl(methyl)amino]propyl] carbamate B- 50-2 25 To a solution of but-2-ynoic acid (100 mg, 1.19 mmol, 1 eq) in DCM (5 mL) were added DIEA (369 mg, 2.85 mmol, 497 μL, 2.4 eq), tert-butyl N-[3-(methylamino)propyl]carbamate hydrochloride B-50-1 (267 mg, 1.19 mmol, 1 eq) and T4P (1.71 g, 2.38 mmol, 50% purity, 2 eq). The mixture was stirred at 0 °C for 1 hr. Upon completion, the reaction mixture was quenched with H2O (10 mL), and extracted with EA (10 mL x 3). The combined organic layers were washed 30 with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, EA) to give tert-butyl N-[3-[but-2- ynoyl(methyl)amino]propyl]carbamate B-50-2 (140 mg, 37% yield, 80% purity) as a yellow oil. Step 2: Synthesis of N-(3-aminopropyl)-N-methyl-but-2-ynamide trifluoroacetate B- 50-3 147 Attorney Docket No.: 51728-013WO2 To a solution of tert-butyl N-[3-[but-2-ynoyl(methyl)amino]propyl]carbamate B-50-2 (100 mg, 393 μmol, 1 eq) in DCM (2 mL) was added TFA (512 mg, 4.49 mmol, 333 μL, 11.4 eq). The mixture was stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was concentrated 5 under reduced pressure to give crude N-(3-aminopropyl)-N-methyl-but-2-ynamide trifluoroacetate B-50-3 (100 mg) as a yellow oil. MS (ESI) m / z 155.2 [M+H]+. Step 3: Synthesis of N-methyl-N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino]propyl]but-2- ynamide 50 10 To a solution of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3-oxo- 7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (80 mg, 176 μmol, 1 eq) and N-(3- aminopropyl)-N-methyl-but-2-ynamide trifluoroacetate B-50-3 (94 mg, 352 μmol, 2 eq) in EtOH (3 mL) were added Ti(i-PrO)4 (100 mg, 352 μmol, 104 μL, 2 eq), TEA (36 mg, 352 μmol, 49 μL, 15 2 eq) and HOAc (1.06 mg, 17.6 μmol, 1 μL, 0.1 eq). The mixture was stirred at 25 °C for 1 hr, then NaBH3CN (111 mg, 1.76 mmol, 10 eq) was added. The mixture was stirred at 25 °C for 0.5 hr. Upon completion, the reaction mixture was quenched with H2O (3 mL), and extracted with EA (5 mL x 3), filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C18250 * 50 mm * 15 um; mobile phase: [H2O (0.1%20 TFA) - ACN]; gradient: 20%-50% B over 10.0 min) to afford N-methyl-N-[3-[[2-[3-[3-methyl-1- (4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl] methylamino]propyl]but-2-ynamide 50 (47.7 mg, 38.1% yield, 99.4% purity, TFA salt) as a white solid. MS (ESI) m / z 593.3 [M+H]+;1H NMR (400 MHz, DMSO-d6+D2O) δ 8.83 (d, J = 1.4 Hz, 1H), 8.23 - 8.10 (m, 2H), 8.06 - 7.92 (m, 1H), 7.72 (br d, J = 8.4 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 25 7.24 (d, J = 7.8 Hz, 1H), 5.24 (s, 2H), 4.36 (d, J = 13.0 Hz, 2H), 3.59 (t, J = 6.8 Hz, 1H), 3.42 - 3.30 (m, 4H), 3.11 (s, 2H), 3.03 - 2.85 (m, 4H), 2.81 (s, 1H), 2.61 - 2.52 (m, 3H), 1.98 (d, J = 6.4 Hz, 3H), 1.94 - 1.79 (m, 2H), 1.07 (d, J = 5.6 Hz, 3H). Example 51: N-[3-[Methyl-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl]amino]propyl]but-2- 30 ynamide 51 Step 1: Synthesis of tert-butyl N-[3-(but-2-ynoylamino)propyl]-N-methyl-carbamate B-51-2 148 Attorney Docket No.: 51728-013WO2 To a solution of but-2-ynoic acid (100 mg, 1.19 mmol, 1 eq) in DCM (3mL) was added DIEA (369 mg, 2.85 mmol, 497 μL, 2.4 eq), tert-butyl N-[3-(methylamino) propyl]carbamate hydrochloride B-51-1 (224 mg, 1.19 mmol, 1 eq) and T4P (1.71 g, 2.38 mmol, 50% purity, 2 eq). 5 The mixture was stirred at 0 °C for 1 hr. Upon completion, the reaction mixture was quenched with H2O (10 mL), and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, EA) to give tert-butyl N-[3-(but-2-ynoylamino) propyl]-N-methyl-carbamate B-51-2 (190 mg, 34.7% yield, 80% purity) as a yellow oil.1H NMR 10 (400 MHz, CDCl3) δ 7.06 - 6.63 (m, 1H), 3.28 - 3.09 (m, 4H), 2.76 (s, 3H), 1.87 (s, 3H), 1.65 - 1.54 (m, 2H), 1.41 (s, 9H). Step 2: Synthesis of N-[3-(methylamino)propyl]but-2-ynamide trifluoroacetate B-51- 3 15 To a solution of tert-butyl N-[3-(but-2-ynoylamino)propyl]-N-methyl-carbamate B-51-2 (135 mg, 531 μmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL, 25 eq). The mixture was stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude N-[3-(methylamino)propyl]but-2-ynamide trifluoroacetate B-51-3 (100 mg) as a yellow oil. MS (ESI) m / z 155.0 [M+H]+. 20 Step 3: Synthesis of N-[3-[methyl-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl] amino]propyl]but-2- ynamide 51 To a solution of [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3- 25 oxo-7-(trifluoromethyl)isoindolin-5-yl]methylmethanesulfonate Int-3-OMs (90 mg, 168 μmol, 1 eq) in ACN (2 mL) were added K2CO3 (93 mg, 673 μmol, 4 eq) and N-[3- (methylamino)propyl]but-2-ynamide trifluoroacetate B-51-3 (68 mg, 253 μmol, 1.5 eq). The mixture was stirred at 80 °C for 1 hr. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: 30 Phenomenex luna C18 250 * 50 mm * 15 um; mobile phase: [H2O (0.1% TFA) - ACN]; 149 Attorney Docket No.: 51728-013WO2 gradient:20%-50% B over 10.0 min) to afford N-[3-[methyl-[[2-[3-[3-methyl-1-(4-methyl-1,2,4- triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5- yl]methyl]amino]propyl]but-2-ynamide 51 (47.7 mg, 47.5% yield, 99.4% purity, TFA salt) as a white solid. MS (ESI) m / z 593.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.99 - 9.74 (m, 1H), 5 8.68 - 8.51 (m, 2H), 8.24 (d, J = 18.0 Hz, 2H), 8.02 (s, 1H), 7.75 (dd, J = 1.4, 8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.23 (br d, J = 7.8 Hz, 1H), 5.28 (s, 2H), 4.74 - 4.40 (m, 2H), 3.29 (s, 3H), 3.22 - 3.03 (m, 4H), 2.94 - 2.84 (m, 2H), 2.68 (s, 3H), 2.62 - 2.54 (m, 3H), 2.08 - 1.65 (m, 5H), 1.10 (br d, J = 5.6 Hz, 3H). Example 52: N-[2,2-Difluoro-3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] 10 phenyl] -3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino]propyl]but-2-ynamide 52 Step 1: Synthesis of tert-butyl N-[3-(but-2-ynoylamino)-2,2-difluoro-propyl] carbamate B-52-2 To a solution of but-2-ynoic acid (54 mg, 642 μmol, 1.5 eq) in DCM (3 mL) were added 15 DIEA (111 mg, 856 μmol, 149 μL, 2 eq) and HATU (212 mg, 557 μmol, 1.3 eq), and the mixture was stirred at 20 °C for 5min. Then tert-butyl N-(3-amino-2,2-difluoro-propyl)carbamate B-52-1 (90 mg, 428 μmol, 1 eq) was added, and the mixture was stirred at 20 °C for 1hr. The mixture was quenched with H2O (2 mL), extracted with DCM (1 mL x 3), washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product obtained20 was purified by prep-TLC (SiO2, PE:EA=1:1). tert-Butyl N-[3-(but-2-ynoylamino)-2,2-difluoro- propyl] carbamate B-52-2 (100 mg, 80.3% yield, 95% purity) was obtained as a colorless oil. MS (ESI) m / z 221.2 [M+H-tBu]+. Step 2: Synthesis of N-(3-amino-2,2-difluoro-propyl)but-2-ynamide trifluoroacetate B-52-3 25 To a solution of tert-butyl N-[3-(but-2-ynoylamino)-2,2-difluoro-propyl] carbamate B-52- 2 (100 mg, 362 μmol, 1 eq) in DCM (3 mL) was added TFA (1 mL), then the mixture was stirred at 20 °C for 0.5hr. The mixture was concentrated under reduced pressure to give crude N-(3- amino-2,2-difluoro-propyl)but-2-ynamide trifluroacetate B-52-3 (110 mg) as a light-yellow oil. 30 MS (ESI) m / z 177.2 [M+H]+. Step 3: Synthesis of N-[2,2-difluoro-3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl] methylamino]propyl]but-2- ynamide 52 150 Attorney Docket No.: 51728-013WO2 To a solution of N-(3-amino-2,2-difluoro-propyl)but-2-ynamide trifluoroacetate B-52-3 (89 mg, 308 μmol, 2 eq) and 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3- oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (70 mg, 154 μmol, 1 eq) in EtOH (3 mL) 5 was added TEA (31 mg, 308 μmol, 43 μL, 2 eq) until pH value is about 7, followed by the addition of Ti(i-PrO)4 (88 mg, 308 μmol, 91 μL, 2 eq) and AcOH (925 μg, 15.4 μmol, 0.9 μL, 0.1 eq), and the mixture was stirred at 20 °C for 1 hr. Then NaBH3CN (97 mg, 1.54 mmol, 10 eq) was added, and the mixture was stirred at 20 °C for 0.5hr. The mixture was diluted with saturated NaHCO3 aqueous solution (20 mL), and extracted with EA (20 mL x 3). The combined organic layers were 10 washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product obtained was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40mm * 3 um; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 10%-40% B over 8.0 min). N-[2,2-Difluoro-3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- (trifluoromethyl) isoindolin-5-yl]methylamino]propyl]but-2-ynamide 52 (50.2 mg, 52.9% yield, 15 99.9% purity, TFA salt) was obtained as a white solid. MS (ESI) m / z 615.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.04 (t, J = 6.0 Hz, 1H), 8.60 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.77 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 5.28 (s, 2H), 4.45 (s, 2H), 3.71 (m, 2H), 3.58 (br t, J = 15.6 Hz, 2H), 3.28 (s, 3H), 2.95 - 2.85 (m, 2H), 2.63 - 2.53 (m, 3H), 1.99 (s, 3H), 1.10 (d, J = 5.6 Hz, 3H). 20 Example 53: 4-Methyl-N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3- yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methylamino]propyl]pent-2- ynamide 53 Step 1: Synthesis tert-butyl N-[3-(4-methylpent-2-ynoylamino)propyl] carbamate B- 53-2 25 To a solution of 4-methylpent-2-ynoic acid B-53-1 (40 mg, 357 μmol, 1 eq) in DCM (2 mL) were added DIEA (138 mg, 1.07 mmol, 186 μL, 3 eq), tert-butyl N-(3- aminopropyl)carbamate B-4-1 (62 mg, 357 μmol, 62 μL, 1 eq) and T4P (514 mg, 713 μmol, 50% purity, 2 eq) subsequently at 0 ℃. The mixture was stirred at 25 ℃ for 1 hr. Upon completion, the 30 reaction mixture was concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, EA, Rf = 0.54) to give tert-butyl N-[3-(4-methylpent-2- ynoylamino)propyl]carbamate B-53-2 (90 mg, 92.1% yield, 98% purity) as a colorless oil. MS (ESI) m / z 169.2 [M+H-Boc]+. 151 Attorney Docket No.: 51728-013WO2 Step 2: Synthesis of N-(3-aminopropyl)-4-methyl-pent-2-ynamide trifluoroacetate B- 53-3 To a solution of tert-butyl N-[3-(4-methylpent-2-ynoylamino)propyl]carbamate B-53-2 5 (50 mg, 186 μmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 72 eq). The mixture was stirred at 25 ℃ for 1 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude N-(3-aminopropyl)-4-methyl-pent-2-ynamide trifluoroacetate B-53-3 (50 mg, 95.1% yield) as a yellow oil. MS (ESI) m / z 169.3 [M+H]+. Step 3: Synthesis of 4-methyl-N-[3-[[2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-10 yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin-5-yl]methyl amino]propyl]pent- 2-ynamide 53 To a solution of N-(3-aminopropyl)-4-methyl-pent-2-ynamide trifluoroacetate B-53-3 (44 mg, 157 μmol, 1.2 eq) in DCM (3 mL) were added TEA (27 mg, 264 μmol, 37 μL, 2 eq), 2 -[3-15 [3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7- (trifluoromethyl)isoindoline-5-carbaldehyde Int-2 (60 mg, 132 μmol, 1 eq), Ti(i-PrO)4 (75 mg, 264 μmol, 78 μL, 2 eq) and HOAc (793 μg, 13.2 μmol, 0.8 μL, 0.1 eq). The mixture was stirred at 25 ℃ for 15 hr. Then NaBH3CN (83 mg, 1.32 mmol, 10 eq) was added and the mixture was stirred at 25 ℃ for 1 hr. Upon completion, the reaction mixture was quenched with H2O (10 mL) at 0 ℃, 20 and extracted with EA (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um; mobile phase: [H2O(0.1%TFA)- ACN]; gradient:15%-45% B over 8.0 min) to afford 4-methyl-N-[3-[[2-[3-[3-methyl-1-(4-methyl- 1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo-7-(trifluoromethyl)isoindolin -5- 25 yl]methylamino]propyl] pent-2-ynamide 53 (32 mg, 32.3% yield, 96% purity, TFA salt) as a white solid. MS (ESI) m / z 607.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.91 (br s, 2H), 8.70 (s, 1H), 8.60 (t, J = 5.8 Hz, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.78 (dd, J = 1.4, 8.2 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 5.28 (s, 2H), 4.42 - 4.38 (m, 2H), 3.30 (s, 3H), 3.15 (q, J = 6.5 Hz, 2H), 3.02 - 2.86 (m, 4H), 2.71 (td, J = 6.9, 13.8 Hz, 1H), 2.64 - 2.56 (m, 30 3H), 1.84 - 1.71 (m, 2H), 1.16 (d, J = 6.9 Hz, 6H), 1.10 (d, J = 5.6 Hz, 3H). Example 54: 2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-6-[(4-prop-2- enoylpiperazin-1-yl)methyl]-4-(trifluoromethyl)isoindolin-1-one 54 Step 1: Synthesis of tert-butyl 4-prop-2-enoylpiperazine-1-carboxylate B-54-2 152 Attorney Docket No.: 51728-013WO2 To a solution of tert-butyl piperazine-1-carboxylate hydrochloride (100 mg, 449 μmol, 1 eq) in DCM (2 mL) at 0 °C were added TEA (136 mg, 1.35 mmol, 187 μL, 3 eq) and prop-2-enoyl chloride (40.6 mg, 449 μmol, 37 μL, 1 eq). The mixture was stirred at 0 °C for 1 hr. Upon 5 completion, the reaction mixture was quenched with H2O (10 mL), and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, EA) to give tert-butyl 4-prop-2-enoylpiperazine-1-carboxylate B-54-2 (60 mg, 54% yield, 97% purity) as a yellow oil. MS (ESI) m / z 185.2 [M+H-tBu]+. 10 Step 2: Synthesis of 1-piperazin-1-ylprop-2-en-1-one trifluoroacetate B-54-3 To a solution of tert-butyl 4-prop-2-enoylpiperazine-1-carboxylate B-54-2 (40 mg, 166 μmol, 1 eq) in DCM (1 mL) was added TFA (768 mg, 6.73 mmol, 0.5 mL, 40 eq). The mixture was stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was concentrated under 15 reduced pressure to give crude 1-piperazin-1-ylprop-2-en-1-one trifluoroacetate B-54-3 (45 mg) as a yellow oil. MS (ESI) m / z 141.3 [M+H]+. Step 3: Synthesis of 2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl) cyclobutyl]phenyl]-6-[(4-prop-2-enoylpiperazin-1-yl)methyl]-4-(trifluoromethyl) isoindolin- 1-one 54 20 To a solution of [2-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl] phenyl]-3- oxo-7-(trifluoromethyl)isoindolin-5-yl]methylmethanesulfonate Int-3-OMs (80 mg, 150 μmol, 1 eq) in ACN (2 mL) were added K2CO3 (103 mg, 748 μmol, 5 eq) and 1-piperazin-1-ylprop-2-en- 1-one trifluroacetate (38 mg, 150 μmol, 1 eq). The mixture was stirred at 80 °C for 1 hr. Upon 25 completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (column: Phenomenex luna C1875 * 30 mm * 3 um; mobile phase: [H2O (0.1% TFA) - ACN]; gradient:10%-40% B over 8.0 min) to afford 2-[3-[3- methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-6-[(4-prop-2-enoylpiperazin-1- yl)methyl] -4-(trifluoromethyl)isoindolin-1-one 54 (78.7 mg, 75.4% yield, 99.3% purity, TFA salt) 153 Attorney Docket No.: 51728-013WO2 as a white solid. MS (ESI) m / z 579.2 [M+H]+;1H NMR (400 MHz, DMSO-d6+D2O) δ 8.93 (s, 1H), 8.19 (d, J = 18.0 Hz, 2H), 8.01 (s, 1H), 7.74 (br d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 6.77 (dd, J = 10.6, 16.8 Hz, 1H), 6.16 (dd, J = 1.8, 16.8 Hz, 1H), 5.85 - 5.70 (m, 1H), 5.26 (s, 2H), 4.56 (s, 2H), 3.91 - 3.75 (m, 2H), 3.61 (br s, 2H), 3.35 (s, 3H), 3.25 (br 5 s, 4H), 3.01 - 2.83 (m, 2H), 2.64 - 2.52 (m, 3H), 1.08 (br d, J = 5.4 Hz, 3H). Example 55: N-[1-[[2-[3-[3-Methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-oxo- 7-(trifluoromethyl)isoindolin-5-yl]methyl]-4-piperidyl]but-2-ynamide 55 Step 1: Synthesis of tert-butyl 4-(but-2-ynoylamino)piperidine-1-carboxylate B-55-2 10 To a solution of tert-butyl 4-aminopiperidine-1-carboxylate hydrochloride B-55-1 (100 mg, 449 μmol, 1 eq) in DCM (3 mL) were added DIEA (194 mg, 1.50 mmol, 261 μL, 3 eq), but-2- ynoic acid (42 mg, 499 μmol, 1 eq) and T4P (720 mg, 999 μmol, 50% purity, 2 eq). The mixture was stirred at 0 °C for 1 hr. Upon completion, the reaction mixture was quenched with H2O (10 mL), and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine,15dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, EA) to give tert-butyl 4-(but-2-ynoylamino)piperidine- 1-carboxylate B-55-1 (130 mg, 88% yield, 90% purity) as a yellow oil. MS (ESI) m...

Claims

Attorney Docket No.: 51728-013WO2 CLAIM 1. A compound of formula I:or tautomers, stereoisomers or a pharmaceutically acceptable salt thereof, wherein: W isor , wherein therepresents a double or triple bond, and the R1band R1dare absent when therepresents a triple bond; R1ais selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 haloalkyl or - C1-6 alkoxy; R1b is selected from the group consisting of is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, or - C1-6 alkoxy； R1c is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6alkylene-O- C2-6alkenyl, C1-6alkylene-O- C2-6alkynyl, or C1-6alkylene-NR2aR2b; wherein the R2aand R2bis independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, -C1-6alkoxy, or C1-6alkylene-5-10 membered heteroaryl (preferably optionally C1-6 alkyl substituted 1,2,3-triazole, 2,3,4-triazole or 1,2,4-triazole); R1d is selected from the group consisting of hydrogen, fluoro, cyano and methyl; 429Attorney Docket No.: 51728-013WO2; wherein represents the position attaching to the ring，represents the position attaching to the W; X is N or O; T is C, N, O or S; n is integers ranging from 0, 1, 2, 3 or 4; m is integers ranging from 0, 1, 2, 3 or 4; When X is O, Ra1 is absent; when X is N, Ra1 is selected from the group consisting of hydrogen, OH, CN, halogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 cycloalkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, alkoxyalkyl, hydroxy, carboxyl, alkoxycarbonyl; each Rb1or each Rb2is independently selected from the group consisting of hydrogen, OH, CN, halogen, C1-6alkyl, C3-6cycloalkyl, C2-6cycloalkoxy, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkoxy, alkoxyalkyl, hydroxy, carboxyl, alkoxycarbonyl; Rc1or Rc2is independently selected from the group consisting of hydrogen, OH, CN, halogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 cycloalkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, alkoxyalkyl, hydroxy, carboxyl, alkoxycarbonyl; when T is O or S, Rc1 and Rc2 is absent; Rd1 or Rd2 is independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 cycloalkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, alkoxyalkyl, alkoxycarbonyl; optionally, Ra1and Rb1are taken together with the carbon atom to which they are attached to form a Re1substituted saturated or unsaturated 4-8 membered heterocyclyl; optionally, Ra1 and Rc1 are taken together with the carbon atom to which they are attached to form a Re1 substituted saturated or unsaturated 4-8 membered heterocyclyl; optionally, Ra1 and Rd1 are taken together with the carbon atom to which they are attached to form a Re1 substituted saturated or unsaturated 4-8 membered heterocycly; optionally, Ra1 and Rc1 are taken together with the carbon atom and Rc2 and R1a are taken together with the carbon atom to form Re1and / or Re2substituted saturated or unsaturated 7-11 membered spiro ring systems; 430Attorney Docket No.: 51728-013WO2 optionally, Ra1and Rc1are taken together with the carbon atom and Rc1and R1aare taken together with the carbon atom to form Re1 and / or Re2 substituted saturated or unsaturated 7-11 membered fused ring systems; optionally, Ra1 and R1a are taken together with the carbon atom to which they are attached to form a Re2 substituted saturated or unsaturated 4-8 membered heterocyclyl; optionally, Rd1and R1aare taken together with the carbon atom to which they are attached to form a Re2substituted saturated or unsaturated 4-8 membered heterocyclyl; optionally, Rc1and R1aare taken together with the carbon atom to which they are attached to form a Re2 substituted saturated or unsaturated 4-8 membered heterocyclyl; and / or optionally, Rb1 and Rb2 are taken together with the carbon atom to which they are attached to form a Re1 substituted saturated or unsaturated 4-8 membered cycloalkyl or heterocyclyl; and wherein each Re1is independently selected from the group consisting of hydrogen, OH, CN, halogen, optionally substituted C1-6alkyl, optionally substituted C1-6alkenyl, optionally substituted C1-6alkynyl, optionally substituted C3-6cycloalkyl, optionally substituted C2-6cycloalkoxy, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkoxy, optionally substituted saturated or unsaturated 4-8 membered heterocyclyl or 5-10 membered heteroaryl (preferably optionally substituted 1,2,3-triazole, 2,3,4-triazole or 1,2,34- triazole); wherein each substitutes on Re1 is independently selected from the group consisting of hydrogen, OH, CN, halogen, C1-6 alkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C2-6cycloalkoxy, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkoxy, C6-10aryl or C6-10heteroaryl; wherein each Re2is independently selected from the group consisting of hydrogen, OH, CN, halogen, optionally substituted C1-6alkyl, optionally substituted C1-6alkenyl, optionally substituted C1-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted C2-6 cycloalkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, optionally substituted saturated or unsaturated 4-8 membered heterocyclyl or 5-10 membered heteroaryl (preferably optionally substituted 1,2,3-triazole, 2,3,4-triazole or 1,2,34- triazole); wherein each substitutes on Re2is independently selected from the group consisting of hydrogen, OH, CN, halogen, C1-6alkyl, C3-6cycloalkyl, C2-6cycloalkoxy, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkoxy; Rf1 is selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, or C3-C6 cycloalkyl; V is C or N; Z is CH or N; Y is absent, C1-C3alkylene, or C1-C3haloalkylene, preferably CH2or CH-halogen; 431Attorney Docket No.: 51728-013WO2 Xd1is N or O; Xd2 is C, N or S; Xd3 is C or S; R1 or R1´ is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-C6 cycloalkyl; when Xd2 is S, R1 is absent; when Xd3 is S, R1´ is absent; each R2and R3is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, 4-8 membered heterocyclyl or C3-C6cycloalkyl, wherein the heterocyclyl or cycloalkyl groups are optionally substituted by one to three R6groups; or R2and R3are taken together with C, N or O atom(s) to which they are attached to form a C3-C10cycloalkyl or 4-10 membered heterocyclyl, wherein the C3-C10 cycloalkyl or 4-10 membered heterocyclyl is mono, fused, spiro or bridged ring systems; each R6 is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, hydroxy, -O-C1-6alkyl, -CN, C1-6alkyl-CN, C1-6alkyl-OH or C1-6haloalkyl; or two R6are taken together with C, N or O atom(s) to which they are attached to form a C3-C10cycloalkyl or 4-10 membered heterocyclyl; R4is halogen, R7, OR7or NR7R8, R7or R8is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl or C1-6 alkoxy, 3-6 membered cycloalkyl; or R7 and R8 formed 3-6 membered cycloalkyl; R5 is selected from the group consisting of C1-6 haloalkyl or C3-6 cycloalkyl; represents a single or double bond, and the two adjacent are not simultaneously doublebonds.

2. The compound of claim 1, wherein W is selected from the group consisting of. 432Attorney Docket No.: 51728-013WO2 3. The compound of claim 2, wherein W is selected from the group consisting of.

4. The compound of any one of claims 1-3, wherein L is selected from the group consisting of, 433Attorney Docket No.: 51728-013WO2.

5. The compound of any one of claims 1-3, wherein the L is selected from the group consisting of; p is integers ranging from 0, 1, 2 or 3. 434Attorney Docket No.: 51728-013WO2 6. The compound of any one of claims 1-3, wherein the L is selected from the group consisting of435Attorney Docket No.: 51728-013WO2.

7. The compound of claim 1, wherein the -L-W is selected from the group consisting of436Attorney Docket No.: 51728-013WO2; p or r independently is integers ranging from 0, 1, 2 or 3.

8. The compound of claim 7, wherein the -L-W is selected from the group consisting of: 440Attorney Docket No.: 51728-013WO2446Attorney Docket No.: 51728-013WO2.

9. The compound of any one of claims 1-8, wherein the formula I is selected from the group consisting of， 447Attorney Docket No.: 51728-013WO2.

10. The compound of any one of claims 1-9, wherein the D ring is selected from the group consisting of11. The compound of any one of claims 1-9, wherein the formula I is selected from the group consisting of formula I(A)to I(G), II (A) to II(F), III (A) to III(F), or IV(A) to IV(F),449Attorney Docket No.: 51728-013WO2451Attorney Docket No.: 51728-013WO2452Attorney Docket No.: 51728-013WO2453Attorney Docket No.: 51728-013WO2454Attorney Docket No.: 51728-013WO2Wherein the L, V, W, Y, Z, R1, R1’, R2, R3, R4, R5, R6, R1a, R1b, R1c, R1d are independently defined in any one of claims 1-8; or tautomers, stereoisomers or a pharmaceutically acceptable salt thereof. 455Attorney Docket No.: 51728-013WO2 12. The compound of any one of claims 1-11, wherein, R5 is selected from the group consisting of -CF3 or cyclopropyl.

13. The compound of any one of claims 1-12, wherein, R1 is selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C4 cycloalkyl; preferably hydrogen, -CH3, -CHF2 or cyclopropyl.

14. The compound of any one of claims 1-13, wherein, R6is independently selected from the group consisting of hydrogen, CH3, fluoro, hydroxy, -OCH3, -CN, -CH2CN, -CH2OH or -CF3; or two R6are taken together with C or O atom(s) to which they are attached to form a C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl.

15. A compound selected from compounds below:456Attorney Docket No.: 51728-013WO213 60 14 61 15 62 457Attorney Docket No.: 51728-013WO2458Attorney Docket No.: 51728-013WO231 78 32 79 33 80 459Attorney Docket No.: 51728-013WO2460Attorney Docket No.: 51728-013WO2461Attorney Docket No.: 51728-013WO2462Attorney Docket No.: 51728-013WO2463Attorney Docket No.: 51728-013WO2464Attorney Docket No.: 51728-013WO2465Attorney Docket No.: 51728-013WO2466Attorney Docket No.: 51728-013WO2467Attorney Docket No.: 51728-013WO2468Attorney Docket No.: 51728-013WO2or tautomers, stereoisomers or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising the compound of any one of claims 1-15, and a pharmaceutically acceptable excipient.

17. A method for treating a tumor by modulating activity of an immune cell, the method comprising contacting the immune cell with an effective amount of a covalent Cbl-b inhibitor, 469Attorney Docket No.: 51728-013WO2 wherein the covalent Cbl-b inhibitor is a compound of any one of claims 1-15 or tautomers, stereoisomers or a pharmaceutically acceptable salt thereof; or the compound of any one of claims 1-15 or tautomers, stereoisomers or a pharmaceutically acceptable salt thereof, for use as a medicament for treating a tumor by modulating activity of an immune cell; or use of the compound of any one of claims 1-15 or tautomers, stereoisomers or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 16 in the manufacture of a medicament for treating a tumor by modulating activity of an immune cell.

18. The method, compound or use of claim 17, wherein the cancer is a hematologic cancer or non- hematologic cancer.

19. The method, compound or use of claim 18, wherein the hematologic cancer is a lymphoma, a leukemia, or a myeloma, the non-hematologic cancer is a sarcoma, a carcinoma, or a melanoma. 470

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