BCL-XL degrading compounds

Abstract

Provided herein are heteroaromatic compounds that target the Bcl-xL proteins for ubiquitination and proteasome degradation. Also provided herein are methods of treating diseases using the compounds.

Description

Background Art

[0001] The BCL-2 (B-cell lymphoma-2) protein family serves as key regulators of the mitochondrial pathway of apoptosis and consists of both anti-apoptotic proteins (such as BCL-2, BCL-XL, BCL-W, A1, and MCL-1) and pro-apoptotic proteins (such as Bak, Bax, Bid, Bim, Bad, Bik, Bmf, Noxa, and Puma) [1-2]. Pro-apoptotic BCL-2 proteins and anti-apoptotic BCL-2 proteins generally act in opposition to each other. Blocking the interaction between them by treatment with small molecules or by RNA interference leads to mitochondrial outer membrane permeabilization (MOMP) and the release of cytochrome c, second mitochondria-derived activator of caspases (SMAC), and other pro-apoptotic factors [3]. These events then trigger a caspase activation cascade and subsequent apoptosis [4].

[0002] BCL-XL belongs to the anti-apoptotic BCL-2 protein family and plays an important role in promoting tumor initiation, progression, and the manifestation of drug resistance by protecting tumor cells from apoptosis [5]. Inhibiting these BCL-2 family proteins with small molecule inhibitors has been widely investigated as a cancer treatment strategy [6-11].

[0003] Retinal vascular diseases are the leading cause of blindness in the industrialized world, and current standards do not fully address these diseases. In aging-related models of retinopathies such as age-related macular degeneration (AMD) and diabetic macular edema (DME), senescent cells affect the tissue microenvironment to drive disease progression. UNITY provides evidence that when pathological preretinal neovascularization forms, cells of the vascular unit rapidly engage a pathway that results in activation of p16INK4A and upregulation of the prosurvival protein BCL-XL, ultimately leading to cellular senescence. UNITY is developing an anti-aging drug (UBX1325) to eliminate senescent cells to restore tissue health

[12] . Focusing on a novel therapeutic paradigm, elimination of vascular senescent cells by a BCL-XL inhibitor or a PROTAC should reconstitute barrier function and reverse disease progression in patients with DME and AMD. A BCL-XL inhibitor or a PROTAC targets a node upstream of anti-VEGF therapy. Targeting the senescence effector / anti-apoptotic protein BCL-XL inhibits pathological angiogenesis, thus providing a target for eliminating dysregulated neovascularization. Summary of the Invention

[0004] Compounds are provided herein that target the Bcl-xL protein for ubiquitination and proteasomal degradation. Methods of treating diseases using the compounds are also provided.

[0005] One embodiment provides a compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, having the structure of formula (I-A):

[0006]

[0007] wherein,

[0008] o is 0, 1, 2 or 3;

[0009] Y is S or CH═CH;

[0010] each R 1 is independently selected from halogen, nitro, cyano, -OR 2 , -N(R 2 )2, -SR 2 , -S(O)R 2 , -S(O)2R 2 , -S(O)2N(R 2 )2, -NR 2 S(O)2R 2 , -NR 2 S(O)2N(R 2 )2, -C(O)R 2 , -C(O)OR 2 , -OC(O)R 2 , -OC(O)OR 2 , -OC(O)N(R 2 )2, -NR 2 C(O)R 2 , -NR 2 C(O)OR 2 , -NR 2 C(O)N(R 2 )2, -C(O)N(R 2 )2, -P(O)(OR 2 )2, -P(O)(R 2 )2, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 2-6 alkyl in which 1 to 2 -CH2- units are replaced by N, O or S, provided that two adjacent -CH2- units are not replaced simultaneously, optionally substituted C 3-12 carbocyclic group and optionally substituted 3 - to 12 - membered heterocyclic group;

[0011] each R 2 is independently hydrogen or optionally substituted C 1-6 alkyl; or

[0012] Two Rs 2 Together with the nitrogen atom to which they are attached, they can form an optionally substituted 3- to 6-membered heterocyclic ring;

[0013] V is a bond, -C≡C-, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted C 3-7 cycloalkyl or an optionally substituted heterocyclic group; or

[0014] Together form a fused bicyclic aryl ring or a fused bicyclic heteroaryl ring, each of which is substituted with o Rs 1 Examples of;

[0015] L is selected from a) C2-C 15 alkylene, b) C 2-15 alkylene, in which one or more -CH2- units are replaced by O, provided that two O atoms are not adjacent, or c) -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*;

[0016] Ak 1 is selected from -(CR 3 R 4 ) k -;

[0017] Ak 2 is selected from -(CR 3 R 4 ) m -;

[0018] Ak 3 is selected from -(CR 3 R 4 ) n -;

[0019] Each of k, m, and n is selected from 0 to 6;

[0020] Each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl and C3 cycloalkyl; or

[0021] R 3 and R 4 Together form an oxo group;

[0022] Z 1 and Z 2 are each independently selected from a bond, -O-, a heteroalkylene group, and a cycloalkylene group; where Z1 and Z 2 at least one of which is a heteroarylene or cycloalkylene; and

[0023] U is a recruitment motif selected from VHL ligands.

[0024] One embodiment provides a pharmaceutical composition comprising a compound of formula (I-A) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, and at least one pharmaceutically acceptable excipient.

[0025] One embodiment provides a compound of formula (I-A) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof for use in a method of treating a human or animal.

[0026] One embodiment provides a compound of formula (I-A) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof for use in a method of treating cancer or a neoplastic disease.

[0027] One embodiment provides the use of a compound of formula (I-A) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof in the manufacture of a medicament for treating cancer or a neoplastic disease.

[0028] One embodiment provides a method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a compound of formula (I-A) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof. Another embodiment provides the method, wherein the disease or disorder is cancer.

[0029] One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of formula (I-A) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Shows tumor volume over time in a mouse xenograft model after treatment with the compounds disclosed herein.

[0031] Figure 2 Shows tumor volume over time in a mouse xenograft model after treatment with the compounds disclosed herein.

[0032] Figure 3 Shows tumor volume over time in a mouse xenograft model after treatment with the compounds disclosed herein.

[0033] Incorporated by reference

[0034] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference for the specific purposes identified herein. Detailed Description

[0035] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a dose" includes a plurality of such doses, and reference to "the cell" includes reference to one or more cells (or a plurality of cells) and equivalents known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formula, all combinations and subcombinations of the ranges and specific embodiments therein are intended to be included. When referring to a number or numerical range, the term "about" means that the indicated number or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus, in some instances, the numerical or numerical range will vary between 1% and 15% of the stated numerical or numerical range. The term "comprising" (and related terms such as "including" or "having" or "containing") is inclusive or open-ended and does not exclude additional, unrecited elements.

[0036] Definitions

[0037] As used in the specification and the appended claims, unless the context dictates otherwise, the following terms have the meanings set forth below.

[0038] "Amino" refers to the –NH2 radical.

[0039] "Cyano" refers to the -CN radical.

[0040] "Nitro" refers to the -NO2 radical.

[0041] "Oxa" refers to the -O- radical.

[0042] "Oxo" refers to the =O radical.

[0043] "Thio" refers to the =S radical.

[0044] "Imino" refers to the =N-H radical.

[0045] "Oximino" refers to the =N-OH radical.

[0046] "Hydrazino" refers to the =N-NH2 radical.

[0047] "Alkyl" refers to a straight-chain or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from one to fifteen carbon atoms (e.g., C1-C 15(alkyl). In certain embodiments, the alkyl contains from one to thirteen carbon atoms (e.g., C1-C 13 (alkyl). In certain embodiments, the alkyl contains from one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl contains from one to six carbon atoms (e.g., C1-C6 alkyl). In other embodiments, the alkyl contains from one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl contains from one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl contains from one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl contains from one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl contains one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl contains from five to fifteen carbon atoms (e.g., C5-C 15 (alkyl). In other embodiments, the alkyl contains from five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl contains from two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl contains from three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is connected to the rest of the molecule by a single bond. Unless otherwise expressly specified in the specification, the alkyl is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O)t N(R a )2 (where t is 1 or 2), wherein each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroaryl alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0048] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, wherein the alkyl is an alkyl chain radical as defined above.

[0049] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having two to twelve carbon atoms. In certain embodiments, the alkenyl contains two to eight carbon atoms. In other embodiments, the alkenyl contains two to four carbon atoms. The alkenyl is connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc. Unless otherwise specifically stated in the specification, the alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a(where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), wherein each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0050] "Alkynyl" means a straight-chain or branched-chain hydrocarbon radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond and having from two to twelve carbon atoms. In certain embodiments, alkynyl contains from two to eight carbon atoms. In other embodiments, alkynyl contains from two to six carbon atoms. In other embodiments, alkynyl contains from two to four carbon atoms. Alkynyl is attached to the remainder of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specifically stated in the specification, alkynyl is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a(where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0051] "Alkylene" or "alkylene chain" refers to a straight-chain or branched-chain divalent hydrocarbon chain that connects the remainder of the molecule to a radical group, consists only of carbon and hydrogen, contains no unsaturation, and has from one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the remainder of the molecule by a single bond and to the radical group by a single bond. The points of attachment of the alkylene chain to the remainder of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, the alkylene contains from one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkyl contains from one to six carbon atoms (e.g., C1-C6 alkylene). In other embodiments, the alkylene contains from one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene contains from one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene contains from one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene contains from one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene contains one carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene contains from five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene contains from two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene contains from three to five carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specifically stated in the specification, the alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(Ra ) 2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0052] "Alkenylene" or "alkenylene chain" means a divalent hydrocarbon chain that connects the remainder of the molecule to a radical group, consists only of carbon and hydrogen, contains at least one carbon-carbon double bond, and has a straight or branched chain with two to twelve carbon atoms. The alkenylene chain is connected to the remainder of the molecule by a single bond and to the radical group by a single bond. In certain embodiments, the alkenylene contains two to eight carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, the alkenylene contains two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, the alkenylene contains two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, the alkenylene contains two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, the alkenylene contains two carbon atoms (e.g., C2 alkenylene). In other embodiments, the alkenylene contains five to eight carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, the alkenylene contains three to five carbon atoms (e.g., C3-C5 alkenylene). Unless otherwise specifically stated in the specification, the alkenylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2(where t is 1 or 2), where each R aIndependently is hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroaryl alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0053] "Alkynylene" or "alkynylene chain" refers to a divalent hydrocarbon chain that connects the remainder of the molecule to the radical group, consists only of carbon and hydrogen, contains at least one carbon-carbon triple bond, and has a straight or branched chain with two to twelve carbon atoms. The alkynylene chain is connected to the remainder of the molecule by a single bond and to the radical group by a single bond. In certain embodiments, the alkynylene contains two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, the alkynylene contains two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, the alkynylene contains two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, the alkynylene contains two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, the alkynylene contains two carbon atoms (e.g., C2 alkynylene). In other embodiments, the alkynylene contains five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, the alkynylene contains three to five carbon atoms (e.g., C3-C5 alkynylene). Unless specifically stated otherwise in the specification, the alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O)t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), wherein each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0054] "Aryl" means a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only carbon and hydrogen and has five to eighteen carbon atoms, wherein at least one ring in the ring system is completely unsaturated, i.e., it contains a cyclic delocalized (4n + 2)π electron system that conforms to Hückel's theory. Ring systems from which aryl is derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetrahydronaphthalene and naphthalene. Unless specifically stated otherwise in the specification, the term "aryl" or the prefix "ar" (such as in "aralkyl") is intended to include aryl radicals optionally substituted by one or more substituents, said one or more substituents being independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic group, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)Ra ,-R b -C(O)OR a ,-R b -C(O)N(R a )2,-R b -O-R c -C(O)N(R a )2,-R b -N(R a )C(O)OR a ,-R b -N(R a )C(O)R a ,-R b -N(R a )S(O) t R a (where t is 1 or 2),-R b -S(O) t R a (where t is 1 or 2),-R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and where unless otherwise indicated, each of the above substituents is unsubstituted.

[0055] "Aralkyl" means a radical of the formula -R c -aryl, where R cis an alkylene chain as defined above, such as methylene, ethylene, etc. The alkylene chain portion of the aralkyl radical is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl radical is optionally substituted as described above for the aryl.

[0056] "Arylenyl" means a radical of the formula –R d -aryl, where R d is an alkenylene chain as defined above. The aryl portion of the arylenyl radical is optionally substituted as described above for the aryl. The alkenylene chain portion of the arylenyl radical is optionally substituted as defined above for the alkenylene.

[0057] "Arylalkynyl" means a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above. The aryl portion of the arylalkynyl radical is optionally substituted as described above for the aryl. The alkynylene chain portion of the arylalkynyl radical is optionally substituted as defined above for the alkynylene chain.

[0058] "Aralkyloxy" means a radical bonded through an oxygen atom of the formula -O-R c -aryl, where R c is an alkylene chain as defined above, such as methylene, ethylene, etc. The alkylene chain portion of the aralkyl radical is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl radical is optionally substituted as described above for the aryl.

[0059] "Carbocyclic group" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, which includes fused, bridged or spiro ring systems and has three to fifteen carbon atoms. In certain embodiments, the carbocyclic group contains three to ten carbon atoms. In other embodiments, the carbocyclic group contains five to seven carbon atoms. The carbocyclic group is attached to the rest of the molecule by a single bond. The carbocyclic group is saturated (i.e., contains only C-C single bonds) or unsaturated (i.e., contains one or more double or triple bonds). A fully saturated carbocyclic radical is also referred to as "cycloalkyl". Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The unsaturated carbocyclic group is also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Polycyclic carbocyclic radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Spiro carbocyclic or cycloalkyl radicals include, for example, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, spiro[2.6]nonane, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[3.6]decane, spiro[4.4]nonane, spiro[4.5]decane, spiro[4.6]undecane, spiro[5.5]undecane, spiro[5.6]dodecane, spiro[6.6]tridecane, etc. Unless specifically stated otherwise in the specification, the term "carbocyclic group" is intended to include a carbocyclic radical optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic group, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-Rb -O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and where unless otherwise indicated, each of the above substituents is unsubstituted.

[0060] "Subcycloalkyl" means a divalent carbocyclic or cycloalkyl group that attaches the remainder of the molecule to the radical.

[0061] "Cycloalkylalkyl" means a radical of the formula –R c -cycloalkyl, where R c is an alkylene chain as defined above. The alkylene chain and the cycloalkyl radical are optionally substituted as defined above.

[0062] "Cycloalkylalkynyl" means a radical of the formula –R c-a radical of a carbocyclic group, wherein R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclic radical are optionally substituted as defined above.

[0063] "Carbocyclic alkoxy" refers to a radical bonded through an oxygen atom of a carbocyclic group of the formula –O-R c -carbocyclic, wherein R c is an alkylene chain as defined above. The alkylene chain and the carbocyclic radical are optionally substituted as defined above.

[0064] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits physical, biological, and / or chemical properties similar to those of a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to

[0065] etc.

[0066] "Halogen group" or "halogen" refers to a bromine, chlorine, fluorine, or iodine substituent.

[0067] "Fluoroalkyl" refers to an alkyl radical as defined above substituted with one or more fluoro radicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for alkyl.

[0068] "Heterocyclic group" refers to a stable 3- to 18-membered non-aromatic ring radical that contains two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated in the specification, the heterocyclic group radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes a fused-ring, bridged-ring, or spiro-ring system. The heteroatoms in the heterocyclic group radical are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heterocyclic group radical is partially or fully saturated. The heterocyclic group is attached to the remainder of the molecule through any atom of the ring. Examples of such heterocyclic group radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl, 1-azaspiro[2.2]pentane, 1-azaspiro[2.3]hexane, 1-azaspiro[2.4]heptane, 1-azaspiro[2.5]octane, 1-azaspiro[2.6]nonane, 2-azaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.6]decane, 2-azaspiro[4.4]nonane, 2-azaspiro[4.5]decane, 2-azaspiro[4.6]undecane, 3-azaspiro[5.5]undecane, 3-azaspiro[5.6]dodecane, 3-azaspiro[6.6]tridecane, 5-azaspiro[2.3]hexane, 5-azaspiro[2.4]heptane, 6-azaspiro[2.5]octane, 6-azaspiro[2.6]nonane, 6-azaspiro[3.4]octane, 7-azaspiro[3.5]nonane, 7-azaspiro[3.6]decane, 8-azaspiro[4.5]decane, 8-azaspiro[4.6]undecane, 9-azaspiro[5.6]dodecane, 1,4-diazaspiro[2.2]pentane, 1,5-diazaspiro[2.3]hexane, 1,5-diazaspiro[2.4]heptane, 1,6-diazaspiro[2.5]octane, 1,6-diazaspiro[2.6]nonane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[3.6]decane, 2,7-diazaspiro[4.4]nonane, 2,8-diazaspiro[4.5]decane, 2,8-diazaspiro[4.6]undecane, 3,9-diazaspiro[5.5]undecane, 3,9-diazaspiro[5.6]dodecane, and 3,10-diazaspiro[6.6]tridecane.Unless otherwise specifically stated in the specification, the term "heterocyclic group" is intended to include a heterocyclic radical as defined above optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic group, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -R. b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2)、-R b -S(O) t R a (where t is 1 or 2)、-R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2), where each R aIndependently is hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b Independently is a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein unless otherwise indicated, each of the above substituents is unsubstituted.

[0069] "Heteroalkyl" means an alkyl in which one or more backbone atoms of the alkyl are selected from atoms other than carbon such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, wherein the heteroalkyl contains 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur or combinations thereof, and wherein the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, –CH2-O-CH2-, –CH2-N(alkyl)-CH2-, –CH2-N(aryl)-CH2-, -OCH2CH2O-, –OCH2CH2OCH2CH2O- or –OCH2CH2OCH2CH2OCH2CH2O-. Unless specifically stated otherwise in the specification, the heteroalkyl is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the heteroalkyl is optionally substituted by halogen.

[0070] "Heterocyclylene" means a divalent heterocyclic group that attaches the remainder of the molecule to a radical group.

[0071] "N - heterocyclic group" or "N - linked heterocyclic group" means a heterocyclic radical as defined above containing at least one nitrogen, and wherein the point of attachment of the heterocyclic radical to the remainder of the molecule is through a nitrogen atom in the heterocyclic radical. The N - heterocyclic radical is optionally substituted as described above for the heterocyclic radical. Examples of such N - heterocyclic radicals include, but are not limited to, 1 - morpholinyl, 1 - piperidinyl, 1 - piperazinyl, 1 - pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0072] "C - heterocyclic group" or "C - linked heterocyclic group" means a heterocyclic radical as defined above containing at least one heteroatom, and wherein the point of attachment of the heterocyclic radical to the remainder of the molecule is through a carbon atom in the heterocyclic radical. The C - heterocyclic radical is optionally substituted as described above for the heterocyclic radical. Examples of such C - heterocyclic radicals include, but are not limited to, 2 - morpholinyl, 2 - piperidinyl or 3 - piperidinyl or 4 - piperidinyl, 2 - piperazinyl, 2 - pyrrolidinyl or 3 - pyrrolidinyl, etc.

[0073] "Heterocyclic alkyl" means a radical of the formula –R c -heterocyclic group, where R c is an alkylene chain as defined above. If the heterocyclic group is a nitrogen - containing heterocyclic group, then the heterocyclic group is optionally attached to the alkyl radical at a nitrogen atom. The alkylene chain of the heterocyclic alkyl radical is optionally substituted as defined above for the alkylene chain. The heterocyclic moiety of the heterocyclic alkyl radical is optionally substituted as defined above for the heterocyclic group.

[0074] "Heterocyclic alkoxy" means a radical bonded through an oxygen atom of the formula –O - R c -heterocyclic group, where R c is an alkylene chain as defined above. If the heterocyclic group is a nitrogen - containing heterocyclic group, then the heterocyclic group is optionally attached to the alkyl radical at a nitrogen atom. The alkylene chain of the heterocyclic alkoxy radical is optionally substituted as defined above for the alkylene chain. The heterocyclic moiety of the heterocyclic alkoxy radical is optionally substituted as defined above for the heterocyclic group.

[0075] "Heteroaryl" refers to a radical derived from an aromatic ring radical having 3 to 18 ring atoms, which contains two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic delocalized (4n + 2)π electron system in accordance with Hückel's theory. Heteroaryl includes fused or bridged ring systems. The heteroatoms in the heteroaryl radical are optionally oxidized. If there is one or more nitrogen atoms, they are optionally quaternized. Heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryl include, but are not limited to, azetidinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzodioxepinyl, benzoxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, chromenyl, chromenone, benzofuranyl, benzofuranone, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzimidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cycloheptatrieno[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraeno[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraeno[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraeno[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinone, oxadiazolyl, 2-oxoazetidinyl yl, aziridinyl, pyranyl, pyridazinyl, pyrimidinyl, pyridyl, pyrazinyl, pyrazolyl, purinyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, 1,2,4,5-tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, triazolyl, and the like. Base, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridyl and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in the specification, the term "heteroaryl" is intended to include heteroaryl radicals as defined above which are optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic group, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)ORa 、 -R b -N(R a )C(O)R a 、 -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), arylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and where unless otherwise indicated, each of the above substituents is unsubstituted.

[0076] “N - heteroaryl” means a heteroaryl radical as defined above containing at least one nitrogen, and where the point of attachment of the heteroaryl radical to the remainder of the molecule is made through a nitrogen atom in the heteroaryl radical. The N - heteroaryl radical is optionally substituted as described above for the heteroaryl radical.

[0077] “C - heteroaryl” means a heteroaryl radical as defined above, and where the point of attachment of the heteroaryl radical to the remainder of the molecule is made through a carbon atom in the heteroaryl radical. The C - heteroaryl radical is optionally substituted as described above for the heteroaryl radical.

[0078] “heteroarylalkyl” means a radical of the formula –R c -heteroaryl, where R cis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, then the heteroaryl is optionally attached to an alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkyl radical is optionally substituted as defined above for the heteroaryl.

[0079] "Heteroarylalkoxy" means a radical bonded through the oxygen atom of the formula –O-R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, then the heteroaryl is optionally attached to an alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkoxy radical is optionally substituted as defined above for the heteroaryl.

[0080] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise stated, the present disclosure is intended to cover all stereoisomeric forms of the compounds disclosed herein. When the compounds described herein contain an olefinic double bond and unless otherwise specified, the present disclosure is intended to include both the E geometric isomer and the Z geometric isomer (e.g., cis or trans). Similarly, all possible isomers and their racemic and optically pure forms and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to the E geometric isomer or the Z geometric isomer of an olefinic double bond (e.g., cis or trans). The term "positional isomer" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0081] In an embodiment of the present disclosure, when a cyclohexyl or cyclobutyl has a set of para-substituted substituents and the two carbon atoms on the cyclohexyl or cyclobutyl that are attached to this set of para-substituted substituents are not chiral centers, the chemical bond notation in the form of merely means that the two chemical bonds attached to this set of para-substituted substituents are in a trans or cis configuration relative to the cyclohexyl or cyclobutyl. Thus, a compound represented by exchanging these two chemical bonds with each other, or a compound represented by transforming the combination into the combination (or vice versa) also falls within the scope of the present disclosure.

[0082] "Tautomers" refer to molecules in which a proton can move from one atom of the molecule to another atom of the same molecule. In certain embodiments, the compounds provided herein exist in tautomeric forms. Where tautomerism is possible, there will be a chemical equilibrium of tautomers. The exact proportions of the tautomers depend on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include:

[0083]

[0084] In some embodiments, the compounds disclosed herein are used in different enriched isotope forms, such as enriched 2 H, 3 H, 11 C, 13 C, and / or 14 C content. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Pat. Nos. 5,846,514 and 6,334,997. As described in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of action of the drug.

[0085] Unless otherwise stated, the structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention are within the scope of this disclosure except where hydrogen is replaced by deuterium or tritium, or carbon is replaced by carbon enriched in 13 C or 14 C.

[0086] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that make up such compounds. For example, the compounds can be isotopically labeled, such as, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). With 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F,18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 All isotope substitutions carried out with F, S, S, S, S, Cl, Cl, Br, Br, and I are considered. In some embodiments, isotope substitution with 18 F is considered. All isotopic variants of the compounds of the invention, whether or not radioactive, are encompassed within the scope of the invention.

[0087] In certain embodiments, some or all of the 1 H atoms of the compounds disclosed herein are replaced by 2 H atoms. Methods for the synthesis of deuterated compounds are known in the art and, by way of non-limiting example only, include the following synthetic methods.

[0088] Deuterated compounds are synthesized using various methods such as those described in: Dean, Dennis C., ed., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; George W.; Varma, Rajender S., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601 - 21; and Evans, Anthony S., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1 - 2), 9 - 32.

[0089] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide the synthesis of deuterated compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0090] Deuterium transfer reagents applicable to nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and can be used to transfer deuterium-substituted carbon atoms to reaction substrates under nucleophilic substitution reaction conditions. The use of CD3I is shown only by way of example in the following reaction schemes.

[0091]

[0092] Deuterium transfer reagents such as lithium aluminum deuteride (LiAlD4) are used to transfer deuterium to reaction substrates under reducing conditions. The use of LiAlD4 is shown only by way of example in the following reaction schemes.

[0093]

[0094] Deuterium gas and palladium catalysts are used to reduce unsaturated carbon-carbon linkages and to effect reductive substitution of aryl carbon-halogen bonds, as shown only by way of example in the following reaction schemes.

[0095]

[0096] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compounds disclosed herein are completely substituted with deuterium atoms and do not contain non-exchangeable 1 H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by the synthetic method in which deuterated building blocks are used as starting materials.

[0097] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Pharmaceutically acceptable salts of any of the heteroaromatic Bcl-xL inhibitory compounds described herein are intended to cover any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0098] "Pharmaceutically acceptable acid addition salts" refers to salts that retain the biological effectiveness and properties of the free base, are not biologically or otherwise undesirable, and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and including for example acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Accordingly, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Also contemplated are salts of amino acids such as arginine salts, gluconates, and galacturonates (see for example Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). In some embodiments, the acid addition salts of the basic compound are prepared by contacting the free base form with a sufficient amount of the desired acid according to methods and techniques familiar to those of ordinary skill in the art to produce the salt.

[0099] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid and are not otherwise undesirable in a biological context or otherwise. These salts are prepared by adding an inorganic base or an organic base to the free acid. In some embodiments, the pharmaceutically acceptable base addition salts are formed with a metal or an amine such as an alkali metal and an alkaline earth metal or an organic amine. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, including substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, diaminobenzyl, N-methylglucamine, glucamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0100] "Pharmaceutically acceptable solvate" refers to a substance composition in the form of a solvent addition. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of the solvent and is formed during the preparation with a pharmaceutically acceptable solvent such as water, ethanol, and the like. A hydrate is formed when the solvent is water, or an alcoholate is formed when the solvent is an alcohol. The solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in an unsolvated form as well as a solvated form.

[0101] The terms "subject" or "patient" encompass mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; experimental animals, including rodents such as rats, mice, and guinea pigs, and the like. In one aspect, the mammal is a human.

[0102] "Prodrug" refers to a compound that undergoes biotransformation before exhibiting its pharmacological action. Thus, a prodrug can be regarded as a drug containing a specialized protecting group that is used in a transient manner to alter the pharmacological properties of the parent molecule.

[0103] As used herein, "treatment / treating" or "alleviating" or "ameliorating" are used interchangeably. These terms refer to a method for obtaining a beneficial or desired result including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. For the purposes of "therapeutic benefit", it means eradicating or ameliorating the underlying disorder being treated. Additionally, a therapeutic benefit is achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, even if the patient still suffers from the underlying disorder. In some embodiments, for a prophylactic benefit, the composition is administered to a patient at risk of developing a particular disease, or a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease has not yet been made.

[0104] Bcl-xL

[0105] The BCL-2 (B-cell lymphoma-2) protein family functions as key regulators of the mitochondrial pathway of apoptosis and consists of both anti-apoptotic proteins (such as BCL-2, BCL-XL, BCL-W, A1, and MCL-1) and pro-apoptotic proteins (such as Bak, Bax, Bid, Bim, Bad, Bik, Bmf, Noxa, and Puma). Pro-apoptotic BCL-2 proteins and anti-apoptotic BCL-2 proteins generally act in opposition to each other. Blocking the interaction between them by treatment with small molecules or by RNA interference results in mitochondrial outer membrane permeabilization (MOMP) and the release of cytochrome c, second mitochondria-derived activator of caspase (SMAC), and other pro-apoptotic factors. These events then trigger the caspase activation cascade and subsequent apoptosis.

[0106] BCL-XL belongs to the anti-apoptotic BCL-2 protein family and plays an important role in promoting tumor initiation, progression, and the manifestation of drug resistance by protecting tumor cells from apoptosis. Inhibition of these BCL-2 family proteins with small molecule inhibitors has been widely investigated as a cancer treatment strategy. Retinal vascular diseases are the leading cause of blindness in the industrialized world, and current standards do not fully address these diseases. In aging-related models of retinopathies such as age-related macular degeneration (AMD) and diabetic macular edema (DME), senescent cells affect the tissue microenvironment to drive disease progression. UNITY provides evidence that when pathological preretinal neovascularization forms, cells of the vascular unit rapidly engage pathways that result in p16INK4A activation and upregulation of the prosurvival protein BCL-XL, ultimately leading to cellular senescence. UNITY is developing an anti-aging drug (UBX1325) to eliminate senescent cells and restore tissue health. Focusing on a novel therapeutic paradigm, elimination of vascular senescent cells by BCL-XL inhibitors or PROTACs should reconstitute barrier function and reverse disease progression in patients with DME and AMD. BCL-XL inhibitors or PROTACs target a node upstream of anti-VEGF therapies. Targeting the senescence effector / anti-apoptotic protein BCL-XL inhibits pathological angiogenesis, thus providing a target for eliminating dysregulated neovascularization.

[0107] Additional information can be found in the following: a) J Kale, EJ Osterlund, and DW Andrews. BCL-2 family proteins: changing partners in the dance towards death. Cell Death & Differentiation. 2018;25:65-80

[13] , b) M Stevens and S Oltean. Modulation of the Apoptosis Gene Bcl-x Function Through Alternative Splicing. Front. Genet. September 6, 2019;10(804)

[14] , and c) LP Billen, CL Kokoski, JF Lovell, B Leber, and DW Andrews. Bcl-XL Inhibits Membrane Permeabilization by Competing with Bax. PLoS Biology. June 10, 2008;6(6):e147

[15] , which are hereby incorporated by reference in their entirety.

[0108] Selective protein degradation

[0109] The level of intracellular protein is determined by both the rate of protein synthesis and the rate of protein degradation. In eukaryotic cells, there are two pathways for selective protein degradation, namely the ubiquitin-proteasome pathway and the lysosomal proteolytic pathway. Generally, selective protein degradation is mediated by the presence of a recruitment motif, which promotes the binding of a protein to be degraded, such as a proteasome-degraded protein or a protein related to the ubiquitin-proteasome pathway. The recruitment motif includes an E3 ligase recognition agent and a proteasome recognition agent. Conjugation of the recruitment motif with a high-affinity ligand of Bcl-xL will provide a compound capable of selectively directing the protein degradation pathway to the Bcl-xL protein itself. Such a result will reduce the level of Bcl-xL activity.

[0110] Heteroaromatic Bcl-xL degrading compound

[0111] In one aspect, the present disclosure provides a heteroaromatic Bcl-xL degrading compound having the general formula provided below:

[0112]

[0113] Wherein the Bcl-xL affinity motif is a molecular construct that has a high affinity for the Bcl-xL protein, independent of the linker motif and / or the recruitment motif, the linker motif is a molecular construct that provides a covalent bond to both the Bcl-xL affinity motif and the recruitment motif, and the recruitment motif is a molecular construct capable of selectively targeting and recruiting protein degradation. In some embodiments, the heteroaromatic Bcl-xL degrading compound has the structure of formula (I-A):

[0114]

[0115] Wherein Y is S or CH═CH, L is a linker motif, and U is a recruitment motif.

[0116] Recruitment motif

[0117] The recruitment motif includes an E3 ligase recognition agent and a proteasome recognition agent. In some embodiments, the recruitment motif is derived from a VHL ligand, nutlin, bestatin, an HIF-1α–VHL binding peptide, a hydroxyproline-HIF-1α-VHL binding peptide, an SCFb-TRCP targeting peptide, or an inhibitor of an apoptotic protein ligand.

[0118] In some embodiments, the recruitment motif (e.g., U in Formula (I-A), Formula (I-B), Formula (I-C1), Formula (I-C2), Formula (I-D1), Formula (I-D2), Formula (I-E1a), Formula (I-E1b), Formula (I-E2a), Formula (I-E2b), Formula (I-F), Formula (I-G), or Formula (I-H)) is selected from molecular constructs related to VHL ligands. In some embodiments, the recruitment motif or VHL ligand has a structure selected from the following:

[0119]

[0120] where the bonding point to the linker motif is indicated by a wavy bond. In some embodiments, the recruitment motif is selected from:

[0121]

[0122] In some embodiments, the recruitment motif is In some embodiments, the recruitment motif is In some embodiments, the recruitment motif is

[0123] The terms “VHL ligand,” “VHL binder,” and “VHL E3 ubiquitin ligase binder” are used interchangeably herein to refer to a compound or motif that binds to the Von Hippel–Lindau tumor suppressor (VHL).

[0124] Linker motif

[0125] A linking motif is a molecular construct that provides a covalent bond to both a Bcl-xL affinity motif and a recruitment motif. In some embodiments, the linking motif comprises a cyclic moiety. In some embodiments, the linking motif comprises an acyclic moiety. In some embodiments, the linking motif comprises an unsaturated moiety. In some embodiments, the linking motif contains between 4 and 50 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif contains between 4 and 20 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif contains between 4 and 25 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif contains between 4 and 30 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif contains between 6 and 18 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif contains between 5 and 10 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 non-hydrogen atoms in a linear sequence. As an example, the following molecular fragment contains 8 non-hydrogen atoms in a linear sequence:

[0126] In some embodiments, the linking motif, such as L in Formula (I-A), Formula (I-B), Formula (I-C1), Formula (I-C2), Formula (I-D1), Formula (I-D2), Formula (I-E1a), Formula (I-E1b), Formula (I-E2a), Formula (I-E2b), Formula (I-F), Formula (I-G), or Formula (I-H), is selected from a) C2-C 15 alkylene, b) C 2-15 alkylene in which one or more -CH2- units are replaced by O, provided that two O atoms are not adjacent, or c) -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*;

[0127] wherein,

[0128] Ak 1 is selected from -(CR 3 R 4 ) k -;

[0129] Ak 2 is selected from -(CR 3 R 4 ) m -;

[0130] Ak 3 is selected from -(CR 3 R4 ) n -;

[0131] Each of k, m, and n is independently selected from 0 to 6;

[0132] Each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl, and C3 cycloalkyl; or

[0133] R 3 and R 4 together form an oxo group; and

[0134] Z 1 and Z 2 are each independently selected from a bond, -O-, a heteroarylene, and a cycloalkylene;

[0135] wherein at least one of Z 1 and Z 2 is a heteroarylene or a cycloalkylene.

[0136] In some embodiments, the linking motif, such as L in formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), or formula (I-H), is selected from C2-C 15 alkylene. In some embodiments, the linking motif is C 4-15 alkylene. In some embodiments, the linking motif is C 4-9 alkylene. In some embodiments, the linking motif is C 5-8 alkylene.

[0137] In some embodiments, the linking motif, such as L in formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), or formula (I-H), is C 2-15 alkylene, wherein one or more -CH2- units are replaced by O, provided that two O atoms are not adjacent. In some embodiments, the linking motif has the structure –(CR 3 R 4 ) x -O–(CR 3 R 4 ) y -*, wherein: each R 3 and R 4Independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl and C3 cycloalkyl; or R 3 and R 4 together form an oxo group; and x is selected from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10); y is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10); wherein the bonding point to the recruitment motif is indicated by an asterisk; and wherein the sum of x and y does not exceed 14. In some embodiments, the linker motif has the structure –(CH2) x -O–(CH2) y -*, wherein: x is selected from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10); y is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10); wherein the bonding point to the recruitment motif is indicated by an asterisk; and wherein the sum of x and y does not exceed 14. In some embodiments, x is from 0 to 7, and y is from 1 to 7. In some embodiments, x is from 0 to 6, and y is from 1 to 6. In some embodiments, the linker motif is C 2-15 alkylene in which one or more -CH2- units are replaced by O, provided that two O atoms are not adjacent, having a structure selected from:

[0138] In some embodiments, the linker motif, such as L in formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G) or formula (I-H), is C 2-15 alkylene in which one or more -CH2- units are replaced by O, provided that two O atoms are not adjacent. In some embodiments, the linker motif has the structure –(CR 3 R 4 ) j —O–(CR 3 R 4 ) p -O–(CH2) v -*, wherein: each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl and C3 cycloalkyl; or R 3 and R 4Together form an oxo group; j is selected from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); p is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); v is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); wherein the bonding point to the recruitment motif is indicated by an asterisk; and wherein the sum of j, p, and v does not exceed 13. In some embodiments, the linker motif has the structure –(CH2) j —O–(CH2) p -O–(CH2) v -*, where: j is selected from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); p is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); v is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); wherein the bonding point to the recruitment motif is indicated by an asterisk; and wherein the sum of j, p, and v does not exceed 13. In some embodiments, j is 0 to 4; p is 1 to 5; and v is 1 to 4. In some embodiments, j is 0 to 2; p is 2 to 4; and v is 1 to 3. In some embodiments, the linker motif is a C 2-15 alkylene in which one or more -CH2- units are replaced by O, provided that two O atoms are not adjacent, having a structure selected from the following:

[0139]

[0140] In some embodiments, the linker motif, such as L in formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), or formula (I-H), is represented by the following formula:

[0141] -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*

[0142] Wherein,

[0143] Ak 1 is selected from -(CR 3 R 4 ) k -;

[0144] Ak 2 is selected from -(CR 3 R 4 ) m -;

[0145] Ak 3 Selected from -(CR 3 R 4 ) n -;

[0146] Each of k, m, and n is independently selected from 0 to 6;

[0147] R 3 and R 4 are each independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl, and C3 cycloalkyl; or R 3 and R 4 together form an oxo group;

[0148] Z 1 and Z 2 are each independently selected from a bond, -O-, a heteroarylene, and a cycloalkylene, wherein at least one of Z 1 and Z 2 is a heteroarylene or a cycloalkylene; and

[0149] The bonding point to the VHL ligand is indicated by an asterisk.

[0150] In some embodiments of formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), or formula (I-H), L is -Ak selected from the molecular fragments shown below 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*:

[0151]

[0152]

[0153] X, X1, and X2 are each independently CH or N;

[0154] k is 0 to 6;

[0155] m is 0 to 6;

[0156] n is 0 to 6; and

[0157] The bonding points to the VHL ligand are indicated by asterisks. In some embodiments, k is from 0 to 3. In some embodiments, m is from 0 to 3. In some embodiments, n is from 0 to 2. In some embodiments, k is from 0 to 3, m is from 0 to 3, and n is from 0 to 2. In some embodiments, each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl, and C3 cycloalkyl. In some embodiments, each R 3 and R 4 is independently selected from hydrogen, halogen, and C 1-3 alkyl. In some embodiments, each R 3 and R 4 is independently selected from hydrogen, fluoro, and -CH3. In some embodiments, R 3 and R 4 are both hydrogen.

[0158] In some embodiments of formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), or formula (I-H), L is -Ak selected from the molecular fragments shown below 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*:

[0159]

[0160]

[0161] X, X1, and X2 are each independently CH or N;

[0162] k is from 0 to 6;

[0163] m is from 0 to 6;

[0164] n is from 0 to 6; and

[0165] wherein the bonding points to the VHL ligand are indicated by asterisks. In some embodiments, m is from 0 to 3. In some embodiments, n is from 0 to 2. In some embodiments, k is from 0 to 3, m is from 0 to 3, and n is from 0 to 2.

[0166] In some embodiments of formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), or formula (I-H), L is -Ak selected from the molecular fragments shown below 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*:

[0167]

[0168] X, X1, and X2 are each independently CH or N;

[0169] k is from 0 to 6;

[0170] m is from 0 to 6;

[0171] n is from 0 to 6; and

[0172] where the point of attachment to the VHL ligand is indicated by an asterisk. In some embodiments, m is from 0 to 3. In some embodiments, n is from 0 to 2. In some embodiments, k is from 0 to 3, m is from 0 to 3, and n is from 0 to 2.

[0173] In some embodiments of formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), or formula (I-H), L is -Ak selected from the molecular fragments shown below 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*:

[0174] and

[0175] where the point of attachment to the VHL ligand is indicated by an asterisk.

[0176] In some embodiments of formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), or formula (I-H), L is -Ak selected from the molecular fragments shown below 1 -Z1 -Ak 2 -Z 2 -Ak 3 -*:

[0177]

[0178] X1, X2, X3, and X4 are each independently CH or N;

[0179] k is from 0 to 6;

[0180] m is from 0 to 6;

[0181] n is from 0 to 6; and

[0182] where the point of attachment to the VHL ligand is indicated by an asterisk. In some embodiments, k is 0 or 1. In some embodiments, m is 0 or 1. In some embodiments, n is from 0 to 2. In some embodiments, k is 0 or 1, m is 0 or 1, and n is from 0 to 2. In some embodiments, each R 3 and R 4 are independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl, and C3 cycloalkyl. In some embodiments, each R 3 and R 4 are independently selected from hydrogen, halogen, and C 1-3 alkyl. In some embodiments, each R 3 and R 4 are independently selected from hydrogen, fluoro, and -CH3. In some embodiments, R 3 and R 4 are both hydrogen.

[0183] In some embodiments of formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), or formula (I-H), L is -Ak selected from the molecular fragments shown below 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*:

[0184]

[0185] X1, X2, X3, and X4 are each independently CH or N;

[0186] k is from 0 to 6;

[0187] m is from 0 to 6;

[0188] n is from 0 to 6; and

[0189] where the bonding point to the VHL ligand is indicated by an asterisk. In some embodiments, k is 0 or 1. In some embodiments, m is 0 or 1. In some embodiments, n is from 0 to 2. In some embodiments, k is 0 or 1, m is 0 or 1, and n is from 0 to 2.

[0190] In some embodiments of formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G) or formula (I-H), L is -Ak selected from the molecular fragments shown below 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*:

[0191]

[0192] and

[0193] where the bonding point to the VHL ligand is indicated by an asterisk.

[0194] Bcl-xL affinity motif

[0195] A-1155463 is a potent Bcl-xL binder with a K of <0.01 nM in a TR-FRET assay, as described in Tao et al., “Discovery of a Potent and Selective BCL-XL Inhibitor with In Vivo Activity” ACS Med. Chem. Lett. 2014. DOI: 10.1021 / ml5001867

[16] , which is incorporated herein by reference. i

[0196]

[0197] Heteroaromatic Bcl-xL degrading compound

[0198] In some embodiments, provided herein is a compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, having the structure of formula (I-A):

[0199]

[0200] wherein,

[0201] o is 0, 1, 2 or 3;

[0202] Y is S or CH=CH;

[0203] each R 1 is independently selected from halogen, nitro, cyano, -OR 2 , -N(R 2 )2, -SR 2 , -S(O)R 2 , -S(O)2R 2 , -S(O)2N(R 2 )2, -NR 2 S(O)2R 2 , -NR 2 S(O)2N(R 2 )2, -C(O)R 2 , -C(O)OR 2 , -OC(O)R 2 , -OC(O)OR 2 , -OC(O)N(R 2 )2, -NR 2 C(O)R 2 , -NR 2 C(O)OR 2 , -NR 2 C(O)N(R 2 )2, -C(O)N(R 2 )2, -P(O)(OR 2 )2, -P(O)(R 2 )2, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 2-6 alkyl, wherein 1 to 2 -CH2- units are replaced by N, O or S, provided that two adjacent -CH2- units are not simultaneously replaced, optionally substituted C 3-12 carbocyclic group and optionally substituted 3 - to 12 - membered heterocyclic group;

[0204] each R 2 is independently hydrogen or optionally substituted C 1-6 alkyl; or

[0205] two R 2 together with the nitrogen atom to which they are attached may form an optionally substituted 3 - to 6 - membered heterocyclic group ring;

[0206] V is a bond, -C≡C-, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted C 3-7 cycloalkyl or an optionally substituted heterocyclic group; or

[0207] together form a fused bicyclic aryl ring or a fused bicyclic heteroaryl ring, each of which is substituted with o R 1 instances;

[0208] L is selected from a) C2-C 15 alkylene, b) C 2-15 alkylene in which one or more -CH2- units are replaced by O, provided that two O atoms are not adjacent, and c) -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*;

[0209] wherein,

[0210] Ak 1 is selected from -(CR 3 R 4 ) k -;

[0211] Ak 2 is selected from -(CR 3 R 4 ) m -;

[0212] Ak 3 is selected from -(CR 3 R 4 ) n -;

[0213] each of k, m, and n is 0 to 6;

[0214] each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl, and C3 cycloalkyl; or

[0215] R 3 and R 4 together form an oxo group;

[0216] Z 1 and Z 2 are each independently selected from a bond, -O-, a heterocyclylene, and a cycloalkylene; wherein at least one of Z 1 and Z 2 is a heterocyclylene or a cycloalkylene; and

[0217] U is a VHL ligand.

[0218] In some embodiments, provided herein is a compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, having a structure of formula (I-A):

[0219]

[0220] wherein,

[0221] o is 0, 1, 2 or 3;

[0222] Y is S or CH═CH;

[0223] Each R 1 is independently selected from halogen, nitro, cyano, -OR 2 , -N(R 2 )2, -SR 2 , -S(O)R 2 , -S(O)2R 2 , -S(O)2N(R 2 )2, -NR 2 S(O)2R 2 , -NR 2 S(O)2N(R 2 )2, -C(O)R 2 , -C(O)OR 2 , -OC(O)R 2 , -OC(O)OR 2 , -OC(O)N(R 2 )2, -NR 2 C(O)R 2 , -NR 2 C(O)OR 2 , -NR 2 C(O)N(R 2 )2, -C(O)N(R 2 )2, -P(O)(OR 2 )2, -P(O)(R 2 )2, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 2-6 alkyl in which 1 to 2 -CH2- units are replaced by N, O or S, provided that two adjacent -CH2- units are not replaced simultaneously, optionally substituted C 3-12 carbocyclic group and optionally substituted 3- to 12-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group and heterocyclic group are independently optionally substituted by one or more Re Substituted;

[0224] Each R 2 is independently hydrogen or optionally substituted C 1-6 alkyl, wherein said alkyl is optionally substituted by one or more R e substituted; or

[0225] Two Rs 2 together with the nitrogen atom to which they are attached may form an optionally substituted 3- to 6-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted by one or more R e substituted;

[0226] Each R e is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl and C1-C6 heteroalkyl; or

[0227] Two Re attached to the same atom together form an oxo group;

[0228] V is a bond, -C≡C-, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted C 3-7 cycloalkyl or optionally substituted heterocyclic group, wherein said heteroaryl, aryl, cycloalkyl or heterocyclic group is optionally substituted by one or more R V substituted; or

[0229] together form a fused bicyclic aryl ring or a fused bicyclic heteroaryl ring, each of which is substituted by o Rs 1 as examples; and

[0230] Each R V is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl and C1-C6 heteroalkyl; or

[0231] Two Rs attached to the same atom of the cycloalkyl or heterocyclic groupV together form an oxo group;

[0232] L is selected from a) C2-C 15 alkylene, b) C 2-15 alkylene in which one or more -CH2- units are replaced by O, provided that two O atoms are not adjacent, and c) -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*;

[0233] wherein,

[0234] Ak 1 is selected from -(CR 3 R 4 ) k -;

[0235] Ak 2 is selected from -(CR 3 R 4 ) m -;

[0236] Ak 3 is selected from -(CR 3 R 4 ) n -;

[0237] each of k, m, and n is selected from 0 to 6;

[0238] each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl, and C3 cycloalkyl; or

[0239] R 3 and R 4 together form an oxo group;

[0240] Z 1 and Z 2 are each independently selected from a bond, -O-, a heteroarylene, and a cycloalkylene; wherein at least one of Z 1 and Z 2 is a heteroarylene or a cycloalkylene; and U is a VHL ligand.

[0241] In some embodiments, provided herein is a compound of formula (I-A) or a pharmaceutically acceptable salt or solvate thereof.

[0242] In some embodiments, Y is S. In some other embodiments, Y is CH=CH.

[0243] In some embodiments, each R 1 is independently selected from optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-3 alkoxy, halogen, -N(R 2 )2, -OR 2 and cyano, wherein the alkyl, haloalkyl and alkoxy are each independently optionally substituted. In some embodiments, each R 1 is independently selected from optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-3 alkoxy, -N(R 2 )2, -OR 2 and cyano, wherein the alkyl, haloalkyl and alkoxy are each independently optionally substituted. In some embodiments, the alkyl, haloalkyl and alkoxy are each independently optionally substituted by one or more R e . In some embodiments, each R 1 is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl. In some embodiments, each R 1 is independently selected from -F, -Cl, -CH3, -CH2CH3 and -CF3. In some embodiments, each R 1 is independently selected from -Cl, -CH3 and -CF3. In some embodiments, each R e is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl and C1-C6 heteroalkyl; or two R e connected to the same atom together form an oxo group.

[0244] In some embodiments, V is a bond. In some embodiments, provided herein is a compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, having the structure of formula (I-B):

[0245]

[0246] Wherein Y is S or CH═CH. In some embodiments, Y is S. In some embodiments, Y is CH═CH.

[0247] In some embodiments, provided herein is a compound of formula (I-B) or a pharmaceutically acceptable salt or solvate thereof.

[0248] In some embodiments, V is an optionally substituted heteroaryl. In some embodiments, V is an optionally substituted N-containing heteroaryl. In some embodiments, V is an optionally substituted N-containing 5- or 6-membered heteroaryl. In some embodiments, V is an optionally substituted N-containing 6-membered heteroaryl selected from pyridyl, pyrimidinyl, and pyridazinyl. In some embodiments, V is an optionally substituted N-containing 5-membered heteroaryl selected from pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, and oxadiazolyl. In some embodiments, V is an optionally substituted N-containing heteroaryl selected from pyrazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, and pyrimidinyl. In some embodiments, the heteroaryl is optionally substituted with one or more R V substituents, and each R V is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(═O)CH3, -S(═O)2CH3, -S(═O)2NH2, -S(═O)2NHCH3, -S(═O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(═O)CH3, -C(═O)OH, -C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl. In some embodiments, each R V is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl. In some embodiments, each R V is independently hydrogen, -Cl, -F, or -CF3. In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, V is In some embodiments, V is In some embodiments, V is In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, V is Wherein the asterisk indicates the point of attachment to L.

[0249] In some embodiments, V is an optionally substituted aryl. In some embodiments, V is an optionally substituted phenyl or naphthyl. In some embodiments, V is an optionally substituted phenyl. In some embodiments, V is an optionally substituted naphthyl. In some embodiments, V is an optionally substituted phenyl by one or more R V substituted phenyl, and each R V is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl. In some embodiments, each R V is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl. In some embodiments, each R V is independently hydrogen, -Cl, -F, or -CF3. In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, V is In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, provided herein is a compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of formula (I-C):

[0250]

[0251] wherein Y is S or CH=CH. In some embodiments, Y is S. In some embodiments, Y is CH=CH.

[0252] In some embodiments, provided herein is a compound of formula (I-C1) or a pharmaceutically acceptable salt or solvate thereof.

[0253] In some embodiments, provided herein is a compound having the structure of formula (I-C2) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof:

[0254]

[0255] Wherein Y is S or CH═CH. In some embodiments, Y is S. In some embodiments, Y is CH═CH.

[0256] In some embodiments, provided herein is a compound of formula (I-C2) or a pharmaceutically acceptable salt or solvate thereof.

[0257] In some embodiments, V is an optionally substituted cycloalkyl. In some embodiments, V is an optionally substituted C 3-7 cycloalkyl. In some embodiments, V is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted. In some embodiments, V is optionally substituted with one or more R V substituents, and each R V is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(═O)CH3, -S(═O)2CH3, -S(═O)2NH2, -S(═O)2NHCH3, -S(═O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(═O)CH3, -C(═O)OH, -C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; or two R V attached to the same atom together form an oxo group. In some embodiments, each R V is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl. In some embodiments, each R V is independently hydrogen, -Cl, -F, or -CF3.

[0258] In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, V is In some embodiments, V is In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, provided herein is a compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of formula (I-D1):

[0259]

[0260] Wherein Y is S or CH═CH. In some embodiments, Y is S. In some embodiments, Y is CH═CH.

[0261] In some embodiments, provided herein is a compound of formula (I-D1) or a pharmaceutically acceptable salt or solvate thereof.

[0262] In some embodiments, provided herein is a compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, having the structure of formula (I-D2):

[0263]

[0264] wherein Y is S or CH═CH. In some embodiments, Y is S. In some embodiments, Y is CH═CH.

[0265] In some embodiments, provided herein is a compound of formula (I-D2) or a pharmaceutically acceptable salt or solvate thereof.

[0266] In some embodiments, V is an optionally substituted heterocyclic group. In some embodiments, V is an optionally substituted N-containing heterocyclic group. In some embodiments, V is pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl, each optionally substituted. In some embodiments, V is optionally substituted with one or more R V substituents, and each R V is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(═O)CH3, -S(═O)2CH3, -S(═O)2NH2, -S(═O)2NHCH3, -S(═O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(═O)CH3, -C(═O)OH, -C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl and C1-C6 heteroalkyl; or two R V groups attached to the same atom together form an oxo group. In some embodiments, each R V is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl. In some embodiments, each R V is independently hydrogen, -Cl, -F or -CF3.

[0267] In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, V is In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, provided herein is a compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, having the structure of formula (I-E1a) or formula (I-E1b):

[0268]

[0269] Wherein Y is S or CH═CH. In some embodiments, Y is S. In some embodiments, Y is CH═CH.

[0270] In some embodiments, provided herein is a compound of formula (I-E1a) or formula (I-E1b) or a pharmaceutically acceptable salt or solvate thereof.

[0271] In some embodiments, provided herein is a compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, having the structure of formula (I-E2a) or formula (I-E2b):

[0272]

[0273] Wherein Y is S or CH═CH. In some embodiments, Y is S. In some embodiments, Y is CH═CH.

[0274] In some embodiments, provided herein is a compound of formula (I-E1a) or formula (I-E1b) or a pharmaceutically acceptable salt or solvate thereof.

[0275] In some embodiments, V is -C≡C-. In some embodiments, provided herein is a compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, having the structure of formula (I-F):

[0276]

[0277] Wherein Y is S or CH═CH. In some embodiments, Y is S. In some embodiments, Y is CH═CH.

[0278] In some embodiments, provided herein is a compound of formula (I-F) or a pharmaceutically acceptable salt or solvate thereof.

[0279] In some embodiments, together form a fused bicyclic aryl ring or a fused bicyclic heteroaryl ring, each of which is substituted with o R 1 instances. In some embodiments, together form a fused bicyclic aryl ring substituted with o R 1 instances. In some embodiments, the fused bicyclic aryl ring is a naphthyl group substituted with o R 1 instances. In some embodiments, is wherein the asterisk indicates the point of attachment to L. In some embodiments, is In some embodiments, provided herein is a compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, having the structure of formula (I-G):

[0280]

[0281] wherein Y is S or CH═CH. In some embodiments, Y is S. In some embodiments, Y is CH═CH.

[0282] In some embodiments, provided herein is a compound of formula (I-G) or a pharmaceutically acceptable salt or solvate thereof.

[0283] In some embodiments, together form a fused bicyclic heteroaryl ring substituted with o R 1 instances. In some embodiments, the fused bicyclic heteroaryl ring is a nitrogen-containing bicyclic heteroaryl ring substituted with o R 1 instances. In some embodiments, the fused bicyclic heteroaryl ring is quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl or indolyl, each substituted with o R 1 instances. In some embodiments, the fused bicyclic heteroaryl ring is quinolinyl or isoquinolinyl, each substituted with o R 1 instances. In some embodiments, is wherein the asterisk indicates the point of attachment to L.

[0284] In some embodiments, is In some embodiments, is In some embodiments, provided herein is a compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, having the structure of formula (I-H):

[0285]

[0286] wherein Y is S or CH═CH. In some embodiments, Y is S. In some embodiments, Y is CH═CH.

[0287] In some embodiments, provided herein is a compound of formula (I-H) or a pharmaceutically acceptable salt or solvate thereof.

[0288] In some embodiments of formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), formula (I-H), L is C2-C 15 alkylene. In some embodiments, L is C2-C 15 alkylene. In some embodiments, L is C 3-15 alkylene. In some embodiments, L is C 4-15 alkylene. In some embodiments, L is C 5-15 alkylene. In some embodiments, L is C 6-15 alkylene. In some embodiments, L is C 7-15 alkylene. In some embodiments, L is C 8-15 alkylene. In some embodiments, L is C 9-15 alkylene. In some embodiments, L is C 10-15 alkylene. In some embodiments, L is C 11-15 alkylene. In some embodiments, L is C 12-15 alkylene. In some embodiments, L is C 13-15 alkylene. In some embodiments, L is C 14-15 alkylene. In some embodiments, L is C 2-14 alkylene. In some embodiments, L is C 2-13 alkylene. In some embodiments, L is C 2-13 alkylene. In some embodiments, L is C 2-12 alkylene. In some embodiments, L is C 2-11 alkylene. In some embodiments, L is C 2-10 alkylene. In some embodiments, L is C 2-9 alkylene. In some embodiments, L is C 2-8 alkylene. In some embodiments, L is C 2-7 alkylene. In some embodiments, L is C 2-8 alkylene. In some embodiments, L is C 2-7 alkylene. In some embodiments, L is C 2-6 alkylene. In some embodiments, L is C 2-5 alkylene. In some embodiments, L is C 2-4 alkylene. In some embodiments, L is C 2-3 alkylene. In some embodiments, L is C 3-8 alkylene. In some embodiments, L is C4-9 Alkylene. In some embodiments, L is C 5-10 Alkylene. In some embodiments, L is C 6-11 Alkylene. In some embodiments, L is C 7-12 Alkylene. In some embodiments, L is C 8-13 Alkylene. In some embodiments, L is C 9-14 Alkylene. In some embodiments, L is C 5-8 Alkylene. In some embodiments, L is C 2-4 Alkylene. In some embodiments, L is C2 alkylene. In some embodiments, L is C3 alkylene. In some embodiments, L is C4 alkylene. In some embodiments, L is C5 alkylene. In some embodiments, L is C6 alkylene. In some embodiments, L is C7 alkylene. In some embodiments, L is C8 alkylene. In some embodiments, L is C9 alkylene. In some embodiments, L is C 10 Alkylene. In some embodiments, L is C 11 Alkylene. In some embodiments, L is C 12 Alkylene. In some embodiments, L is C 13 Alkylene. In some embodiments, L is C 14 Alkylene. In some embodiments, L is C 15 Alkylene. In some embodiments, each carbon atom of the alkylene is independently optionally substituted with R 3 and R 4 (e.g., (CR 3 R 4 ) 2-15 ), and each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl and C3 cycloalkyl, or R 3 and R 4 together form an oxo group on the same carbon atom. In some embodiments, the alkylene is unsubstituted.

[0289] In some embodiments of Formula (I-A), Formula (I-B), Formula (I-C1), Formula (I-C2), Formula (I-D1), Formula (I-D2), Formula (I-E1a), Formula (I-E1b), Formula (I-E2a), Formula (I-E2b), Formula (I-F), Formula (I-G), Formula (I-H), L is C 2-15 alkylene, wherein one or more -CH2- units are replaced by O, provided that two O atoms are not adjacent. In some embodiments, L is C 3-8An alkylene group in which one or more -CH2- units are replaced by O. In some embodiments, L is C 4-9 An alkylene group in which one or more -CH2- units are replaced by O. In some embodiments, L is C 5-8 An alkylene group in which one or more -CH2- units are replaced by O. In some embodiments, each carbon atom of the alkylene group is independently optionally substituted by R 3 and R 4 substituted (e.g., (CR 3 R 4 )) 2-15 ), and each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl and C3 cycloalkyl, or R 3 and R 4 together form an oxo group on the same carbon atom. In some embodiments, the alkylene group is unsubstituted. In some embodiments, L is C 2-15 An alkylene group in which one -CH2- unit is replaced by O. In some embodiments, L is C 2-15 An alkylene group in which one -CH2- unit is replaced by O, having the structure –(CR 3 R 4 )) x -O–(CR 3 R 4 )) y -*, where: x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; y is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; where the bonding point to the recruitment motif is indicated by an asterisk; and where the sum of x and y does not exceed 14. In some embodiments, L is C 2-15 An alkylene group in which one -CH2- unit is replaced by O, having the structure –(CH2) x -O–(CH2) y-*, where: x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; the bonding point to the recruitment motif is indicated by an asterisk; and the sum of x and y does not exceed 14. In some embodiments, x is from 0 to 9, and y is from 1 to 10. In some embodiments, x is from 0 to 8, and y is from 1 to 10. In some embodiments, x is from 0 to 7, and y is from 1 to 10. In some embodiments, x is from 0 to 6, and y is from 1 to 10. In some embodiments, x is from 0 to 10, and y is from 1 to 9. In some embodiments, x is from 0 to 10, and y is from 1 to 8. In some embodiments, x is from 0 to 10, and y is from 1 to 7. In some embodiments, x is from 0 to 10, and y is from 1 to 6. In some embodiments, x is from 0 to 7, and y is from 1 to 7. In some embodiments, x is from 0 to 6, and y is from 1 to 7. In some embodiments, x is from 0 to 7, and y is from 1 to 6. In some embodiments, x is from 0 to 6, and y is from 1 to 6. In some embodiments, L has a structure selected from the following: In some embodiments, L is C 4-15 alkylene in which two -CH2- units are replaced by O. In some embodiments, L is C 4-15 alkylene in which two -CH2- units are replaced by O, having the structure –(CR 3 R 4 ) j —O–(CR 3 R 4 ) p -O–(CR 3 R 4 ) v -*, where: j is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; v is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; the bonding point to the recruitment motif is indicated by an asterisk; and the sum of p, j, and v does not exceed 13. In some embodiments, L is C 4-15 alkylene in which two -CH2- units are replaced by O, having the structure –(CH2) j —O–(CH2) p -O–(CH2) v-*, where: j is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; v is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; where the bonding point to the recruitment motif is indicated by an asterisk; and where the sum of p, j, and v does not exceed 13. In some embodiments, j is from 0 to 10, p is from 1 to 10, and v is from 1 to 10. In some embodiments, j is from 0 to 10, p is from 1 to 5, and v is from 1 to 10. In some embodiments, j is from 0 to 10, p is from 1 to 10, and v is from 1 to 4. In some embodiments, j is from 0 to 4, p is from 1 to 10, and v is from 1 to 10. In some embodiments, j is from 0 to 4, p is from 1 to 5, and v is from 1 to 10. In some embodiments, j is from 0 to 4, p is from 1 to 10, and v is from 1 to 4. In some embodiments, j is from 0 to 10, p is from 1 to 5, and v is from 1 to 4. In some embodiments, j is from 0 to 4, p is from 1 to 5, and v is from 1 to 4. In some embodiments, j is from 0 to 4, p is from 2 to 4, and v is from 1 to 4. In some embodiments, j is from 0 to 4, p is from 1 to 5, and v is from 1 to 3. In some embodiments, j is from 0 to 4, p is from 2 to 4, and v is from 1 to 3. In some embodiments, j is from 0 to 2, p is from 1 to 5, and v is from 1 to 4. In some embodiments, j is from 0 to 2, p is from 2 to 4, and v is from 1 to 4. In some embodiments, j is from 0 to 2, p is from 1 to 5, and v is from 1 to 3. In some embodiments, j is from 0 to 2, p is from 2 to 4, and v is from 1 to 3. In some embodiments, L has a structure selected from the following:

[0290] In some embodiments of formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), formula (I-H), L has the structure

[0291] -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*;

[0292] where,

[0293] Ak 1 is selected from -(CR 3 R 4 ) k -;

[0294] Ak 2 Selected from -(CR 3 R 4 ) m -;

[0295] Ak 3 Selected from -(CR 3 R 4 ) n -;

[0296] Each of k, m, and n is from 0 to 6;

[0297] Each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl, and C3 cycloalkyl; or R 3 and R 4 together form an oxo group;

[0298] Z 1 and Z 2 are each independently selected from a bond, -O-, a heteroarylene, and a cycloalkylene; wherein at least one of Z 1 and Z 2 is a heteroarylene or a cycloalkylene; and

[0299] wherein the point of attachment to U is indicated by an asterisk.

[0300] In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* has a structure selected from:

[0301] wherein X, X1, and X2 are each independently CH or N, and wherein each k is independently 0, 1, 2, 3, 4, 5, or 6, each m is independently 0, 1, 2, 3, 4, 5, or 6, and each n is independently 0, 1, 2, 3, 4, 5, or 6. In some embodiments, R 3 and R 4 are independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl, and C3 cycloalkyl. In some embodiments, R 3 and R 4 are independently selected from hydrogen, halogen, hydroxy, C 1-3 alkyl, and C3 cycloalkyl. In some embodiments, R 3 and R 4 are independently selected from hydrogen, halogen, C 1-3 alkyl, and C3 cycloalkyl. In some embodiments, R 3and R 4 are independently selected from hydrogen, fluoro groups, and methyl groups. In some embodiments, R 3 and R 4 are both hydrogen. In some embodiments,

[0302] -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* has a structure selected from the following: wherein X, X1, and X2 are each independently CH or N, and wherein each k is independently 0, 1, 2, 3, 4, 5, or 6, each m is independently 0, 1, 2, 3, 4, 5, or 6, and each n is independently 0, 1, 2, 3, 4, 5, or 6. In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* has a structure selected from the following: wherein X, X1, and X2 are each independently CH or N, and wherein each k is independently 0, 1, 2, 3, 4, 5, or 6, each m is independently 0, 1, 2, 3, 4, 5, or 6, and each n is independently 0, 1, 2, 3, 4, 5, or 6. In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* has a structure selected from the following: wherein X, X1, and X2 are each independently CH or N, and wherein each k is independently 0, 1, 2, 3, 4, 5, or 6, each m is independently 0, 1, 2, 3, 4, 5, or 6, and each n is independently 0, 1, 2, 3, 4, 5, or 6. In some embodiments, k is 0, 1, 2, or 3. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, k is 0, 1, 2, or 3, m is 0, 1, 2, or 3, and n is 0, 1, or 2. In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* has a structure selected from the following: And the bonding points to the VHL ligand are indicated by asterisks. In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak2 -Z 2 -Ak 3 -*yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*yes In some embodiments, -Ak1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*Yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*Yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*Yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*Yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*Yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*Yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*Yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*Yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*Yes In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3-* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is

[0303] In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-* has a structure selected from the following:

[0304] X1, X2, X3, and X4 are each independently CH or N; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6; and the point of attachment to U is indicated by an asterisk. In some embodiments, k is 0, 1, 2, or 3; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3. In some embodiments, R 3 and R 4 are each independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl, and C3 cycloalkyl. In some embodiments, R 3 and R 4 are each independently selected from hydrogen, halogen, hydroxy, C 1-3 alkyl, and C3 cycloalkyl. In some embodiments, R 3 and R 4 are each independently selected from hydrogen, halogen, C 1-3 alkyl, and C3 cycloalkyl. In some embodiments, R 3 and R 4 are each independently selected from hydrogen, fluoro, and methyl. In some embodiments, R 3 and R 4 are both hydrogen. In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* has a structure selected from the following:

[0305] X1, X2, X3, and X4 are each independently CH or N; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6; and the point of attachment to U is indicated by an asterisk. In some embodiments, k is 0, 1, 2, or 3; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3. In some embodiments, k is 0 or 1. In some embodiments, m is 0 or 1. In some embodiments, n is 0, 1, or 2. In some embodiments, k is 0 or 1, m is 0 or 1, and n is from 0 to 2. In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* has a structure selected from the following: where the point of attachment to U is indicated by an asterisk. In some embodiments, -Ak 1 -Z 1-Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is and In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is

[0306] In some embodiments, the compounds described herein have the structures provided in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7. In some embodiments, the compounds described herein have the structure provided in Table 1.

[0307] Table 1

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343] In some embodiments, the compounds as described herein have the structures provided in Table 2.

[0344] Table 2

[0345]

[0346] In some embodiments, the compounds as described herein have the structures provided in Table 3.

[0347] Table 3

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362] In some embodiments, the compounds as described herein have the structures provided in Table 4.

[0363] Table 4

[0364]

[0365] In some embodiments, the compounds as described herein have the structures provided in Table 5.

[0366] Table 5

[0367]

[0368] In some embodiments, the compounds as described herein have the structures provided in Table 6.

[0369] Table 6

[0370]

[0371] In some embodiments, the compounds as described herein have the structures provided in Table 7.

[0372] Table 7

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385] Preparation of the Compounds

[0386] The compounds used in the reactions described herein are prepared from commercially available chemicals and / or starting from compounds described in the chemical literature according to organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" are obtained from standard commercial sources, including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0387] Suitable reference books and monographs that detail the synthesis of the reactants for preparing the compounds described herein, or provide citations to articles describing the preparation, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions", 2nd ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, "Heterocyclic Chemistry", 2nd ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., Wiley-Interscience, New York, 1992. Other suitable reference books and monographs that detail the synthesis of the reactants for preparing the compounds described herein, or provide citations to articles describing the preparation, include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd ed. (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th ed. (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J.(Editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T.W.G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942 - 2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0388] Specific and analogous reactants are optionally identified through the Index of Known Chemicals compiled by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries, and through online databases (for more details, contact the American Chemical Society, Washington, D.C.). Known but non-commercially available chemicals in the catalog are optionally prepared through custom chemical synthesis facilities, and many standard chemical suppliers (such as those listed above) offer custom synthesis services. A useful reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P.H. Stahl and C.G. Wermuth, "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0389] Pharmaceutical composition

[0390] In certain embodiments, the heteroaromatic Bcl-xL degrading compounds described herein are administered as pure chemicals. In other embodiments, the heteroaromatic Bcl-xL degrading compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier), which is selected based on the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed., Mack Pub. Co., Easton, PA (2005)).

[0391] Provided herein is a pharmaceutical composition comprising at least one heteroaromatic Bcl-xL degrading compound or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, and one or more pharmaceutically acceptable carriers. One or more carriers (or one or more excipients) are acceptable or suitable if they are compatible with the other components of the composition and are not harmful to the recipient of the composition (i.e., the subject or patient).

[0392] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), formula (I-H) or a pharmaceutically acceptable salt or solvate thereof.

[0393] One embodiment provides a method for preparing a pharmaceutical composition, the method comprising mixing a compound of formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), formula (I-H) or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutically acceptable carrier.

[0394] In certain embodiments, the heteroaromatic Bcl-xL degrading compound as described by formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), formula (I-H) or a pharmaceutically acceptable salt or solvate thereof is substantially pure as it contains less than about 5% or less than about 1% or less than about 0.1% of other organic small molecules such as unreacted intermediates or synthetic by-products generated, for example, in one or more steps of the synthetic method.

[0395] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules made of hard or soft gelatin, methylcellulose or other suitable materials that are readily soluble in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. (See, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed. Mack Pub. Co., Easton, PA (2005))).

[0396] In some embodiments, a heteroaromatic Bcl-xL degrading compound described by Formula (I-A), Formula (I-B), Formula (I-C1), Formula (I-C2), Formula (I-D1), Formula (I-D2), Formula (I-E1a), Formula (I-E1b), Formula (I-E2a), Formula (I-E2b), Formula (I-F), Formula (I-G), Formula (I-H), or a pharmaceutically acceptable salt or solvate thereof is formulated for administration by injection. In some cases, the injection formulation is an aqueous formulation. In some cases, the injection formulation is a non-aqueous formulation. In some cases, the injection formulation is an oil-based formulation, such as sesame oil and the like.

[0397] The dosage of a composition comprising at least one heteroaromatic Bcl-xL degrading compound as described herein varies according to the condition of the subject or patient (e.g., human). In some embodiments, such factors include overall health status, age, and other factors.

[0398] The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dosage, as well as the suitable duration and frequency of administration, will be determined by factors such as the condition of the patient, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, the appropriate dosage and treatment regimen provide an amount of the composition sufficient to provide a therapeutic and / or prophylactic benefit (e.g., improvement in clinical outcome, such as more frequent complete or partial remission, or longer disease-free survival and / or overall survival, or reduction in symptom severity). The optimal dosage is typically determined using experimental models and / or clinical trials. The optimal dosage depends on the body mass, weight, or blood volume of the patient.

[0399] Method of treatment

[0400] One embodiment provides a compound of Formula (I-A), Formula (I-B), Formula (I-C1), Formula (I-C2), Formula (I-D1), Formula (I-D2), Formula (I-E1a), Formula (I-E1b), Formula (I-E2a), Formula (I-E2b), Formula (I-F), Formula (I-G), Formula (I-H), or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a human or animal body.

[0401] One embodiment provides a compound of Formula (I-A), Formula (I-B), Formula (I-C1), Formula (I-C2), Formula (I-D1), Formula (I-D2), Formula (I-E1a), Formula (I-E1b), Formula (I-E2a), Formula (I-E2b), Formula (I-F), Formula (I-G), Formula (I-H), or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating cancer or a neoplastic disease.

[0402] One embodiment provides for the use of a compound of formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), formula (I-H) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

[0403] In some embodiments, a method of treating cancer in a patient in need thereof is described herein, the method comprising administering to the patient a compound of formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), formula (I-H) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating cancer in a patient in need thereof is described herein, the method comprising administering to the patient a pharmaceutical composition comprising a compound of formula (I-A), formula (I-B), formula (I-C1), formula (I-C2), formula (I-D1), formula (I-D2), formula (I-E1a), formula (I-E1b), formula (I-E2a), formula (I-E2b), formula (I-F), formula (I-G), formula (I-H) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

[0404] Methods are provided herein in which the pharmaceutical composition is administered orally. Methods are provided herein in which the pharmaceutical composition is administered by injection.

[0405] According to the present disclosure, other embodiments and uses will be apparent to those skilled in the art. The following examples are provided only as illustrations of the various embodiments and should not be construed as limiting the invention in any way.

[0406] Examples

[0407] I. Chemical Synthesis

[0408] In some embodiments, the compounds disclosed herein are synthesized according to the following examples. Unless otherwise indicated, as used hereinafter and throughout the specification of the present invention, the following abbreviations should be understood to have the following meanings:

[0409] °C degrees Celsius

[0410] δ H Chemical shift expressed in parts per million downfield relative to tetramethylsilane

[0411] DCM dichloromethane (CH2Cl2)

[0412] DMF Dimethylformamide

[0413] DMSO Dimethyl sulfoxide

[0414] EA Ethyl acetate

[0415] ESI Electrospray ionization

[0416] Et Ethyl

[0417] g Gram

[0418] h Hour

[0419] HPLC High performance liquid chromatography

[0420] Hz Hertz

[0421] J Coupling constant (in NMR spectroscopy)

[0422] LCMS Liquid chromatography - mass spectrometry

[0423] μ Micro

[0424] m Multiplet (spectrum); meter; milli

[0425] M Molarity

[0426] M + Parent molecular ion

[0427] Me Methyl

[0428] MHz Megahertz

[0429] min Minute

[0430] mol Mole; molecule (as in mol wt)

[0431] mL Milliliter

[0432] MS Mass spectrometry

[0433] nm Nanometer

[0434] NMR Nuclear magnetic resonance

[0435] pH Degree of acidity or alkalinity; measure of the acidity or alkalinity of an aqueous solution

[0436] PE Petroleum ether

[0437] RT Room temperature

[0438] s Singlet (spectrum)

[0439] t Triplet (spectrum)

[0440] T Temperature

[0441] TFA Trifluoroacetic acid

[0442] THF Tetrahydrofuran

[0443] DIEA Diisopropylethylamine

[0444] HATU O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate

[0445] Example 1: Compound 1

[0446]

[0447] Step A: Methyl 9-oxononanoate

[0448] To a solution of 9-hydroxynonanoic acid (2.00 g, 11.478 mmol) in MeOH (20 mL) was added AcCl (1 mL, 14.013 mmol), and the mixture was stirred at 25 °C for 1 hour. The resulting mixture was combined, and then DCM (40 mL), molecular sieve (4A) (3 g), and PCC (3.5 g, 16.237 mmol) were added, and the resulting mixture was stirred at 25 °C for 1 hour. The reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The organic layers were combined and washed with brine (4 × 100 mL). The obtained residue was purified by silica gel chromatography (0 - 20% ethyl acetate / petroleum ether) to give methyl 9-oxononanoate.

[0449] Step B: Methyl dec-9-ynoate

[0450] To a solution of methyl 9-oxononanoate (1.1 g, 5.91 mmol) in MeOH (20 mL) were added K2CO3 (1.63 g, 11.82 mmol) and dimethyl 1-diazo-2-oxopropylphosphonate (1.70 g, 8.859 mmol). The resulting mixture was stirred at 25 °C overnight. The reaction was concentrated and then quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined and concentrated. The obtained residue was purified by silica gel chromatography (0 - 20% ethyl acetate / petroleum ether) to give methyl dec-9-ynoate.

[0451] Step C: 9-Decynoic acid

[0452] To a solution of methyl dec-9-ynoate (800 mg, 4.39 mmol) in MeOH (5 mL) and H2O (5 mL) was added KOH (1231.31 mg, 21.94 mmol). The resulting mixture was stirred at 45 °C for 1.5 h. After cooling to room temperature, the pH of the resulting mixture was adjusted to 5 using 2 M HCl solution. Then it was extracted with EA (3 × 15 mL) and washed with brine (4 × 15 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford 9-decynoic acid.

[0453] Step D: 10-{4-[3-(2-{8-[(1,3-Benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-4-(ethoxycarbonyl)-1,3-thiazol-5-yl)propoxy]phenyl}dec-9-ynoic acid

[0454] To a solution of ethyl 2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-[3-(4-iodophenoxy)propyl]-1,3-thiazole-4-carboxylate (170.00 mg, 0.235 mmol) in DMF (3 mL) was added 9-decynoic acid (118.41 mg, 0.705 mmol), DIEA (151.60 mg, 1.175 mmol), Pd(PPh3)2Cl2 (82.33 mg, 0.12 mmol) and CuI (13.40 mg, 0.070 mmol). The resulting mixture was stirred at 25 °C under nitrogen for 1 h. The reaction was purified by reverse-phase column to afford 10-{4-[3-(2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-4-(ethoxycarbonyl)-1,3-thiazol-5-yl)propoxy]phenyl}dec-9-ynoic acid. LC / MS: MS(ESI) M / Z 765.5 [M+H] + 。

[0455] Step E: Ethyl 2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-{3-[4-(9-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}non-1-yn-1-yl)phenoxy]propyl}-1,3-thiazole-4-carboxylate

[0456] To a solution of 10-{4-[3-(2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-4-(ethoxycarbonyl)-1,3-thiazol-5-yl)propoxy]phenyl}dec-9-ynoic acid (170.00 mg, 0.222 mmol) in DMF (5 mL) was added DIEA (143.61 mg, 1.110 mmol), HATU (101.40 mg, 0.266 mmol), and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (114.82 mg, 0.266 mmol). The resulting mixture was stirred at 25 °C for 1 h. The reaction was quenched with H2O (10 mL), followed by extraction with EA (3 × 10 mL) and washing with brine (4 × 10 mL). The organic layers were combined and concentrated. The residue obtained was purified by TLC (1 / 14 MeOH / DCM) to afford ethyl 2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-{3-[4-(9-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}non-1-yn-1-yl)phenoxy]propyl}-1,3-thiazole-4-carboxylate. LC / MS: MS (ESI) m / z 1177.4 [M+H] + .

[0457] Step F: 2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-{3-[4-(9-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}non-1-yn-1-yl)phenoxy]propyl}-1,3-thiazole-4-carboxylic acid

[0458] To a solution of ethyl 2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-{3-[4-(9-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}non-1-yn-1-yl)phenoxy]propyl}-1,3-thiazole-4-carboxylate (160.00 mg, 0.136 mmol) in MeOH (4 mL) was added 2 M NaOH (5 mL). The mixture was stirred at 50 °C for 3 h. After cooling to room temperature, the reaction was quenched with H2O (5 mL). The pH of the aqueous phase was adjusted to 5 with HCl solution (2 M) and filtered. Then it was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: aqueous solution of 10 mmol / L NH4HCO3 + 0.1% NH3.H2O, mobile phase B: CH3CN (37% to 50% in 13 min, 50% to 100% in 0.1 min, 100% to 100% in 2 min, 100% to 37% in 0.1 min, 37% to 37% in 1 min); detector, UV 254 nm, to give 2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-{3-[4-(9-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}non-1-yn-1-yl)phenoxy]propyl}-1,3-thiazole-4-carboxylic acid. 1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.58(t,J=6.4Hz,1H),7.81 - 8.08(m,2H),7.65 - 7.80(m,2H),7.12 - 7.50(m,11H),6.65 - 6.95(m,2H),4.80 - 4.92(m,1H),4.51 - 4.60(m,1H),4.40 - 4.50(m,2H),4.30 - 4.39(m,1H),4.19 - 4.29(m,1H),3.90 - 4.00(m,1H),3.61 - 3.88(m,5H),3.11 - 3.21(m,2H),3.00 - 3.10(m,3H),2.44(s,3H),2.21 - 2.40(m,4H),1.89 - 2.18(m,5H),1.45 - 1.52(m,3H),1.21 - 1.40(m,7H),0.93(s,9H). LC / MS:MS(ESI)M / Z1149.4[M + H] + 。

[0459] Example 2: Compound 2

[0460]

[0461] Step A: 3-(Prop-2-yn-1-yloxy)propan-1-ol

[0462] At 0 °C, NaH (1.14 g, 60% w / w) was added to a solution of 1,3-propanediol (3 g, 39.42 mmol) in DMF (90 mL). The mixture was stirred at room temperature for 0.5 h. Subsequently, propargyl bromide (3.75 g, 31.54 mmol) was added. The mixture was stirred at room temperature for 3 h. After completion, the reaction was quenched with water (100 mL). The mixture was extracted with EA (3 × 200 mL), and the organic layer was dried over Na2SO4 and filtered. The organic layer was concentrated. The crude product was purified by silica gel column (0 - 50% PE:EtOAc). The organic layer was concentrated under reduced pressure to afford 3-(prop-2-yn-1-yloxy)propan-1-ol. LCMS: MS(ESI) M / Z: 115 [M + H] + 。

[0463] Step B: tert-Butyl 2-(3-(prop-2-yn-1-yloxy)propoxy)acetate

[0464] To a solution of 3-(prop-2-yn-1-yloxy)propan-1-ol (2.09 g, 18.31 mmol) in DCM (30 mL) was added tert-butyl 2-bromoacetate (5.36 g, 27.46 mmol), 35% NaOH (aqueous solution, 30 mL) and Bu4NCl (5.07 g, 18.310 mmol). The mixture was stirred overnight at room temperature. After completion, the reaction was quenched with water (50 mL). The mixture was extracted with DCM (3 × 100 mL), and the organic layer was dried over Na2SO4 and filtered. The organic layer was concentrated. The crude product was purified by silica gel column (0 - 50% PE:EtOAc). The organic layer was concentrated under reduced pressure to afford tert-butyl 2-[3-(prop-2-yn-1-yloxy)propoxy]acetate. LC / MS: MS(ESI) M / Z 229 [M+H] + .

[0465] Step C: 2-(3-(prop-2-yn-1-yloxy)propoxy)acetic acid

[0466] To a solution of tert-butyl 2-[3-(prop-2-yn-1-yloxy)propoxy]acetate (2 g, 8.761 mmol) in THF (10 mL), MeOH (10 mL) and H2O (10 mL) was added LiOH (2.10 g, 87.610 mmol). The mixture was stirred at 30 °C for 3 h. After completion, the reaction was quenched with water (30 mL). The pH of the solution was adjusted to 4 - 5 with HCl. The mixture was extracted with EA (3 × 50 mL), and the organic layer was dried over Na2SO4 and filtered. The organic layer was concentrated under reduced pressure to afford [3-(prop-2-yn-1-yloxy)propoxy]acetic acid. LC / MS: MS(ESI) M / Z 173 [M+H] + .

[0467] Step D: 2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-[3-(4-{3-[3-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)propoxy]prop-1-yn-1-yl}phenoxy)propyl]-1,3-thiazole-4-carboxylic acid

[0468] Compound 2 was prepared according to a procedure similar to that described in Example 1. 11H NMR (300 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.64 (t, J = 6.1 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.69 - 7.76 (m, 2H), 7.26 - 7.40 (m, 12H), 6.89 (d, J = 8.3 Hz, 2H), 4.85 (s, 2H), 4.56 (d, J = 9.6 Hz, 1H), 4.44 - 4.19 (m, 5H), 4.03 - 3.86 (m, 4H), 3.50 - 3.71 (m, 5H), 3.22 - 3.11 (m, 2H), 3.02 (t, J = 6.0 Hz, 2H), 2.32 - 2.60 (m, 5H), 1.70 - 2.16 (m, 6H), 0.94 (s, 9H). LC / MS: MS (ESI) M / Z 1153.4 [M + H] + 。

[0469] Example 3: Compound 3

[0470]

[0471] Step A: Ethyl (E)-4-(2-(benzyloxy)ethoxy)but-2-enoate

[0472] To a solution of DMSO (1.6 g) in DCM (20 mL) was added (COCl)2 (1.95 g), and the mixture was stirred at -78 °C under a nitrogen atmosphere. After 30 min, a solution of 2-(2-(benzyloxy)ethoxy)ethan-1-ol (2 g, 1.00 equiv) in DCM was added. After 1 h, TEA (5.0 g, 5 equiv) was added. The resulting mixture was stirred at 25 °C for 1 h. Then, methyl 2-(triphenyl-λ5-phosphanylidene)acetate (4.20 g, 1.2 equiv) was added. The resulting mixture was stirred at 25 °C for 2 h. The reaction was concentrated. The obtained residue was purified by silica gel chromatography (0 - 50% ethyl acetate / petroleum ether) to afford ethyl (E)-4-(2-(benzyloxy)ethoxy)but-2-enoate. LC / MS: MS (ESI) M / Z 265.1 [M + H] + 。

[0473] Step B: Ethyl 4-(2-hydroxyethoxy)butanoate

[0474] To a solution of ethyl (E)-4-(2-(benzyloxy)ethoxy)but-2-enoate (1.9 g) in MeOH (20 mL) was added Pd / C (1.9 g, 10% w / w). The mixture was stirred for 16 h at 50 °C under a hydrogen atmosphere. The reaction was filtered and concentrated. The obtained residue was purified by silica gel chromatography (0 - 30% ethyl acetate / petroleum ether) to afford ethyl 4-(2-hydroxyethoxy)butanoate. LC / MS: MS(ESI) M / Z 177.1 [M+H] + 。

[0475] Step C: Ethyl 4-(2-oxoethoxy)butanoate

[0476] To a solution of DMSO (0.89 g) in DCM (15 mL) was added (COCl)2 (1.08 g, 8.512 mmol), and the mixture was stirred at -78 °C under a nitrogen atmosphere. After 30 min, a solution of ethyl 4-(2-hydroxyethoxy)butanoate (1 g) in DCM was added, and after 1 h, TEA (2.88 g) was added. The resulting mixture was stirred at 25 °C for 1 h. The reaction was concentrated. The obtained residue was purified by silica gel chromatography (0 - 50% ethyl acetate / petroleum ether) to afford ethyl 4-(2-oxoethoxy)butanoate. LC / MS: MS(ESI) M / Z 175.1 [M+H] + 。

[0477] Step D: Ethyl 4-(prop-2-yn-1-yloxy)butanoate

[0478] To a solution of ethyl 4-(2-oxoethoxy)butanoate (600 mg) in MeOH (10 mL) were added K2CO3 (950 mg), dimethyl 1-diazo-2-oxopropylphosphonate (990 mg). The resulting mixture was stirred overnight at 25 °C. The reaction was concentrated and then quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined and concentrated. The obtained residue was purified by silica gel chromatography (0 - 30% ethyl acetate / petroleum ether) to afford ethyl 4-(prop-2-yn-1-yloxy)butanoate. LC / MS: MS(ESI) M / Z 171.1 [M+H] + 。

[0479] Step E: 4-(Prop-2-yn-1-yloxy)butanoic acid

[0480] To a solution of methyl 4-(but-3-yn-1-yloxy)butanoate (220 mg) in THF (3 mL) and MeOH (3 mL) was added LiOH·H2O (271.20 mg) and H2O (3 mL). The resulting mixture was stirred at 25 °C for 16 h. The pH of the resulting mixture was adjusted to 6 using 2N HCl solution. The resulting mixture was extracted with EA (3 × 10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford 4-(prop-2-yn-1-yloxy)butanoic acid. LC / MS: MS(ESI) M / Z 141.1 [M-H] - 。

[0481] Step F: 2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-(3-{4-[3-(3-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}propoxy)prop-1-yn-1-yl]phenoxy}propyl)-1,3-thiazole-4-carboxylic acid

[0482] The compound was prepared according to a procedure similar to that described in Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.72 - 7.51 (m, 2H), 7.28 - 7.49 (m, 10H), 6.93 - 6.84 (m, 2H), 4.85 (s, 2H), 4.54 (d, J = 9.3 Hz, 1H), 4.49 - 4.39 (m, 2H), 4.33 (d, J = 16.4 Hz, 3H), 4.22 - 4.30 (m, 1H), 3.99 (t, J = 6.2 Hz, 2H), 3.75 - 3.61 (m, 4H), 3.31 - 3.54 (m, 3H), 3.17 (t, J = 7.6 Hz, 2H), 3.02 (t, J = 6.0 Hz, 2H), 2.44 (s, 3H), 2.34 - 2.15 (m, 2H), 2.09 - 1.96 (m, 3H), 1.90 - 1.95 (m, 1H), 1.75 - 1.85 (m, 2H), 0.93 (s, 9H). LC / MS: MS(ESI) M / Z 1123.4 [M+H] + 。

[0483] Example 4: Compound 4

[0484]

[0485] Step A: tert-Butyl 2-(4-(benzyloxy)butoxy)acetate

[0486] At room temperature, 35% NaOH (aqueous solution, 10 mL) and tetrabutylammonium chloride (3.08 g, 11.096 mmol) were added portionwise to a stirred mixture of 4-(benzyloxy)butan-1-ol (2 g, 11.10 mmol) and tert-butyl 2-bromoacetate (3.25 g, 16.64 mmol) in DCM (10 mL). The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to afford tert-butyl 2-[4-(benzyloxy)butoxy]acetate. LC / MS: MS(ESI) M / Z 295.2 [M+H] + 。

[0487] Step B: tert-Butyl 2-(4-hydroxybutoxy)acetate

[0488] At 50 °C, under a hydrogen atmosphere, Pd / C (1 g, 9.40 mmol, 10% w / w) was added portionwise to a stirred solution of tert-butyl 2-[4-(benzyloxy)butoxy]acetate (1.74 g, 5.91 mmol) in MeOH (20 mL). The resulting mixture was stirred overnight at 50 °C under a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (3 × 20 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 2-(4-hydroxybutoxy)acetate. The crude product was used directly in the next step without further purification. LC / MS: MS(ESI) M / Z 227.0 [M+Na] + 。

[0489] Step C: tert-Butyl 2-(4-(prop-2-yn-1-yloxy)butoxy)acetate

[0490] At room temperature, 35% aqueous NaOH solution (10 mL) and tetrabutylammonium chloride (1.38 g, 4.966 mmol) were added portionwise to a stirred mixture of tert-butyl 2-(4-hydroxybutoxy)acetate (1.0178 g, 4.983 mmol) and propargyl bromide (0.89 g, 7.481 mmol) in DCM (10.18 mL). The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to afford tert-butyl 2-[4-(prop-2-yn-1-yloxy)butoxy]acetate. LC / MS: MS(ESI) M / Z 242.2 [M+H] + 。

[0491] Step D: 2-(4-(prop-2-yn-1-yloxy)butoxy)acetic acid

[0492] At room temperature, LiOH.H2O (1229.76 mg, 29.310 mmol) was added to a solution of tert-butyl 2-[(6-hydroxyhex-3-yn-1-yl)oxy]acetate (669 mg, 2.931 mmol) in MeOH (3 mL), THF (3 mL) and H2O (3 mL). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 5 with 2M HCl. The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford [(6-hydroxyhex-3-yn-1-yl)oxy]acetic acid. The crude product was used directly in the next step without further purification. LC / MS: MS(ESI) M / Z 185.0 [M+H] + 。

[0493] Step E: 2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-[3-(4-{3-[4-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)butoxy]prop-1-yn-1-yl}phenoxy)propyl]-1,3-thiazole-4-carboxylic acid

[0494] The compound was prepared according to a procedure similar to that described in Example 1. 11H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.63 (t, J = 6.1 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.69 - 7.76 (m, 2H), 7.27 - 7.48 (m, 11H), 6.89 (d, J = 8.4 Hz, 2H), 4.86 (s, 2H), 4.56 (d, J = 9.6 Hz, 1H), 4.22 - 4.49 (m, 6H), 3.90 - 4.04 (m, 4H), 3.57 - 3.75 (m, 4H), 3.50 (d, J = 5.5 Hz, 5H), 3.16 (t, J = 7.5 Hz, 2H), 3.00 - 3.05 (m, 2H), 2.44 (s, 3H), 1.86 - 2.11 (m, 4H), 1.59 - 1.65 (m, 4H), 0.94 (s, 9H). LC / MS: MS (ESI) M / Z 1167.4 [M + H] + 。

[0495] Example 5: Compound 5

[0496]

[0497] Step A: tert-Butyl 2-(hept-6-yn-1-yloxy)acetate

[0498] To a solution of hept-6-yn-1-ol (2.0 g, 17.83 mmol) in DCM (20 mL) was added tert-butyl 2-bromoacetate (5.22 g, 26.74 mmol), 35% NaOH (aqueous solution, 20 mL), and tetrabutylammonium chloride (4.96 g, 17.830 mmol). The mixture was stirred overnight at 25 °C. The reaction was quenched with H2O (50 mL). The resulting mixture was extracted with DCM (3 × 50 mL). The organic layers were combined and concentrated. The obtained residue was purified by silica gel column chromatography (0 - 30% ethyl acetate / petroleum ether) to afford tert-butyl 2-(hept-6-yn-1-yloxy)acetate.

[0499] Step B: (Hept-6-yn-1-yloxy)acetic acid

[0500] To a solution of tert-butyl 2-(hept-6-yn-1-yloxy)acetate (1.4 g, 6.186 mmol) in THF (8 mL) was added LiOH·H₂O (2.60 g, 61.958 mmol), H₂O (8 mL), and MeOH (8 mL). The resulting mixture was stirred at 30 °C for 1 h. The reaction was concentrated to remove MeOH, and then the pH of the resulting mixture was adjusted to 7 with 2N HCl solution. Then it was extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to afford (hept-6-yn-1-yloxy)acetic acid.

[0501] Step C: 2-{8-[(1,3-Benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-(3-{4-[7-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)hept-1-yn-1-yl]phenoxy}propyl)-1,3-thiazole-4-carboxylic acid

[0502] This compound was prepared according to a procedure similar to that described in Example 1. 1 H NMR (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.62 (t, J = 6.0 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.66 - 7.78 (m, 2H), 7.20 - 7.50 (m, 12H), 6.80 - 6.90 (m, 2H), 4.84 - 4.88 (m, 2H), 4.56 (d, J = 9.6 Hz, 1H), 4.41 - 4.49 (m, 1H), 4.34 - 4.38 (m, 2H), 4.21 - 4.30 (m, 1H), 3.85 - 3.99 (m, 4H), 3.60 - 3.75 (m, 4H), 3.48 - 3.55 (m, 3H), 3.14 - 3.18 (m, 2H), 3.00 - 3.04 (m, 2H), 2.44 (s, 3H), 2.35 - 2.40 (m, 2H), 1.89 - 2.10 (m, 4H), 1.51 - 1.61 (m, 3H), 1.46 - 1.50 (m, 3H), 1.24 (s, 1H), 0.93 (s, 9H). LC / MS: MS (ESI) M / Z 1151.5 [M + H] +

[0503] Example 6: Compound 6

[0504]

[0505] Step A: Ethyl (E)-4-(2-(benzyloxy)ethoxy)but-2-enoate

[0506] Under a N2 atmosphere, (COCl)2 (1.94 g, 15.29 mmol) was added to a solution of DMSO (1.59 g) in DCM (20 mL). The mixture was stirred for 30 min at -78 °C. 2-[2-(Benzyloxy)ethoxy]ethanol (2 g, 10.19 mmol) was added to the mixture. The mixture was stirred for 1 h at -78 °C. TEA (5.16 g, 50.96 mmol) was added to the mixture and the mixture was stirred for 1 h at room temperature. tert-Butyl 2-(triphenyl-λ5-phosphanylidene)acetate (4.60 g, 12.229 mmol) was added to the mixture and the mixture was stirred for 2 h at room temperature. After completion, the reaction was quenched with water (50 mL). The mixture was extracted with EA (3 × 50 mL) and the organic layer was dried over Na2SO4 and filtered. The organic layer was concentrated. The crude product was purified by silica gel column (0 - 50% PE:EtOAc). The organic layer was concentrated under reduced pressure to afford tert-butyl (2E)-4-[2-(benzyloxy)ethoxy]but-2-enoate. LC / MS: MS(ESI) M / Z 265 [M+H] + 。

[0507] Step B: Ethyl 4-(2-hydroxyethoxy)butanoate

[0508] At 50 °C, under a H2(g) (10 atm) atmosphere, a solution of ethyl (2E)-4-[2-(benzyloxy)ethoxy]but-2-enoate (2.7 g, 10.22 mmol) and Pd / C (1.5 g, 10% w / w) in MeOH (30 mL) was stirred overnight. The mixture was filtered through a Celite pad. The organic layer was concentrated. The organic layer was concentrated under reduced pressure to afford ethyl 4-(2-hydroxyethoxy)butanoate as a white oil. LC / MS: MS(ESI) M / Z 177 [M+H] + 。

[0509] Step C: Ethyl 4-(2-(prop-2-yn-1-yloxy)ethoxy)butanoate

[0510] To a solution of ethyl 4-(2-hydroxyethoxy)butyrate (1.5 g, 8.51 mmol) in DCM (22.5 mL) was added propargyl bromide (1.52 g, 12.77 mmol), 35% NaOH (aqueous solution, 22.5 mL), and Bu4NCl (2.36 g, 8.51 mmol). The mixture was stirred overnight at room temperature. After completion, the reaction was quenched with water (50 mL). The mixture was extracted with DCM (3 × 100 mL), and the organic layer was dried over Na2SO4 and filtered. The organic layer was concentrated. The crude product was purified by silica gel column (0 - 50% PE:EtOAc). The organic layer was concentrated under reduced pressure to afford ethyl 4-[2-(prop-2-yn-1-yloxy)ethoxy]butyrate. LC / MS: MS(ESI) M / Z 215 [M+H] + 。

[0511] Step D: 4-(2-(prop-2-yn-1-yloxy)ethoxy)butyric acid

[0512] To a solution of ethyl 4-[2-(prop-2-yn-1-yloxy)ethoxy]butyrate (1.18 g, 5.51 mmol) in MeOH (6 mL) and H2O (6 mL) was added KOH (3.09 g, 55.07 mmol). The mixture was stirred for 3 h at room temperature. After completion, the reaction was quenched with water (20 mL). The pH of the solution was adjusted to 4 - 5 with HCl. The mixture was extracted with EA (3 × 30 mL), and the organic layer was dried over Na2SO4 and filtered. The organic layer was concentrated under reduced pressure to afford 4-[2-(prop-2-yn-1-yloxy)ethoxy]butyric acid. LC / MS: MS(ESI) M / Z 187 [M+H] + 。

[0513] Step E: 2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-[3-(4-{3-[2-(3-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}propoxy)ethoxy]prop-1-yn-1-yl}phenoxy)propyl]-1,3-thiazole-4-carboxylic acid

[0514] The compound was prepared according to a procedure similar to that described in Example 1. 11H NMR (300 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.58 (t, J = 6.1 Hz, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 7.3 Hz, 1H), 7.52 - 7.29 (m, 10H), 6.90 (d, J = 8.3 Hz, 2H), 4.84 (s, 2H), 4.55 (d, J = 9.3 Hz, 1H), 4.31 - 4.60 (m, 5H), 4.22 (dd, J = 15.8, 5.4 Hz, 1H), 3.99 (s, 2H), 3.69 - 3.79 (m, 2H), 3.64 - 3.69 (m, 2H), 3.61 (d, J = 4.8 Hz, 2H), 3.52 (dd, J = 5.8, 3.3 Hz, 2H), 3.32 - 3.43 (m, 3H), 3.17 (s, 2H), 3.04 (s, 2H), 2.45 (s, 3H), 2.13 - 2.40 (m, 2H), 1.83 - 2.11 (m, 4H), 1.72 (s, 2H), 0.94 (s, 9H). LC / MS: MS (ESI) M / Z 1167.4 [M + H] + 。

[0515] Example 7: Compound 7

[0516]

[0517] Step A: Ethyl 6-(prop-2-yn-1-yloxy)hexanoate

[0518] At 0 °C, NaH (0.3 g, 60% purity) was added to a solution of ethyl 6-hydroxyhexanoate (1.0 g, 6.84 mmol) in DMF (5 mL). After 1 hour, 3-bromoprop-1-yne (0.82 g, 6.893 mmol) was added. The resulting mixture was stirred at 25 °C for 2 h. The reaction was quenched with H2O (10 mL) and extracted with EA (3 × 20 mL), washed with brine (3 × 20 mL), the organic layers were combined and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EA / PE to afford ethyl 6-(prop-2-yn-1-yloxy)hexanoate.

[0519] Step B: 6-(Prop-2-yn-1-yloxy)hexanoic acid

[0520] To a solution of ethyl 6-(prop-2-yn-1-yloxy)hexanoate (660 mg, 3.58 mmol) in MeOH (4 mL) and H2O (4 mL) was added KOH (660 mg, 11.76 mmol). The resulting mixture was stirred at 45 °C for 1 h. 2 M HCl was added to the reaction to reach pH ~6 and extracted with EA (3 × 20 mL), washed with brine (3 × 20 mL), the organic layers were combined and concentrated in vacuo to afford 6-(prop-2-yn-1-yloxy)hexanoic acid. LCMS: MS(ESI) M / Z: 155.1 [M-H] - .

[0521] Step C: 2-{8-[(1,3-Benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-[3-(4-{3-[(5-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}pentyl)oxy]prop-1-yn-1-yl}phenoxy)propyl]-1,3-thiazole-4-carboxylic acid.

[0522] The compound was prepared according to a procedure similar to that described in Example 1. 1 HNMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.57 (t, J = 6.0 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.81 - 7.91 (m, 1H), 7.72 - 7.80 (m, 1H), 7.62 - 7.71 (m, 1H), 7.22 - 7.58 (m, 11H), 6.82 - 6.98 (m, 2H), 4.85 (s, 2H), 4.49 - 4.60 (m, 1H), 4.39 - 4.48 (m, 2H), 4.18 - 4.38 (m, 4H), 3.92 - 4.01 (m, 2H), 3.61 - 3.71 (m, 4H), 3.40 - 3.51 (m, 3H), 3.12 - 3.21 (m, 2H), 3.00 - 3.10 (m, 2H), 2.50 (s, 3H), 2.20 - 2.31 (m, 1H), 2.09 - 2.19 (m, 1H), 1.95 - 2.08 (m, 3H), 1.88 - 1.94 (m, 1H), 1.45 - 1.61 (m, 4H), 1.18 - 1.38 (m, 2H), 0.93 (s, 9H). LC / MS: MS(ESI) M / Z 1151.4 [M+H] + .

[0523] Example 8: Compound 8

[0524]

[0525] Step A: Methyl 5-(but-3-yn-1-yloxy)pentanoate

[0526] To a solution of but-3-yn-1-ol (2.0 g, 28.57 mmol) in DCM (20 mL) was added methyl 5-bromopentanoate (8.31 g, 42.86 mmol), 35% NaOH (aqueous solution, 40 mL) and tetrabutylammonium chloride (7.91 g, 28.57 mmol). The mixture was stirred overnight at 25 °C. The reaction was quenched with H2O (50 mL). The resulting mixture was extracted with DCM (3 × 50 mL). The organic layers were combined and concentrated. The obtained residue was purified by silica gel column chromatography (0 - 30% ethyl acetate / petroleum ether) to afford methyl 5-(but-3-yn-1-yloxy)pentanoate.

[0527] Step B: 5-(but-3-yn-1-yloxy)pentanoic acid

[0528] To a solution of methyl 5-(but-3-yn-1-yloxy)pentanoate (1.5 g, 8.16 mmol) in THF (8 mL) was added LiOH.H2O (3.26 g, 81.57 mmol), H2O (8 mL), MeOH (8 mL). The resulting mixture was stirred at 30 °C for 1 h. The reaction was concentrated to remove MeOH, and then the pH of the resulting mixture was adjusted to 7 using 2N HCl solution. Then it was extracted with EtOAc (3 × 50 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-(but-3-yn-1-yloxy)pentanoic acid.

[0529] Step C: 2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-(3-{4-[4-(4-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}butoxy)but-1-yn-1-yl]phenoxy}propyl)-1,3-thiazole-4-carboxylic acid

[0530] This compound was prepared according to a procedure similar to that described in Example 1. 11H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.59 (t, J = 6.0 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.91 - 7.84 (m, 1H), 7.70 - 7.80 (m, 1H), 7.60 - 7.69 (m, 1H), 7.20 - 7.45 (m, 11H), 6.86 (d, J = 8.4 Hz, 2H), 4.88 - 4.84 (m, 2H), 4.58 - 4.52 (m, 1H), 4.49 - 4.39 (m, 2H), 4.38 - 4.33 (m, 1H), 4.27 - 4.17 (m, 1H), 4.01 - 3.93 (m, 2H), 3.65 - 3.72 (m, 4H), 3.50 - 3.52 (m, 2H), 3.40 - 3.42 (m, 2H), 3.20 - 3.12 (m, 2H), 3.04 - 3.00 (m, 2H), 2.65 - 2.57 (m, 2H), 2.43 (s, 3H), 2.21 - 2.30 (m, 1H), 2.18 - 2.10 (m, 1H), 2.07 (s, 1H), 1.82 - 2.05 (m, 4H), 1.20 - 1.75 (m, 5H), 0.91 (s, 9H). LC / MS: MS (ESI) M / Z 1151.4 [M + H] + 。

[0531] Example 9: Compound 9

[0532]

[0533] Step A: tert-Butyl 2-(hex-5-yn-1-yloxy)acetate

[0534] To a solution of hex-5-yn-1-ol (1.0 g, 10.19 mmol) in DCM (10 mL) was added NaOH (10 M) (aqueous solution, 10 mL), tert-butyl 2-bromoacetate (2.38 g, 12.23 mmol) and TBAC (2.8 g, 10.20 mmol). The resulting mixture was stirred at 25 °C for 16 h. The reaction was extracted with DCM (3 × 30 mL), washed with brine (3 × 40 mL), the organic layers were combined and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EA / PE to afford tert-butyl 2-(hex-5-yn-1-yloxy)acetate.

[0535] Step B: 2-(hex-5-yn-1-yloxy)acetic acid

[0536] To a solution of tert-butyl 2-(hex-5-yn-1-yloxy)acetate (1.8 g, 8.48 mmol) in THF (5 mL), MeOH (5 mL) and H2O (5 mL) was added LiOH.H2O (3.56 g, 84.79 mmol). The resulting mixture was stirred at 25 °C for 1 h. The pH was adjusted to 6 using 2 M HCl, extracted with EA (3 × 40 mL), washed with brine (3 × 50 mL), the organic layers were combined and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EA / PE to afford (hex-5-yn-1-yloxy)acetic acid. LC / MS: MS(ESI) M / Z 155.1 [M-H] - 。

[0537] Step C: 2-{8-[(1,3-Benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-(3-{4-[6-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)hex-1-yn-1-yl]phenoxy}propyl)-1,3-thiazole-4-carboxylic acid.

[0538] The compound was prepared according to a procedure similar to that described in Example 1. 1 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.62 (t, J = 6.0 Hz, 1H), 7.91 - 8.05 (m, 1H), 7.61 - 7.81 (m, 2H), 7.20 - 7.52 (m, 12H), 6.75 - 6.95 (m, 2H), 4.85 (s, 2H), 4.51 - 4.67 (m, 1H), 4.31 - 4.50 (m, 3H), 4.21 - 4.30 (m, 1H), 3.89 - 4.00 (m, 4H), 3.60 - 3.75 (m, 4H), 3.50 - 3.55 (m, 2H), 3.10 - 3.20 (m, 2H), 3.00 - 3.09 (m, 2H), 2.41 - 2.45 (m, 6H), 1.89 - 2.11 (m, 4H), 1.58 - 1.71 (m, 4H), 0.94 (s, 9H). LC / MS: MS(ESI) M / Z 1137.4 [M+H] + 。

[0539] Example 10: Compound 10

[0540]

[0541] Step A: Methyl 10-oxodecanoate

[0542] To a solution of 10-hydroxydecanoic acid (2 g, 10.62 mmol) in MeOH (20 mL) was added AcCl (1.3 mL, 18.22 mmol), and the mixture was stirred at 25 °C for 1 h. The resulting mixture was combined, and then DCM (40 mL), molecular sieves (4A) (3 g), and PCC (3.5 g, 16.24 mmol) were added, and the resulting mixture was stirred at 25 °C for 1 h. The reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The organic layers were combined and washed with brine (4 × 100 mL). The obtained residue was purified by silica gel chromatography (0 - 20% ethyl acetate / petroleum ether) to afford methyl 10-oxodecanoate.

[0543] Step B: Methyl undec-10-ynoate

[0544] To a solution of methyl 10-oxodecanoate (1.37 g, 6.84 mmol) in MeOH (15 mL) were added K2CO3 (1.89 g, 13.68 mmol) and dimethyl 1-diazo-2-oxopropylphosphonate (1.97 g, 10.26 mmol). The resulting mixture was stirred at 25 °C overnight. The reaction was concentrated and then quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined and concentrated. The obtained residue was purified by silica gel chromatography (0 - 20% ethyl acetate / petroleum ether) to afford methyl undec-10-ynoate.

[0545] Step C: 10-Undecynoic acid

[0546] To a solution of methyl undec-10-ynoate (1.0 g, 5.10 mmol) in MeOH (5 mL) and H2O (5 mL) was added KOH (1.43 g, 25.48 mmol). The resulting mixture was stirred at 45 °C for 1.5 h. After cooling to room temperature, the pH of the resulting mixture was adjusted to 5 using 2 M HCl solution. Then it was extracted with EA (3 × 15 mL) and washed with brine (4 × 15 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to afford 10-undecynoic acid.

[0547] Step D: 2-{8-[(1,3-Benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-{3-[4-(10-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}dec-1-yn-1-yl)phenoxy]propyl}-1,3-thiazole-4-carboxylic acid.

[0548] The compound was prepared according to a procedure similar to that described in Example 1. 1 HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.59(t,J=8.0Hz,1H),7.81 - 8.01(m,2H),7.62 - 7.70(m,2H),7.00 - 7.60(m,10H),6.65 - 6.92(m,2H),4.82 - 4.91(m,1H),4.51 - 4.61(m,1H),4.40 - 4.50(m,2H),4.30 - 4.39(m,1H),4.19 - 4.29(m,1H),3.90 - 4.09(m,2H),3.60 - 3.89(m,5H),3.11 - 3.21(m,2H),3.00 - 3.10(m,2H),2.44 - 2.50(m,4H),2.20 - 2.40(m,3H),1.79 - 2.15(m,5H),1.42 - 1.61(m,4H),1.32 - 1.41(m,2H),1.20 - 1.30(m,6H),0.93(s,9H). LC / MS: MS(ESI) M / Z 1163.6[M + H] + 。

[0549] Example 11: Compound 11

[0550]

[0551] Step A: tert-Butyl 2-(2-(benzyloxy)ethoxy)acetate

[0552] At room temperature, tetrabutylammonium chloride (3.65 g, 13.14 mmol) was added portionwise to a stirred mixture of tert-butyl 2-bromoacetate (3.84 g, 19.71 mmol) and ethylene glycol monobenzyl ether (2.00 g, 13.14 mmol) in DCM (20.00 mL) and 35% NaOH (aqueous solution, 20 mL). The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to afford tert-butyl 2-[2-(benzyloxy)ethoxy]acetate. LC / MS: MS(ESI) M / Z 289.0 [M+Na] + 。

[0553] Step B: tert-butyl 2-(2-hydroxyethoxy)acetate

[0554] At room temperature, under a hydrogen atmosphere, Pd / C (1 g, 10% w / w) was added portionwise to a stirred solution of tert-butyl 2-[2-(benzyloxy)ethoxy]acetate (2.67 g) in MeOH (20 mL), and the mixture was stirred overnight. The resulting mixture was filtered and the cake was washed with MeOH (4 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to afford tert-butyl 2-(2-hydroxyethoxy)acetate. LC / MS: MS(ESI) M / Z177.2 [M+H] + 。

[0555] Step C: tert-butyl 2-(2-iodoethoxy)acetate

[0556] At room temperature, imidazole (0.53 g, 7.726 mmol) and I2 (1.80 g, 7.092 mmol) were added portionwise to a stirred mixture of tert-butyl 2-(2-hydroxyethoxy)acetate (1.1345 g, 6.44 mmol) and PPh3 (1.86 g, 7.082 mmol) in DCM (10 mL). The resulting mixture was stirred for 2 h at room temperature. At room temperature, the reaction was quenched with saturated sodium dithionite (aqueous solution). The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to afford tert-butyl 2-(2-iodoethoxy)acetate. LC / MS: MS(ESI) M / Z 309.0 [M+Na] + 。

[0557] Step D: tert-Butyl 2-(2-(but-3-yn-1-yloxy)ethoxy)acetate

[0558] At room temperature, tetrabutylammonium chloride (1.11 g, 3.99 mmol) was added portionwise to a stirred mixture of tert-butyl 2-(2-iodoethoxy)acetate (1.38 g, 4.81 mmol) and 3-butyn-1-ol (0.281 g, 4.01 mmol) in 35% NaOH (aqueous solution, 10 mL) and DCM (10 mL), and the mixture was stirred overnight at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to afford tert-butyl 2-[(6-hydroxyhex-3-yn-1-yl)oxy]acetate. LC / MS: MS(ESI) M / Z 246.2 [M+H2O] + 。

[0559] Step E: 2-(2-(but-3-yn-1-yloxy)ethoxy)acetic acid

[0560] At room temperature, LiOH.H2O (809 mg, 19.73 mmol) was added to a solution of tert-butyl 2-(2-(but-3-yn-1-yloxy)ethoxy)acetate (450 mg, 1.97 mmol) in MeOH (3 mL), THF (3 mL) and H2O (3 mL). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 5 with 2M HCl. The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(2-(but-3-yn-1-yloxy)ethoxy)acetic acid. The crude product was used directly in the next step without further purification. LC / MS: MS(ESI) M / Z 171.2 [M-H] - 。

[0561] Step F: 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(4-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)but-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylic acid

[0562] The compound was prepared according to a procedure similar to that described in Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.61 (s, 1H), 7.99 (s, 1H), 7.63 - 7.81 (m, 2H), 7.13 - 7.52 (m, 12H), 6.84 (s, 2H), 4.86 (s, 2H), 4.58 (d, J = 9.6 Hz, 1H), 4.30 - 4.54 (m, 3H), 4.17 - 4.31 (s, 1H), 3.90 - 4.10 (m, 3H), 3.52 - 3.79 (m, 8H), 3.16 (s, 2H), 3.03 (s, 2H), 2.62 - 2.71 (m, 2H), 2.37 - 2.46 (m, 5H), 1.78 - 2.16 (m, 6H), 0.95 (s, 9H). LC / MS: MS (ESI) M / Z 1153.4 [M + H] + 。

[0563] Example 12: Compound 12

[0564]

[0565]

[0566] Step A: Methyl 8-hydroxyoctanoate

[0567] AcCl (449.09 mg, 1.54 mmol) was added to a solution of 8-hydroxyoctanoic acid (1.0 g, 6.24 mmol) in MeOH (20 mL). The resulting mixture was stirred at room temperature for 1 h. Subsequently, the resulting mixture was concentrated to afford methyl 8-hydroxyoctanoate.

[0568] Step B: Methyl 8-oxooctanoate

[0569] PCC (1.75 g, 8.13 mmol) and 4A MS (1.5 g) were added to a solution of methyl 8-hydroxyoctanoate (600 mg, 3.44 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 1 h. Subsequently, the reaction was filtered and extracted with DCM (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel chromatography (0 - 20% ethyl acetate / petroleum ether) to afford methyl 8-oxooctanoate.

[0570] Step C: Methyl non-8-ynoate

[0571] To a solution of methyl 8-oxooctanoate (770 mg, 4.47 mmol) in MeOH (15 mL) was added K2CO3 (1.1 g, 7.96 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (1.0 g, 5.19 mmol). The resulting mixture was stirred at room temperature for 16 h. Subsequently, the reaction was filtered and concentrated. The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% ethyl acetate / petroleum ether) to afford methyl non-8-ynoate.

[0572] Step D: Non-8-ynoic acid

[0573] To a solution of methyl non-8-ynoate (469 mg, 2.79 mmol) in MeOH (5 mL) and H2O (5 mL) was added KOH (469 mg, 8.36 mmol). The resulting mixture was stirred at 45 °C for 1 h. After cooling to room temperature, the reaction was quenched with water (10 mL). 2N HCl was added to the resulting mixture to reach pH ca. 6 and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to afford 8-nonynoic acid.

[0574] LC / MS: MS(ESI) M / Z 153.2 [M-H] - 。

[0575] Step E: 9-(4-(3-(2-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(ethoxycarbonyl)thiazol-5-yl)propoxy)phenyl)non-8-ynoic acid

[0576] To a solution of ethyl 2-[8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-(4-iodophenoxy)propyl]-1,3-thiazole-4-carboxylate (50 mg, 0.069 mmol) in DMF (2 mL) was added 8-nonynoic acid (30 mg, 0.20 mmol), DIPEA (0.05 mL, 0.39 mmol), CuI (4 mg, 0.02 mmol), Pd(PPh3)2Cl2 (15 mg, 0.021 mmol). The resulting mixture was maintained under nitrogen and stirred at room temperature for 16 h. Subsequently, the reaction was quenched with water (10 mL). The resulting mixture was purified by reverse phase column (0 - 90%) to afford 9-[4-[3-(2-[8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-4-(ethoxycarbonyl)-1,3-thiazol-5-yl)propoxy]phenyl]non-8-ynoic acid. LC / MS: MS (ESI) M / Z 751.3 [M+H] + .

[0577] Step F: Ethyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(9-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxonon-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylate

[0578] To a solution of 9-[4-[3-(2-[8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-4-(ethoxycarbonyl)-1,3-thiazol-5-yl)propoxy]phenyl]non-8-ynoic acid (100 mg, 0.13 mmol) in DMF (5 mL) was added (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (65 mg, 0.15 mmol), HATU (62 mg, 0.16 mmol), and DIEA (0.07 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (3 × 50 mL) and concentrated. The residue obtained was purified by silica gel chromatography (0 - 10% MeOH / DCM) to afford the crude ethyl 2-[8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-(8-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]oct-1-yn-1-yl)phenoxy]propyl]-1,3-thiazole-4-carboxylate. LC / MS: MS(ESI) M / Z 1163.4 [M+H] + 。

[0579] Step G: 2-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(9-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxonon-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylic acid

[0580] To a solution of ethyl 2-[8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-(8-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]oct-1-yn-1-yl)phenoxy]propyl]-1,3-thiazole-4-carboxylate (100 mg, 0.086 mmol) in MeOH (4 mL) was added 2 M NaOH (aqueous solution, 2 mL). The resulting mixture was stirred at 50 °C for 3 h. Then the reaction was cooled to room temperature and the pH of the resulting mixture was adjusted to 5 with 2 N HCl. The mixture was filtered and dried in vacuo. The residue obtained was purified by preparative HPLC under the following conditions (1#waters2767-5): column, Xselect CSH OBD column 30*150 mm 5 um, n; mobile phase, phase A: aqueous solution of 10 mmol / L NH4HCO3 + 0.1% NH3.H2O, phase B: CH3CN (40% CH3CN increased to 70% in 10 min, then 70% to 100% in 1 min, held at 100% for 1 min, decreased to 40% in 1 min, held at 40% for 1 min); detector, UV220 and 254 nm, to afford 2-[8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-(8-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]oct-1-yn-1-yl)phenoxy]propyl]-1,3-thiazole-4-carboxylic acid. 1HNMR (300 MHz, DMSO-d6) δ: 9.00 (s, 1H), 8.50 - 8.65 (m, 1H), 7.88 - 8.00 (brs, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.60 - 7.75 (m, 2H), 7.10 - 7.50 (m, 11H), 6.65 - 6.92 (m, 2H), 4.87 (brs, 2H), 4.52 - 4.64 (m, 1H), 4.30 - 4.50 (m, 3H), 4.15 - 4.28 (m, 1H), 3.60 - 4.02 (m, 8H), 2.98 - 3.24 (m, 5H), 2.45 (s, 3H), 2.20 - 2.40 (m, 2H), 1.85 - 2.17 (m, 4H), 1.20 - 1.70 (m, 8H), 0.95 (s, 9H). LC / MS: MS(ESI) M / Z 1135.6 [M + H] + 。

[0581] Example 13: Compound 13

[0582]

[0583]

[0584] Step A: 3-Azaspiro[5.5]undecan-9-one

[0585] To a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1.0 g, 3.74 mmol) in DCM (10 mL) was added HCl / dioxane (4 M, 2 mL). The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to give a crude product. The crude product was used in the next step without further purification.

[0586] Step B: Benzyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate

[0587] To a solution of 3-azaspiro[5.5]undecan-9-one (630 mg, 3.09 mmol, HCl salt) and CbzCl (791.38 mg, 4.64 mmol) in DCM (10 mL) was added TEA (938.84 mg, 9.28 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was treated with water (100 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 200 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography, eluting with PE:EA = 10:1 to 2:1 to give benzyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate. LC / MS: MS(ESI) M / Z 302.3 [M+H] + 。

[0588] Step C: Benzyl 9-(2-(tert-butoxy)-2-oxoethylidene)-3-azaspiro[5.5]undecane-3-carboxylate

[0589] At 0 °C, to a solution of tert-butyl 2-diethoxyphosphorylacetate (987.62 mg, 3.92 mmol) in THF (10 mL) was added NaH (156.61 mg, 3.92 mmol, 60% purity). After 0.5 h, benzyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (590 mg, 1.96 mmol) was added to the mixture and stirred at 25 °C for 18 h. The reaction mixture was quenched with water (100 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography, eluting with PE:EA = 50:1 to 15:1 to give benzyl 9-(2-tert-butoxy-2-oxoethylidene)-3-azaspiro[5.5]undecane-3-carboxylate. LC / MS: MS(ESI) M / Z 422.3 [M+Na] + 。

[0590] Step D: tert-Butyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate

[0591] To a solution of benzyl 9-(2-tert-butoxy-2-oxo-ethylidene)-3-azaspiro[5.5]undecane-3-carboxylate (530 mg, 1.33 mmol) in MeOH (20 mL) was added Pd / C (128.89 mg, 10% w / w). The resulting mixture was degassed under vacuum and purged with H2 three times. At 25 °C, under H2, the mixture was stirred for 6 h. The reaction mixture was filtered through a Celite pad and the cake was washed with MeOH (3 × 20 mL). The combined filtrates were concentrated to dryness in vacuo to afford tert-butyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate. The crude product was used in the next step without further purification. LC / MS: MS (ESI) M / Z 268.4 [M+H] + .

[0592] Step E: tert-Butyl 2-(3-(prop-2-yn-1-yl)-3-azaspiro[5.5]undecan-9-yl)acetate

[0593] At 0 °C, to a suspension of tert-butyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate (480 mg, 1.80 mmol) in MeOH (10 mL) was added K2CO3 (297.70 mg, 2.15 mmol). After 0.1 h, 3-bromoprop-1-yne (256.24 mg, 2.15 mmol, 185.68 μL) was added and the mixture was stirred at 0 °C for 1 h. The reaction mixture was warmed to room temperature and treated with water and extracted with DCM. The organic phase was washed with brine and concentrated to give the crude. The residue was purified by column chromatography (PE:EA = 15:1 to 2:1) to afford tert-butyl 2-(3-prop-2-ynyl-3-azaspiro[5.5]undecan-9-yl)acetate. 1 1H-NMR (400 MHz, CDCl3) δ 3.28 (t, J = 2.3 Hz, 2H), 2.51 - 2.46 (m, 4H), 2.24 - 2.21 (m, 2H), 2.09 (d, J = 7.1 Hz, 2H), 1.70 - 1.62 (m, 2H), 1.57 - 1.49 (m, 4H), 1.44 - 1.39 (m, 11H), 1.16 - 1.09 (m, 4H).

[0594] Step F: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(9-(2-(tert-butoxy)-2-oxoethyl)-3-azaspiro[5.5]undecan-3-yl)prop-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylate

[0595] To a solution of tert-butyl 2-(3-prop-2-ynyl-3-azaspiro[5.5]undecan-9-yl)acetate (128.96 mg, 422.18 μmol) and methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-(4-iodophenoxy)propyl]thiazole-4-carboxylate (150 mg, 211.09 μmol) in DMF (10 mL) was added CuI (20.10 mg, 105.54 μmol), Pd(PPh3)4 (121.96 mg, 105.54 μmol) and DIEA (109.13 mg, 844.35 μmol). The tube was degassed and backfilled with N2 five times. At 60 °C, under N2, the resulting mixture was stirred for 4 h. The reaction mixture was cooled to room temperature, quenched with water (100 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na2SO4 and concentrated in vacuo. The residue obtained was purified by silica gel column chromatography, eluting with DCM:MeOH = 50:1 to 5:1 to afford methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[9-(2-tert-butoxy-2-oxo-ethyl)-3-azaspiro[5.5]undecan-3-yl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate. LC / MS: MS(ESI) M / Z 445.4 [M+2H] + / 2。

[0596] Step G: 2-(3-(3-(4-(3-(2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)prop-2-yn-1-yl)-3-azaspiro[5.5]undecan-9-yl)acetic acid

[0597] At 40 °C, a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[9-(2-tert-butoxy-2-oxo-ethyl)-3-azaspiro[5.5]undecan-3-yl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate (135 mg, 152.00 μmol) in FA (5 mL) was stirred for 4 h. The reaction mixture was concentrated in vacuo to afford 2-(3-(3-(4-(3-(2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)prop-2-yn-1-yl)-3-azaspiro[5.5]undecan-9-yl)acetic acid. LC / MS: MS(ESI) M / Z 417.1 [M+2H] + / 2。

[0598] Step H: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(9-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-3-azaspiro[5.5]undecan-3-yl)prop-1-yn-1-yl)phenoxy)propyl]thiazole-4-carboxylate

[0599] To a mixture of 2-[3-[3-[4-[3-[2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]prop-2-ynyl]-3-azaspiro[5.5]undecan-9-yl]acetic acid (140 mg, 168.26 μmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (144.89 mg, 336.52 μmol) in DMF (5 mL) was added HATU (319.89 mg, 841.31 μmol) and DIEA (217.46 mg, 1.68 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with water and extracted with EA (3 × 25 mL). The combined organic layers were washed with saturated NH4Cl solution, brine, dried over Na2SO4 and concentrated to dryness. The residue obtained was purified by preparative TLC (MeOH / DCM = 1:10) to afford methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[9-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylaminocarbonyl]pyrrolidin-1-yl]-2,2-dimethyl-propyl]amino]-2-oxo-ethyl]-3-azaspiro[5.5]undecan-3-yl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate as an off-white solid. LC / MS: MS(ESI) M / Z 622.9 [M+2H] + / 2。

[0600] Step I: 2-(8-(Benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(9-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)aminocarbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-3-azaspiro[5.5]undecan-3-yl)prop-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylic acid

[0601] To a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[9-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethyl]-3-azaspiro[5.5]undecan-3-yl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate (75 mg, 60.26 μmol) in MeOH (5 mL) and THF (5 mL) was added LiOH (7.20 mg, 301.30 μmol). The resulting mixture was stirred at 25 °C for 2 h. The resulting mixture was stirred at 25 °C for 2 h. The pH of the reaction mixture was adjusted to pH = 3 with 0.1 M HCl solution and extracted with DCM (3 × 25 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue obtained was purified by preparative HPLC (10 mmol / L NH4HCO3 - ACN, 66% - 86%; YMC-Actus Triart C18, 150*20 mm, 5 um; flow rate: 20 mL / min). The eluate was concentrated in vacuo and lyophilized to afford 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[9-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethyl]-3-azaspiro[5.5]undecan-3-yl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid. LC / MS: MS (ESI) M / Z 616.4 [M+2H] + / 2。 1H-NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.61 (s, 2H), 7.32 - 7.26 (m, 11H), 7.17 (d, J = 0.8 Hz, 1H), 6.74 (d, J = 8.5 Hz, 2H), 6.44 (d, J = 7.1 Hz, 1H), 4.88 (t, J = 17.5 Hz, 2H), 4.67 (t, J = 7.8 Hz, 1H), 4.59 - 4.51 (m, 3H), 4.27 (d, J = 15.4 Hz, 1H), 4.11 (d, J = 12.6 Hz, 1H), 3.91 (t, J = 6.0 Hz, 2H), 3.77 (d, J = 6.0 Hz, 2H), 3.59 (d, J = 7.7 Hz, 2H), 3.27 (s, 2H), 3.01 (t, J = 5.8 Hz, 2H), 2.72 (s, 3H), 2.48 (s, 4H), 2.06 (d, J = 6.3 Hz, 4H), 1.54 (m, 9H), 1.26 (s, 2H), 1.05 - 0.93 (m, 14H).

[0602] Example 14: Compound 14

[0603]

[0604] Step A: Methyl 1-(4-(2-(tert-butoxy)-2-oxoethyl)cyclohexyl)azetidine-3-carboxylate

[0605] At 0 °C, NaBH(OAc)3 (22.47 g, 105.99 mmol) and AcOH (2.12 g, 35.33 mmol) were slowly added to a solution of tert-butyl 2-(4-oxocyclohexyl)acetate (8.25 g, 38.86 mmol) and methyl azetidine-3-carboxylate (4.07 g, 35.33 mmol) in DCE (200 mL). The resulting mixture was stirred at 25 °C for 6 h. The reaction mixture was quenched by adding H2O (120 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (60 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 10 - 50% EtOAc) to afford methyl 1-[4-(2-tert-butoxy-2-oxo-ethyl)cyclohexyl]azetidine-3-carboxylate. LC / MS: MS (ESI) M / Z 312.3 [M + H] + .

[0606] Step B: tert-Butyl 2-(4-(3-formylazetidin-1-yl)cyclohexyl)acetate

[0607] At -78 °C, under a N2 atmosphere, a toluene solution of DIBAL-H (18.5 mL, 18.5 mmol) was added dropwise to a solution of methyl 1-[4-(2-tert-butoxy-2-oxo-ethyl)cyclohexyl]azetidine-3-carboxylate (2.30 g, 7.39 mmol) in anhydrous DCM (100 mL). The resulting mixture was stirred at -78 °C for 30 min. The reaction mixture was quenched by adding sodium sulfate decahydrate (about 6 g) and stirred at -78 °C for 30 min. The reaction mixture was filtered through a Celite pad and the cake was washed with DCM (3 × 80 mL). The combined filtrates were concentrated to afford tert-butyl 2-(4-(3-formylazetidin-1-yl)cyclohexyl)acetate, which was used in the next step without further purification. LC / MS: MS(ESI) M / Z 282.4 [M+H] + 。

[0608] Step C: tert-butyl 2-(4-(3-ethynylazetidin-1-yl)cyclohexyl)acetate

[0609] To a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (1.30 g, 6.83 mmol) in MeOH (60 mL) was added K2CO3 (943 mg, 6.83 mmol). The mixture was stirred at 25 °C for 0.5 h. tert-Butyl 2-[4-(3-formylazetidin-1-yl)cyclohexyl]acetate (1.61 g, 5.69 mmol) was added. The resulting mixture was stirred at 25 °C for 11.5 h. The reaction mixture was quenched by adding H2O (100 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 0 - 20% EtOAc) to afford tert-butyl 2-(4-(3-ethynylazetidin-1-yl)cyclohexyl)acetate. LC / MS: MS(ESI) M / Z 278.3 [M+H] + 。

[0610] Step D: 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[2-[1-[4-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethyl]cyclohexyl]azetidin-3-yl]ethynyl]phenoxy]propyl]thiazole-4-carboxylic acid

[0611] The compound was prepared according to a procedure similar to that described in Example 13. 1 H NMR(400MHz,CD3OD)δ8.86(s,1H),7.89(d,J=7.2Hz,1H),7.75(d,J=8.4Hz,1H),7.61(d,J=7.2Hz,1H),7.44-7.28(m,10H),6.82(d,J=7.6Hz,2H),4.99-4.90(m,4H),4.63-4.30(m,7H),4.19-4.15(m,2H),3.98-3.95(m,2H),3.89-3.76(m,5H),3.35-3.31(m,2H),3.25-3.21(m,2H),3.06-3.03(m,2H),2.44(s,3H),2.28-2.03(m,6H),1.78–1.27(m,6H),1.01(s,9H). LC / MS:MS(ESI)M / Z1202.6[M+H] + 。

[0612] Example 15: Compound 15

[0613]

[0614] Step A: tert-Butyl 1-(1-((benzyloxy)carbonyl)azetidin-3-yl)piperidine-4-carboxylate

[0615] To a suspension of benzyl 3-oxoazetidine-1-carboxylate (5.02 g, 24.39 mmol) and tert-butyl piperidine-4-carboxylate (5.40 g, 24.37 mmol) in THF (100 mL) was added AcOH (731.6 mg, 12.18 mmol). The resulting mixture was stirred at room temperature for 5 min. Then NaBH(OAc)3 (15.49 g, 73.10 mmol) was added. The resulting mixture was stirred at 25 °C for 4 h. H2O (80 mL) was added to the mixture, and the mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 10 - 50% EtOAc) to give tert-butyl 1-(1-(benzyloxycarbonyl)azetidin-3-yl)piperidine-4-carboxylate. LCMS: MS(ESI) M / Z: 375.3 [M+H] + 。

[0616] Step B: tert-Butyl 1-(azetidin-3-yl)piperidine-4-carboxylate

[0617] To a solution of tert-butyl 1-(1-(benzyloxycarbonyl)azetidin-3-yl)piperidine-4-carboxylate (4.80 g, 12.82 mmol) in MeOH (100 mL) was added Pd / C (1.21 g, 50% purity) and AcOH (2.31 g, 38.45 mmol). The resulting mixture was degassed under vacuum and purged with H2 three times. At room temperature, under H2, the mixture was stirred for 1 h. The reaction mixture was filtered through a Celite pad and the cake was washed with MeOH (3 × 30 mL). The combined filtrates were concentrated to afford tert-butyl 1-(azetidin-3-yl)piperidine-4-carboxylate. LC / MS: MS(ESI) M / Z 241.3 [M+H] + 。

[0618] Step C: tert-butyl 1-(1-(prop-2-yn-1-yl)azetidin-3-yl)piperidine-4-carboxylate

[0619] At 0 °C, a solution of 3-bromoprop-1-yne (990 mg, 8.32 mmol) in CH3CN (5 mL) was added dropwise to a suspension of tert-butyl 1-(azetidin-3-yl)piperidine-4-carboxylate (2.5 g, 8.32 mmol, AcOH salt) and K2CO3 (3.45 g, 24.97 mmol) in CH3CN (100 mL). The resulting mixture was stirred at 25 °C for 2 h. The solid was removed by filtration and washed with EtOAc (2 × 10 mL). The filtrate was concentrated to dryness. The residue was purified by column chromatography (silica gel, eluent: DCM / 0 - 5% MeOH) to afford tert-butyl 1-(1-prop-2-ynylazetidin-3-yl)piperidine-4-carboxylate. 1 1H-NMR (400 MHz, CDCl3) δ 3.44 - 3.48 (m, 2H), 3.26 (d, J = 2.4 Hz, 2H), 3.02 - 3.06 (m, 2H), 2.89 - 2.95 (m, 1H), 2.67 - 2.70 (m, 2H), 2.22 (t, J = 2.4 Hz, 1H), 2.07 - 2.19 (m, 2H), 1.81 - 1.86 (m, 4H), 1.63 - 1.73 (m, 2H), 1.41 (s, 9H). LC / MS: MS(ESI) M / Z 279.3 [M+H] + 。

[0620] Step D: 2-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[3-[4-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]carbamoyl]-1-piperidinyl]azetidin-1-yl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid.

[0621] The compound was prepared according to a procedure similar to that described in Example 13. 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.57 (t, J = 6.0 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.32 - 7.49 (m, 11H), 6.89 (d, J = 8.8 Hz, 2H), 4.83 (s, 1H), 4.52 (d, J = 9.2 Hz, 1H), 4.40 - 4.45 (m, 2H), 4.34 (m, 1H), 4.18 - 4.24 (m, 1H), 3.98 (t, J = 6.4 Hz, 2H), 3.71 (t, J = 6.0 Hz, 2H), 3.60 - 3.68 (m, 2H), 3.33 (t, J = 6.4 Hz, 5H), 3.16 (t, J = 7.6 Hz, 2H), 2.98 - 3.03 (m, 4H), 2.79 - 2.86 (m, 1H), 2.69 - 2.73 (m, 2H), 2.44 (s, 3H), 2.31 - 2.39 (m, 1H), 1.96 - 2.01 (m, 3H), 1.86 - 1.92 (m, 1H), 1.65 - 1.75 (m, 3H), 1.45 - 1.54 (m, 3H), 0.92 (s, 9H). LC / MS: 1023.70 [M+H] + .

[0622] Example 16: Compound 16

[0623]

[0624] Step A: tert-Butyl 7-(methoxymethylene)-2-azaspiro[3.5]nonane-2-carboxylate

[0625] At 0 °C, t-BuOK (2.11 g, 18.80 mmol) was added to a solution of methoxymethyl(triphenyl)phosphonium (4.30 g, 12.54 mmol) in THF (60 mL). After 0.5 h, tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (1.5 g, 6.27 mmol) was added to the mixture and stirred at 70 °C for 4 h. The reaction mixture was treated with water (100 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 200 mL), dried over Na2SO4 and concentrated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography, eluting with PE:EA = 20:1 to 8:1, to give tert-butyl 7-(methoxymethylene)-2-azaspiro[3.5]nonane-2-carboxylate. 1 1H-NMR (400 MHz, CDCl3) δ 5.76 (s, 1H), 3.59 (s, 4H), 3.51 (s, 3H), 2.14 (s, 2H), 1.92 - 1.89 (m, 2H), 1.64 - 1.61 (m, 4H), 1.43 (s, 9H).

[0626] Step B: tert-butyl 7-formyl-2-azaspiro[3.5]nonane-2-carboxylate

[0627] TFA:H2O = 1:10 (5 mL) was added to a solution of tert-butyl 7-(methoxymethylene)-2-azaspiro[3.5]nonane-2-carboxylate (1.47 g, 5.50 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 4 h. The reaction mixture was treated with water (100 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (3 × 200 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound as a crude product, which was used in the next step without further purification. 1 1H-NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 3.57 (d, J = 2.5 Hz, 4H), 2.23 - 2.18 (m, 1H), 1.89 - 1.84 (m, 4H), 1.55 - 1.48 (m, 4H), 1.43 (s, 9H).

[0628] Step C: tert-butyl 7-ethynyl-2-azaspiro[3.5]nonane-2-carboxylate

[0629] To a solution of tert-butyl 7-formyl-2-azaspiro[3.5]nonane-2-carboxylate (1.2 g, 4.74 mmol) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (1.36 g, 7.11 mmol) in MeOH (20 mL) was added K2CO3 (981.97 mg, 7.11 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (80 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography, eluting with PE:EA = 50:1 to 10:1, to afford tert-butyl 7-ethynyl-2-azaspiro[3.5]nonane-2-carboxylate. 1 1H-NMR (400 MHz, CDCl3) δ 3.56 (d, J = 16.2 Hz, 4H), 2.36 (s, 1H), 2.03 (d, J = 2.5 Hz, 1H), 1.89 - 1.83 (m, 2H), 1.74 (s, 2H), 1.53 - 1.46 (m, 4H), 1.42 (s, 9H).

[0630] Step D: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((2-(tert-butoxycarbonyl)-2-azaspiro[3.5]nonan-7-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate

[0631] At room temperature, CuI (40.20 mg, 211.09 μmol), Pd(PPh3)4 (243.93 mg, 211.09 μmol) and DIEA (218.25 mg, 1.69 mmol) were added to a solution of tert-butyl 7-ethynyl-2-azaspiro[3.5]nonane-2-carboxylate (210.54 mg, 844.35 μmol) and methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-(4-iodophenoxy)propyl]thiazole-4-carboxylate (300 mg, 422.18 μmol) in DMF (5 mL). The resulting mixture was degassed under vacuum and purged with N2 three times. At 60 °C, under N2, the resulting mixture was stirred for 4 h. The reaction mixture was quenched with water (50 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na2SO4 and concentrated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:1 to 20:1) and preparative TLC to give methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[2-(2-tert-butoxycarbonyl-2-azaspiro[3.5]nonan-7-yl)ethynyl]phenoxy]propyl]thiazole-4-carboxylate. LC / MS: MS(ESI) M / Z 833.4 [M+H] + 。

[0632] Step E: Methyl 5-(3-(4-(2-azaspiro[3.5]nonan-7-ylethynyl)phenoxy)propyl)-2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate

[0633] FA (5 mL) was added to a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[2-(2-tert-butoxycarbonyl-2-azaspiro[3.5]nonan-7-yl)ethynyl]phenoxy]propyl]thiazole-4-carboxylate (460 mg, 552.86 μmol). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo to give methyl 5-[3-[4-[2-(2-azaspiro[3.5]nonan-7-yl)ethynyl]phenoxy]propyl]-2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]thiazole-4-carboxylate, which was used in the next step without further purification. LC / MS: MS(ESI) M / Z 366.8 [M+2H]+ / 2。

[0634] Step F: 2-(7-((4-(3-(2-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)ethynyl)-2-azaspiro[3.5]nonan-2-yl)acetic acid

[0635] To a solution of 2-(7-((4-(3-(2-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)ethynyl)-2-azaspiro[3.5]nonan-2-yl)acetic acid and glyoxylic acid (788.98 mg, 10.66 mmol) in DMF (5 mL) and DCE (5 mL) was added AcOH (95.99 mg, 1.60 mmol) and NaBH(OAc)3 (173.74 mg, 819.76 μmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to give a crude product. The crude reaction mixture was filtered and purified by preparative HPLC (10 mmol / L NH4HCO3 - ACN, 66% - 86%; YMC - Actus Triart C18, 150*20 mm, 5um; flow rate: 20 mL / min). The eluate was concentrated in vacuo and lyophilized to give 2-[7-[2-[4-[3-[2-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]ethynyl]-2-azaspiro[3.5]nonan-2-yl]acetic acid. LC / MS: MS(ESI) M / Z 395.4 [M+2H] + / 2。

[0636] Step G: Methyl 2-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-2-azaspiro[3.5]nonan-7-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate

[0637] To a solution of 2-[7-[2-[4-[3-[2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]ethynyl]-2-azaspiro[3.5]nonan-2-yl]acetic acid (25 mg, 31.65 μmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (16.35 mg, 37.98 μmol) in DMF (1 mL) was added EDCI (30.33 mg, 158.24 μmol), HOBT (21.45 mg, 158.88 μmol) and DIEA (40.90 mg, 316.47 μmol). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water (50 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na2SO4 and concentrated in vacuo. The reaction mixture was purified by preparative TLC to afford methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-yl]-2,2-dimethyl-propyl]amino]-2-oxo-ethyl]-2-azaspiro[3.5]nonan-7-yl]ethynyl]phenoxy]propyl]thiazole-4-carboxylate. LC / MS: MS(ESI) M / Z 417.1 [M+2H] + / 2。

[0638] Step H: 2-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)aminocarbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-2-azaspiro[3.5]nonan-7-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylic acid

[0639] To a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethyl]-2-azaspiro[3.5]nonan-7-yl]ethynyl]phenoxy]propyl]thiazole-4-carboxylate (16 mg, 13.31 μmol) in MeOH (1 mL) and THF (1 mL) was added LiOH (3.19 mg, 133.06 μmol). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo. The pH of the reaction mixture was adjusted to pH = 4 - 5 with 0.1 M HCl solution. The reaction mixture was filtered and the cake was washed with H2O (3 × 1 mL) to afford 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethyl]-2-azaspiro[3.5]nonan-7-yl]ethynyl]phenoxy]propyl]thiazole-4-carboxylic acid. LC / MS: MS (ESI) m / z 1189.7 [M+H] + 。 1H-NMR(400MHz, DMSO-d6) δ 12.86(s, 1H), 10.30(s, 1H), 8.95(s, 1H), 8.57(t, J = 5.9Hz, 1H), 8.00(d, J = 8.0Hz, 1H), 7.75(d, J = 8.2Hz, 1H), 7.63(d, J = 7.1Hz, 1H), 7.46 - 7.30(m, 9H), 7.21(d, J = 8.5Hz, 2H), 6.81(d, J = 8.8Hz, 2H), 5.14(s, 1H), 4.79(s, 2H), 4.50(d, J = 9.6Hz, 1H), 4.43 - 4.33(m, 3H), 4.19(dd, J = 15.8, 5.1Hz, 1H), 3.93(t, J = 6.2Hz, 2H), 3.69 - 3.63(m, 3H), 3.54(d, J = 10.2Hz, 1H), 3.12(t, J = 7.4Hz, 2H), 2.98(t, J = 5.9Hz, 2H), 2.40(s, 3H), 2.04 - 1.87(m, 6H), 1.68 - 1.41(m, 6H), 1.19(s, 6H), 1.12(d, J = 7.4Hz, 1H), 0.91(s, 9H)

[0640] Example 17: Compound 17

[0641]

[0642] Step A: tert-Butyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate

[0643] To a solution of (methoxymethyl)(methyl)diphenylphosphonium chloride (4.30 g, 1.25 mmol) in THF (50 mL) was added t-BuOK (1.5 g, 1.34 mmol). The reaction was stirred for 0.5 h at 15 °C under N2. Then tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (2.0 g, 835.7 mmol) was added. The resulting solution was stirred for an additional 2 h at 70 °C under N2. The mixture was cooled to room temperature. The reaction mixture was quenched by the addition of H2O (40 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 10 - 30% EtOAc) to afford tert-butyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate.

[0644] Step B: tert-Butyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate

[0645] To a solution of tert-butyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate (2.01 g, 7.49 mmol) in MeCN (30 mL) and H2O (7.5 mL) was added TFA (0.3 mL). The mixture was stirred at room temperature for 2 h. The pH of the resulting mixture was adjusted to 9 by using saturated Na2CO3. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate (1.99 g, crude), which was used in the next step without purification.

[0646] Step C: tert-Butyl 2-ethynyl-7-azaspiro[3.5]nonane-7-carboxylate

[0647] To a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (1.82 g, 9.47 mmol) in MeOH (20 mL) was added K2CO3 (1.31 g, 9.47 mmol). The resulting solution was stirred at room temperature for 0.5 h. Then tert-butyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate (2.01 g, 7.89 mmol) was added. The mixture was stirred at room temperature for an additional 1.5 h. H2O (60 mL) was added to the mixture and it was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 0 - 20% EtOAc) to afford tert-butyl 2-ethynyl-7-azaspiro[3.5]nonane-7-carboxylate.

[0648] Step D: 2-Ethynyl-7-azaspiro[3.5]nonane

[0649] To a solution of tert-butyl 2-ethynyl-7-azaspiro[3.5]nonane-7-carboxylate (400 mg, 1.61 mmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at 30 °C for 2 h. The mixture was concentrated under reduced pressure to afford crude 2-ethynyl-7-azaspiro[3.5]nonane as a yellow oil (410 mg, TFA salt), which was used in the next step without purification.

[0650] Step E: tert-Butyl 3-(2-ethynyl-7-azaspiro[3.5]nonane-7-yl)propionate

[0651] To a solution of crude 2-ethynyl-7-azaspiro[3.5]nonane (400 mg, TFA salt) and tert-butyl 3-bromopropionate (476 mg, 2.28 mmol) in MeCN (10 mL) was added TEA (615 mg, 6.08 mmol, 847.70 μL). The mixture was stirred at 30 °C for 16 h. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 10 - 40% EtOAc) to afford tert-butyl 3-(2-ethynyl-7-azaspiro[3.5]nonan-7-yl)propionate. LC / MS: MS(ESI) M / Z 278.3 [M+H] + 。

[0652] Step F: 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((7-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropyl)-7-azaspiro[3.5]nonan-2-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylic acid.

[0653] This compound was prepared according to a procedure similar to that described in Example 13. 1 1H-NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 8.54 (t, J = 6.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.38 - 7.23 (m, 8H), 7.12 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 4.80 (s, 1H), 4.50 - 4.43 (m, 4H), 4.34 - 4.23 (m, 1H), 3.90 - 3.85 (m, 3H), 3.73 - 3.66 (m, 3H), 3.40 - 3.27 (m, 4H), 3.16 (t, J = 7.2 Hz, 2H), 2.97 (t, J = 6.0 Hz, 2H), 2.89 - 2.83 (m, 2H), 2.76 - 2.67 (m, 1H), 2.37 - 1.70 (m, 14H), 1.29 - 1.13 (m, 4H), 0.977 (s, 9H). LC / MS: MS(ESI) M / Z 1202.6 [M+H] + 。

[0654] Example 18: Compound 18

[0655]

[0656] Step A: tert-Butyl 3-(methoxymethylene)cyclobutanecarboxylate

[0657] At 0 °C, potassium tert-butoxide (5.27 g, 47.00 mmol) was added to a solution of (methoxymethyl)triphenylphosphonium chloride (15.11 g, 44.06 mmol) in THF (150 mL). The mixture was stirred at 0 °C under N2 for 30 min, then at room temperature under N2 for 60 min. The mixture was cooled to 0 °C and tert-butyl 3-oxocyclobutanecarboxylate (5 g, 29.38 mmol) was added as a solution in THF (3 mL). The resulting mixture was stirred at room temperature for 3 h, then at 70 °C for another three hours. The mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NH4Cl (50 mL). The organic layer was separated and dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (EtOAc / heptane, 0 to 80%) to give tert-butyl 3-(methoxymethylene)cyclobutanecarboxylate. 1 1H NMR (400 MHz, CDCl3) δ 5.80 - 5.78 (m, 1H), 3.54 (s, 3H), 3.08 - 3.00 (m, 1H), 2.92 - 2.75 (m, 4H), 1.46 - 1.42 (s, 9H).

[0658] Step B: tert-Butyl 3-formylcyclobutanecarboxylate

[0659] At room temperature, H2O:TFA = 25:1 (15 mL) was added to a solution of tert-butyl 3-(methoxymethylene)cyclobutanecarboxylate (1.5 g, 7.57 mmol) in DCM (60 mL). The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica chromatography, eluting with PE / EtOAc = 20 / 1, to give tert-butyl 3-formylcyclobutanecarboxylate. 1 1H NMR (400 MHz, CDCl3) δ 9.69 (d, 1H), 3.10 - 2.98 (m, 2H), 2.49 - 2.36 (m, 4H), 1.44 (m, 9H)

[0660] Step C: tert-Butyl 4-ethynylpiperidine-1-carboxylate

[0661] To a solution of 1-diazo-1-dimethoxyphosphoryl-propan-2-one (11.71 g, 60.95 mmol) in MeOH (100 mL) was added K2CO3 (12.96 g, 93.78 mmol). The resulting mixture was stirred at room temperature for 1 h and a solution of tert-butyl 4-formylpiperidine-1-carboxylate (10 g, 46.89 mmol) in THF (20 mL) was added. The reaction solution was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. H2O (200 mL) was added to the mixture and it was extracted with EA (3 × 100 mL). The combined organic layers were washed with water (3 × 10 mL), brine (3 × 20 mL), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography (silica gel: 300 - 400 mesh, PE / EtOAc 0 - 10 / 1) to give tert-butyl 4-ethynylpiperidine-1-carboxylate. LC / MS: MS(ESI) M / Z 154.2 [M + H - t-Bu] + 。

[0662] Step D: 4-Ethynylpiperidine hydrochloride

[0663] At room temperature, to a solution of tert-butyl 4-ethynylpiperidine-1-carboxylate (2.5 g, 11.95 mmol) in dioxane-HCl (4 M, 20 mL) was added, and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated to give 4-ethynylpiperidine hydrochloride (1.70 g, crude), which was used in the next step without further purification.

[0664] Step E: tert-Butyl 3-[(4-ethynyl-1-piperidinyl)methyl]cyclobutanecarboxylate

[0665] At room temperature, a solution of 4-ethynylpiperidine hydrochloride (513.80 mg) and tert-butyl 3-formylcyclobutanecarboxylate (500 mg, 2.71 mmol, 0.76 equiv) in DCE:MeOH = 1:1 (4 mL) was stirred for 1 h. Then sodium triacetoxyborohydride (1.16 g, 5.43 mmol) was added and the mixture was stirred at room temperature for 16 h. Brine (80 mL) was added and it was extracted with EA (3 × 50 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel chromatography, eluting with (DCM / MeOH = 20 / 1) to give tert-butyl 3-[(4-ethynyl-1-piperidinyl)methyl]cyclobutanecarboxylate. LC / MS: MS(ESI) M / Z 278.3 [M + H] + 。

[0666] Step F: 2-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[2-[1-[[3-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-carbonyl]-2,2-dimethyl-propyl]carbamoyl]cyclobutyl]methyl]-4-piperidinyl]ethynyl]phenoxy]propyl]thiazole-4-carboxylic acid

[0667] The compound was prepared according to a procedure similar to that described in Example 13. LC / MS: MS(ESI) M / Z 1203.6 [M+H] + 。 1 H NMR(400 MHz, CD3OD) δ 8.79(s, 1H), 7.84(d, J = 8.0 Hz, 1H), 7.68(d, J = 8.2 Hz, 1H), 7.53(d, J = 7.1 Hz, 1H), 7.38 - 7.16(m, 13H), 6.71(d, J = 8.5 Hz, 2H), 4.57 - 4.42(m, 4H), 3.88(m, 2H), 3.72(m, 3H), 3.55 - 3.60(m, 1H), 3.11 - 2.96(m, 7H), 2.38 - 2.30(m, 4H), 2.16 - 2.09(m, 1H), 2.02 - 1.97(m, 6H), 1.92 - 1.84(m, 3H), 1.36(s, 1H), 1.30 - 1.20(m, 9H), 1.18 - 1.14(m, 1H), 0.94 - 0.91(m, 9H).

[0668] Example 19: Compound 19

[0669]

[0670]

[0671] Step A: Benzyl 4-vinylpiperidine-1-carboxylate

[0672] A solution of methyltriphenylphosphonium bromide (21.67 g, 60.66 mmol) in THF (100 mL) was cooled to 0 °C and t-BuOK (7.25 g, 64.70 mmol) was added slowly, followed by stirring at 25 °C for 1 h. 4-Benzyl 4-formylpiperidine-1-carboxylate (10.0 g, 40.44 mmol) was added and the mixture was stirred at 25 °C for 2 h. The mixture was quenched with NH4Cl (aqueous solution) and diluted with EA. The mixture was extracted with EA (3 × 200 ml) and the organic layers were combined, washed with brine, concentrated in vacuo and the crude product was purified by silica gel column chromatography using PE:EA = 5:1 to afford 4-benzyl 4-vinylpiperidine-1-carboxylate. LCMS: MS (ESI) M / Z: 246.2 [M+H] + 。

[0673] Step B: 4-Benzyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidine-1-carboxylate

[0674] To a solution of 4-benzyl 4-vinylpiperidine-1-carboxylate (4.5 g, 18.34 mmol) in dioxane (50 mL) was added POCl3 (3.09 g, 20.18 mmol) and Zn-Cu couple and the mixture was cooled to 0 °C. 2,2,2-Trichloroacetyl chloride (13.34 g, 73.37 mmol) was added dropwise and the mixture was stirred at 25 °C for 16 h. The mixture was quenched with NaHCO3 (aqueous solution) in ice water, followed by extraction with EA (3 × 100 ml), the organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 4-benzyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidine-1-carboxylate. LCMS: MS (ESI) M / Z: 356.2 [M+H] + 。

[0675] Step C: 4-Benzyl 4-(3-oxocyclobutyl)piperidine-1-carboxylate

[0676] To a solution of 4-benzyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidine-1-carboxylate (7.5 g, 21.05 mmol) in methanol (100 mL) and water (10 mL) was added Zn (4.10 g, 63.15 mmol), NH4Cl (4.50 g, 84.20 mmol), followed by stirring at 25 °C for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography using PE:EA = 4:1 to give 4-benzyl 4-(3-oxocyclobutyl)piperidine-1-carboxylate. LCMS: MS (ESI) M / Z: 288.3 [M+H] + 。

[0677] Step D: tert-Butyl 4-(3-oxocyclobutyl)piperidine-1-carboxylate

[0678] To a solution of benzyl 4-(3-oxocyclobutyl)piperidine-1-carboxylate (4.7 g, 16.36 mmol) in methanol (150 mL) was added Pd / C (500 mg, 10% w / w), di-tert-butyl dicarbonate (3.75 g, 17.17 mmol, 1.05 equiv), and TEA (4.14 g, 40.89 mmol). The mixture was stirred at 25 °C under H2 for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo, and the crude product was purified by silica gel column chromatography using PE:EA = 8:1 to afford tert-butyl 4-(3-oxocyclobutyl)piperidine-1-carboxylate. LCMS: MS(ESI) M / Z: 239.2 [M+H-t-Bu+MeCN] + 。

[0679] Step E: tert-Butyl 4-(3-(methoxymethylene)cyclobutyl)piperidine-1-carboxylate

[0680] A solution of (methoxymethyl)triphenylphosphonium bromide (4.59 g, 11.84 mmol) in THF (20 mL) was cooled to 0 °C and t-BuONa (1.16 g, 12.63 mmol) was added, followed by stirring at room temperature for 1 h. tert-Butyl 4-(3-oxocyclobutyl)piperidine-1-carboxylate (2.0 g, 7.89 mmol) was added at 0 °C and the mixture was stirred at 25 °C for 16 h. The mixture was quenched with NH4Cl (aqueous solution) and extracted with EA (3 × 50 mL). The organic layers were combined, washed with brine and concentrated in vacuo, and the crude product was purified by silica gel column chromatography using PE:EA = 5:1 to afford tert-butyl 4-(3-(methoxymethylene)cyclobutyl)piperidine-1-carboxylate. LCMS: MS(ESI) M / Z: 226.3 [M+H] + 。

[0681] Step F: tert-Butyl 4-(3-formylcyclobutyl)piperidine-1-carboxylate

[0682] To a solution of tert-butyl 4-(3-(methoxymethylene)cyclobutyl)piperidine-1-carboxylate (1.6 g, 5.69 mmol) in ACN (15 mL) was added TFA (10%, in water, 5 mL), and the mixture was stirred at 25 °C for 16 h. NaHCO3 (aqueous solution) was added to the mixture and the mixture was extracted with EA (3 × 20 mL). The organic layers were combined and concentrated in vacuo to afford tert-butyl 4-(3-formylcyclobutyl)piperidine-1-carboxylate. LCMS: MS(ESI) M / Z: 253.3 [M+H-56+41] + 。

[0683] Step G: tert-Butyl 4-(3-ethynylcyclobutyl)piperidine-1-carboxylate

[0684] To a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (2.30 g, 11.97 mmol) in methanol (20 mL) was added K2CO3 (2.48 g, 17.95 mmol) and the mixture was stirred at room temperature for 30 min. Then tert-butyl 4-(3-formylcyclobutyl)piperidine-1-carboxylate (1.6 g, 5.98 mmol) was added and the mixture was stirred at 25 °C for 5 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography using PE:EA = 5:1 to afford tert-butyl 4-(3-ethynylcyclobutyl)piperidine-1-carboxylate.

[0685] Step H: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((3-(1-(tert-butoxycarbonyl)piperidin-4-yl)cyclobutyl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate

[0686] To a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-(4-iodophenoxy)propyl]thiazole-4-carboxylate (300 mg, 422.18 μmol) and tert-butyl 4-(3-ethynylcyclobutyl)piperidine-1-carboxylate (166.79 mg, 633.26 μmol) in DMF (5 mL) were added Pd(PPh3)2Cl2 (59.19 mg, 84.44 μmol), CuI (32.16 mg, 168.87 μmol) and DIEA (164.65 mg, 1.27 mmol), and then the mixture was stirred at 25 °C for 16 h. The mixture was diluted with NH4Cl (aqueous solution), the aqueous layer was extracted with EA (3 × 20 mL), the organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by preparative TLC using DCM:MeOH = 20:1 to afford methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((3-(1-(tert-butoxycarbonyl)piperidin-4-yl)cyclobutyl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate. LCMS: MS (ESI) M / Z: 846.4 [M+H] + 。

[0687] Step I: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((3-(piperidin-4-yl)cyclobutyl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate

[0688] At 30 °C, a solution of methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((3-(1-(tert-butoxycarbonyl)piperidin-4-yl)cyclobutyl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate (160 mg, 189.11 μmol) in FA (3 mL) was stirred for 0.5 h, and the mixture was concentrated in vacuo to afford methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((3-(piperidin-4-yl)cyclobutyl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate. LCMS: MS(ESI) M / Z: 746.4 [M+H] + 。

[0689] Step J: 2-(4-(3-((4-(3-(2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)ethynyl)cyclobutyl)piperidin-1-yl)acetic acid

[0690] To a solution of methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((3-(piperidin-4-yl)cyclobutyl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate (140 mg, 187.68 μmol) and glyoxylic acid monohydrate (34.55 mg, 375.36 μmol) in methanol (5 mL) was added AcOH (33.78 mg, 563.04 μmol). The mixture was then stirred at room temperature for 30 min and NaBH3CN (29.56 mg, 469.20 μmol) was added, and the mixture was stirred at 25 °C for 16 h. The mixture was filtered and the cake was concentrated in vacuo to afford 2-(4-(3-((4-(3-(2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)ethynyl)cyclobutyl)piperidin-1-yl)acetic acid. LCMS: MS(ESI) M / Z: 804.4 [M+H] + 。

[0691] Step K: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((3-(1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)piperidin-4-yl)cyclobutyl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate

[0692] To a solution of 2-(4-(3-((4-(3-(2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)ethynyl)cyclobutyl)piperidin-1-yl)acetic acid (90 mg, 111.94 μmol, 1.0 equiv) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (48.20 mg, 111.94 μmol) in DMF (2 mL) was added DIEA (43.66 mg, 335.83 μmol) and HATU (51.05 mg, 134.33 μmol), and the mixture was then stirred at 25 °C for 1 h. The mixture was diluted with EA and water and the aqueous layer was extracted with EA (3 × 30 mL), the organic layer was washed with brine and dried over Na2SO4, and concentrated in vacuo. The crude product was purified by preparative TLC using MeOH:DCM = 1:10 to afford methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((3-(1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)piperidin-4-yl)cyclobutyl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate. LCMS: MS(ESI) M / Z: 1216.7 [M+H] + 。

[0693] Step L: 2-(8-(Benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((3-(1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)piperidin-4-yl)cyclobutyl)ethynyl)phenoxy)propyl)thiazole-4-carboxylic acid

[0694] To a solution of methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((3-(1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)piperidin-4-yl)cyclobutyl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate (72 mg, 59.18 μmol) in dioxane (2 mL) was added an aqueous NaOH solution (2 M, 591.85 μL), and the mixture was stirred at 25 °C for 2 h. The crude reaction mixture was filtered and subjected to reversed-phase preparative HPLC (preparative C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution from 50% MeCN / water to 55% MeCN / water over a 7 min period, where both solvents contained 0.1% TFA) to afford 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((3-(1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)piperidin-4-yl)cyclobutyl)ethynyl)phenoxy)propyl)thiazole-4-carboxylic acid. LCMS: MS(ESI) M / Z: 1202.7 [M+H] + 。 1H-NMR(400MHz, DMSO-d6) δ 12.72 - 13.09(m, 1H), 9.00(s, 1H), 8.80 - 8.61(m, 2H), 8.04(d, J = 7.4Hz, 1H), 7.80(d, J = 8.0Hz, 1H), 7.67(d, J = 7.7Hz, 1H), 7.50 - 7.34(m, 8H), 7.26(q, J = 9.1Hz, 2H), 6.88 - 6.83(m, 2H), 4.83(s, 2H), 4.59(d, J = 9.1Hz, 1H), 4.49 - 4.37(m, 3H), 4.26 - 4.19(m, 1H), 4.05 - 3.96(m, 4H), 3.73 - 3.60(m, 4H), 3.51 - 3.43(m, 2H), 3.16(t, J = 7.4Hz, 3H), 3.07 - 2.95(m, 5H), 2.45(s, 3H), 2.40 - 2.33(m, 1H), 2.13 - 1.88(m, 6H), 1.77 - 1.74(m, 4H), 1.53 - 1.23(m, 3H), 0.95(s, 9H).

[0695] Example 20: Compound 20

[0696]

[0697] Step A: tert-Butyl 4-(2-oxoethyl)piperidine-1-carboxylate

[0698] At 25 °C, under a nitrogen atmosphere, DMP (6.10 g, 14.39 mmol) was slowly added to a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (3.0 g, 13.08 mmol) in anhydrous DCM (30 mL), and the reaction mixture was stirred at 25 °C for 8 h. The reaction mixture was diluted with H2O (50 mL) and the pH of the solution was adjusted to 5 - 6 with NaHCO3 (aqueous solution). It was then extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography, eluting with PE:EtOAc = 3:1 to give tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate. LC / MS: MS(ESI) M / Z 172.1 [M + H - Boc] + .

[0699] Step B: tert-Butyl 4-prop-2-ynylpiperidine-1-carboxylate

[0700] At 25 °C, under a nitrogen atmosphere, K2CO3 (2.16 g, 15.66 mmol) was slowly added to a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (1.81 g, 9.40 mmol) in anhydrous MeOH (20 mL), and the reaction mixture was stirred at 25 °C for 30 min. Then a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (1.78 g, 7.83 mmol) in anhydrous MeOH (20 mL) was added and the mixture was stirred for another 8 h. The reaction mixture was concentrated to dryness and diluted with H2O (200 mL). Then it was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography, eluting with PE:EtOAc = 3:1 to afford tert-butyl 4-prop-2-ynylpiperidine-1-carboxylate. LC / MS: MS(ESI) M / Z 168.1 [M+H-Boc] + 。

[0701] Step C: 4-Prop-2-ynylpiperidine

[0702] At 25 °C, HCl-dioxane (4 M, 1 mL) was added to a solution of tert-butyl 4-prop-2-ynylpiperidine-1-carboxylate (1.484 g, 3.06 mmol) in dioxane (1 mL), and the resulting mixture was stirred at 25 °C in N2 for 2 h. The reaction mixture was concentrated to dryness to give the product 4-prop-2-ynylpiperidine (1.047 g, crude), which was used in the next step without further purification. LC / MS: MS(ESI) M / Z 168.1 [M+H-Boc] + 。

[0703] Step D: tert-Butyl 3-(4-prop-2-ynyl-1-piperidyl)cyclobutanecarboxylate

[0704] At 50 °C, under a nitrogen atmosphere, 4-prop-2-ynylpiperidine (497 mg, 4.03 mmol) was added to a solution of tert-butyl 3-oxocyclobutanecarboxylate (755.32 mg, 4.44 mmol) in anhydrous DCE (10 mL), and the reaction mixture was stirred at 50 °C for 30 min. Then a solution of sodium triacetoxyborohydride (1.71 g, 8.07 mmol) in anhydrous DCE was added and the mixture was stirred at 50 °C for another 8 h. The reaction mixture was diluted with H2O (10 mL) and the pH of the solution was adjusted to 7 - 8 with aqueous NaHCO3 solution. Then it was extracted with DCM (3 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography, eluting with PE:EtOAc = 3:1 to give tert-butyl 3-(4-prop-2-ynyl-1-piperidinyl)cyclobutanecarboxylate.

[0705] Step E: Methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[1-(3-tert-butoxycarbonylcyclobutyl)-4-piperidinyl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate

[0706] At 25 °C, tetrakis(triphenylphosphine)palladium (32.52 mg, 28.15 μmol) and CuI (10.72 mg, 56.29 μmol) were added to a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-(4-iodophenoxy)propyl]thiazole-4-carboxylate (200 mg, 281.45 μmol) and tert-butyl 3-(4-prop-2-ynyl-1-piperidinyl)cyclobutanecarboxylate (195.19 mg, 703.63 μmol) in THF (4 mL). The resulting mixture was stirred at 60 °C in N2 for 2 h. The crude product was purified by silica gel chromatography, eluting with PE:EtOAc = 1:2 to give methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[1-(3-tert-butoxycarbonylcyclobutyl)-4-piperidinyl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate. LC / MS: MS(ESI) M / Z 430.8 [M / 2 + H] + 。

[0707] Step F: 3-[4-[3-[4-[3-[2-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]prop-2-yn-1-yl]-1-piperidinyl]cyclobutanecarboxylic acid

[0708] At 25 °C, a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[1-(3-tert-butoxycarbonylcyclobutyl)-4-piperidinyl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate (110 mg, 127.89 μmol) in HCOOH (9 mL) was stirred in N2 at room temperature for 7 h. The reaction mixture was concentrated to dryness to give the product 3-[4-[3-[4-[3-[2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]prop-2-yn-1-yl]-1-piperidinyl]cyclobutanecarboxylic acid (88.00 mg, crude) which was used in the next step without further purification. LC / MS: MS(ESI) M / Z 403.1 [M / 2+H] +

[0709] Step G: 2-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[1-[3-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylaminocarbonyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]aminocarbonyl]cyclobutyl]-4-piperidinyl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate methyl ester

[0710] At 25 °C, to a solution of (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (47.13 mg, 109.45 μmol) and 3-[4-[3-[4-[3-[2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]prop-2-ynyl]-1-piperidinyl]cyclobutanecarboxylic acid (88 mg, 109.45 μmol) in DMF (4 mL) was added DIEA (42.44 mg, 328.36 μmol) and HATU (61.94 mg, 164.18 μmol). The resulting mixture was stirred at 25 °C under a N2 atmosphere for 2 h. The crude reaction mixture was filtered and subjected to reverse-phase preparative HPLC (preparative C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution from 61.5% MeCN / water to 81.5% MeCN / water over a 10 min period, where both solvents contained 0.05% NH3H2O) to afford methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[1-[3-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]carbamoyl]cyclobutyl]-4-piperidinyl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate. LC / MS: MS (ESI) M / Z 609.1 [M / 2+H] +

[0711] Step H: 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[1-[3-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]carbamoyl]cyclobutyl]-4-piperidinyl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid

[0712] At 25 °C, to a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[1-[3-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]carbamoyl]cyclobutyl]-4-piperidinyl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate (20 mg, 16.44 μmol) in dioxane (2 mL) was added LiOH·H2O (1.38 mg, 32.88 μmol) in H2O (0.4 mL). The resulting mixture was stirred at 25 °C in N2 for 2 h. The reaction mixture was diluted with H2O (1 mL) and the pH of the solution was adjusted to 5 - 6 with aqueous HCl (1 M). The reaction mixture was filtered and dried in vacuo to afford 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[1-[3-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]carbamoyl]cyclobutyl]-4-piperidinyl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid. LC / MS: MS(ESI) M / Z 1203.6 [M+H] +

[0713] 1H-NMR (400 MHz, CD3OD) δ 8.84 (d, J = 2.7 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.58 (dd, J = 7.0, 1.8 Hz, 1H), 7.44 - 7.27 (m, 8H), 7.21 - 7.17 (m, 2H), 6.79 - 6.74 (m, 2H), 4.71 (s, 2H), 4.61 (s, 1H), 4.55 - 4.46 (m, 2H), 3.94 (t, J = 6.5 Hz, 2H), 3.76 (dd, J = 10.7, 4.1 Hz, 3H), 3.22 (q, J = 7.1 Hz, 2H), 3.02 (t, J = 5.9 Hz, 2H), 2.89 - 2.77 (m, 2H), 2.72 - 2.64 (m, 1H), 2.44 (s, 3H), 2.31 - 2.15 (m, 5H), 2.12 - 1.98 (m, 6H), 1.86 - 1.78 (m, 4H), 1.41 - 1.35 (m, 1H), 1.31 - 1.24 (m, 5H), 0.98 (d, J = 9.3 Hz, 9H).

[0714] Example 21: Compound 21

[0715]

[0716]

[0717] Step A: 3 - Azaspiro[5.5]undecan - 9 - one hydrochloride

[0718] At 25 °C, HCl (4 M in dioxane, 18.70 mL) was added to a solution of tert - butyl 9 - oxo - 3 - azaspiro[5.5]undecane - 3 - carboxylate (2.0 g, 7.48 mmol) in DCM (60.0 mL). The mixture was stirred at 25 °C for 2 h. TLC showed the reaction was complete. The reaction solution was concentrated under reduced pressure to afford the title 3 - azaspiro[5.5]undecan - 9 - one (1.50 g, crude, HCl), which was used directly in the next reaction without further purification. LCMS: MS(ESI) M / Z: 168.2 [M + H] + 。 1 1H - NMR (400 MHz, DMSO - d6) δ 9.08 (s, 2H), 3.03 (d, J = 1.6 Hz, 4H), 2.25 (t, J = 6.8 Hz, 4H), 1.74 - 1.69 (m, 8H).

[0719] Step B: Benzyl 9 - oxo - 3 - azaspiro[5.5]undecane - 3 - carboxylate

[0720] At 0 °C, CbzCl (1.41 g, 8.25 mmol) was added to a solution of 3 - azaspiro[5.5]undecan - 9 - one hydrochloride (1.4 g, 6.87 mmol) and NaHCO3 (1.73 g, 20.62 mmol) in THF (30 mL). The mixture was stirred at 25 °C for 16 h. The reaction solution was filtered and washed with EA (30 mL). The combined organic layers were concentrated and purified by silica gel chromatography, eluting with PE:EtOAc = 2:1 to afford benzyl 9 - oxo - 3 - azaspiro[5.5]undecane - 3 - carboxylate. LCMS: MS(ESI) M / Z: 302.2 [M + H] + 。 1 1H - NMR (400 MHz, CDCl3) δ 7.37 - 7.31 (m, 5H), 5.14 (s, 2H), 3.53 - 3.50 (m, 4H), 2.36 - 2.32 (m, 4H), 1.78 - 1.75 (m, 4H), 1.57 (s, 4H).

[0721] Step C: Benzyl 9-(methoxymethylene)-3-azaspiro[5.5]undecane-3-carboxylate

[0722] At -30 °C, under N2, a solution of (methoxymethyl)triphenylphosphonium chloride (1.71 g, 4.98 mmol) in THF (20.0 mL) was added to a THF solution of KHMDS (1.00 M, 6.64 mL). The mixture was stirred at -30 °C for 0.5 h. After 0.5 h, at -30 °C, under N2, the above mixture (10 mL) was added to a solution of benzyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1.00 g, 3.32 mmol) in THF (5.0 mL). The mixture was stirred at -30 °C for 0.5 h and at 25 °C for 2 h. After cooling to 0 °C, the reaction mixture was quenched with 5.0 mL of saturated aqueous NH4Cl. The resulting solution was extracted with EA (2 × 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography, eluting with PE:EtOAc = 3:1 to afford the title benzyl 9-(methoxymethylene)-3-azaspiro[5.5]undecane-3-carboxylate. LCMS: MS (ESI) M / Z: 330.3 [M+H] + 。 1 1H-NMR (400 MHz, CDCl3) δ 7.36 - 7.26 (m, 5H), 5.77 (s, 1H), 5.12 (s, 2H), 3.53 (s, 3H), 3.46 (t, J = 2.0 Hz, 4H), 2.18 (t, J = 6.4 Hz, 2H), 1.95 (t, J = 6.4 Hz, 2H), 1.44 - 1.39 (m, 8H).

[0723] Step D: Benzyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate

[0724] At 25 °C, 1 M aqueous HCl solution (1.0 M, 5.46 mL) was added to a solution of benzyl 9-(methoxymethylene)-3-azaspiro[5.5]undecane-3-carboxylate (900.0 mg, 2.73 mmol) in THF (10.0 mL), and the mixture was stirred at 25 °C for 16 h. The mixture was diluted with sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to afford benzyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate. LCMS: MS (ESI) M / Z: 316.3 [M+H] + 。

[0725] Step E: 3-((Benzyloxy)carbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid

[0726] At 0 °C, NaOH (114.14 mg, 2.85 mmol) and H2O (20 mL) were added to a solution of benzyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate (900 mg, 2.85 mmol) and KMnO4 (901.70 mg, 5.71 mmol) in acetone (20 mL). The mixture was stirred at 25 °C for 4 h. The mixture was acidified to pH ~2 with HCl (2 M) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to afford the title crude 3-benzyloxycarbonyl-3-azaspiro[5.5]undecane-9-carboxylic acid.

[0727] LCMS: MS(ESI) M / Z: 332.3 [M+H] + 。 1 1H-NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 7.35 - 7.26 (m, 5H), 5.02 (s, 2H), 3.29 (s, 4H), 2.06 (d, J = 12.8 Hz, 1H), 1.61 - 1.21 (m, 10H), 1.09 (d, J = 6.4 Hz, 2H).

[0728] Step F: Benzyl 3-azaspiro[5.5]undecane-3,9-dicarboxylate 9-tert-butyl ester

[0729] At 25 °C, under N2, (Boc)2O (710.43 mg, 3.26 mmol) was added to a solution of 3-benzyloxycarbonyl-3-azaspiro[5.5]undecane-9-carboxylic acid (900.0 mg, 2.72 mmol) and DMAP (66.36 mg, 543.14 μmol) in THF (20.00 mL). The mixture was stirred at 25 °C for 3 h. After cooling to 0 °C, the reaction mixture was quenched with 5.0 mL of saturated aqueous NH4Cl. The resulting solution was extracted with EA (2 × 10 mL). The combined organic layers were washed with water (10 ml) and brine (10 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography, eluting with PE:EtOAc = 3:1, to afford the title benzyl 3-azaspiro[5.5]undecane-3,9-dicarboxylate 9-tert-butyl ester. LCMS: MS(ESI) M / Z: 388.3 [M+H] + 。 1H-NMR (400 MHz, DMSO-d6) δ 7.39 - 7.31 (m, 5H), 5.05 (s, 2H), 3.37 - 3.32 (m, 4H), 2.14 (d, J = 3.2 Hz, 1H), 1.63 - 1.61 (m, 4H), 1.42 - 1.40 (m, 13H), 1.27 - 1.24 (m, 2H), 1.22 - 1.12 (m, 2H).

[0730] Step G: Benzyl 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylate

[0731] At 25 °C, Pd / C (166.11 mg, 10% w / w) was added to a stirred solution of benzyl 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylate (530 mg, 1.37 mmol) in MeOH (20 mL). The reaction was stirred under H2 at room temperature for 16 h. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography, eluting with DCM:MeOH = 0 - 5% to afford the title tert-butyl 3-azaspiro[5.5]undecane-9-carboxylate. LCMS: MS (ESI) M / Z: 254.3 [M+H] + .

[0732] Step H: tert-Butyl 3-(prop-2-yn-1-yl)-3-azaspiro[5.5]undecane-9-carboxylate

[0733] At 0 °C, DIEA (56.00 mg, 434.13 μmol) was added to a solution of tert-butyl 3-azaspiro[5.5]undecane-9-carboxylate (100.0 mg, 394.67 μmol) in ACN (2.0 mL). After stirring at 0 °C for 10 min, 3-bromoprop-1-yne (46.95 mg, 394.67 μmol) was added dropwise to the above mixture at 0 °C over 20 min. The reaction was stirred at 25 °C for 1 h. After completion, the reaction mixture was quenched by addition of a solution of NH4Cl (2.0 mL) and extracted with DCM (2 × 5.0 mL). The organic layers were combined, dried and concentrated in vacuo at 25 °C to afford the title tert-butyl 3-(prop-2-yn-1-yl)-3-azaspiro[5.5]undecane-9-carboxylate. LCMS: MS (ESI) M / Z: 292.3 [M+H] + .

[0734] Step I: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(9-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-3-yl)prop-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylate

[0735] At 25 °C, Pd(PPh3)2Cl2 (24.33 mg, 34.31 μmol), CuI (13.07 mg, 68.63 μmol), TEA (104.17 mg, 1.03 mmol) and tert-butyl 3-prop-2-ynyl-3-azaspiro[5.5]undecane-9-carboxylate (100.0 mg, 343.14 μmol) were added to a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-(4-iodophenoxy)propyl]thiazole-4-carboxylate (243.84 mg, 343.14 μmol) in anhydrous DMF (2.00 mL). The reaction mixture was stirred at 25 °C under N2 for 16 h. After completion, H2O (50.0 mL) was poured into the reaction mixture and filtered. The combined organic solids were washed with water (5.0 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title product methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-(9-tert-butoxycarbonyl-3-azaspiro[5.5]undecan-3-yl)prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate. LCMS: MS (ESI) M / Z: 874.7 [M+H] + 。

[0736] Step J: 3-(3-(4-(3-(2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)prop-2-yn-1-yl)-3-azaspiro[5.5]undecane-9-carboxylic acid

[0737] At 30 °C, under N2, a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-(9-tert-butoxycarbonyl-3-azaspiro[5.5]undecan-3-yl)prop-1-yn-1-yl]phenoxy]propyl]thiazole-4-carboxylate (40 mg, 45.76 μmol) in FA (0.5 mL) was stirred for 2 h. After completion, the reaction mixture was concentrated in vacuo at 25 °C to afford 3-[3-[4-[3-[2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]prop-2-yn-1-yl]-3-azaspiro[5.5]undecane-9-carboxylic acid. LCMS: MS (ESI) M / Z: 818.5 [M+H] +

[0738] Step K: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(9-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)-3-azaspiro[5.5]undecan-3-yl)prop-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylate

[0739] At room temperature, a solution of 3-[3-[4-[3-[2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]prop-2-ynyl]-3-azaspiro[5.5]undecane-9-carboxylic acid (38.00 mg, 46.45 μmol), HATU (22.95 mg, 60.39 μmol), DIEA (17.98 mg, 139.36 μmol), and (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (22.00 mg, 51.10 μmol) in anhydrous DMF (4.0 mL) was stirred for 16 h. After completion, the mixture was poured into water (20.0 mL) and extracted with EA (3 × 5.0 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by preparative HPLC to afford the product methyl 2-[8-(5,6-dihydro-1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[9-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylaminocarbonyl]pyrrolidin-1-yl]-2,2-dimethyl-propyl]aminocarbonyl]-3-azaspiro[5.5]undecane-3-yl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate. LCMS: MS(ESI) M / Z: 1230.7 [M+H] +

[0740] Step L: 2-(8-(Benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(9-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)aminocarbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)aminocarbonyl)-3-azaspiro[5.5]undecane-3-yl)prop-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylic acid

[0741] At 25 °C, NaOH (1.0 mL, 2 M) was added to a solution of methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(9-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)-3-azaspiro[5.5]undecan-3-yl)prop-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylate (39.93 mg, 32.45 μmol) in dioxane:H2O (v:v = 1:1, 4.0 mL). The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (3 mL) and the pH of the solution was adjusted to 6 with aqueous HCl (1 M), and extracted with DCM. The organic layers were combined, dried and concentrated in vacuo at 25 °C. The crude product was purified by preparative HPLC and lyophilization to afford the title 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[9-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]carbamoyl]-3-azaspiro[5.5]undecan-3-yl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid. LCMS: MS (ESI) M / Z: 1216.7 [M+H] + 。 1 1H-NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.44 - 7.38 (m, 10H), 6.94 (d, J = 8.8 Hz, 2H), 4.82 (s, 2H), 4.51 (s, 1H), 4.40 - 4.29 (m, 6H), 3.71 - 3.62 (m, 4H), 3.52 (s, 4H), 3.16 - 3.02 (m, 5H), 2.43 (s, 3H), 2.33 (s, 1H), 2.01 - 1.99 (m, 6H), 1.52 - 1.31 (m, 7H), 1.22 (s, 3H), 7.25 (dd, J = 14.6, 8.8 Hz, 2H), 0.91 (d, J = 8.8 Hz, 9H).

[0742] Example 22: Compound 22

[0743]

[0744]

[0745] Step A: tert-Butyl 2-(2-ethoxy-2-oxoethylidene)-7-azaspiro[3.5]nonane-7-carboxylate

[0746] At 0 °C, NaH (2.50 g, 62.7 mmol, 60% purity) was added portionwise to a solution of ethyl 2-(diethoxyphosphoryl)acetate (14.01 g, 62.7 mmol) in DMF (150 mL). The mixture was stirred for 20 min at the same temperature. Then tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (10.0 g, 41.8 mmol) in THF (30 mL) was added dropwise under N2. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by adding H2O (600 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 0 - 40% EtOAc) to afford tert-butyl 2-(2-ethoxy-2-oxoethylidene)-7-azaspiro[3.5]nonane-7-carboxylate. LC / MS: MS(ESI) M / Z 295.3 [M-t-Bu+MeCN+H] + 。

[0747] Step B: tert-Butyl 2-(2-ethoxy-2-oxoethyl)-7-azaspiro[3.5]nonane-7-carboxylate

[0748] Under N2, Pd / C (2.0 g, 50% purity) was added to a solution of tert-butyl 2-(2-ethoxy-2-oxoethylidene)-7-azaspiro[3.5]nonane-7-carboxylate (9.02 g, 29.3 mmol) in MeOH (90 mL). The suspension was degassed under vacuum and purged with H2 three times. At room temperature, the resulting mixture was stirred under H2 for 1 h. The reaction mixture was filtered through a Celite pad and the cake was washed with MeOH (3 × 100 mL). The combined filtrates were concentrated to afford tert-butyl 2-(2-ethoxy-2-oxoethyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0749] Step C: tert-Butyl 2-(2-(methoxy(methyl)amino)-2-oxoethyl)-7-azaspiro[3.5]nonane-7-carboxylate

[0750] At 0 °C, i-PrMgCl (2 M, 16 mL, 32.0 mmol) was added portionwise to a solution of tert-butyl 2-(2-ethoxy-2-oxoethyl)-7-azaspiro[3.5]nonane-7-carboxylate (2.01 g, 6.41 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.25 g, 12.8 mmol) in THF (35 mL). The reaction mixture was stirred for 2 h at room temperature under N2. The reaction mixture was quenched by the addition of NH4Cl (60 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-(methoxy(methyl)amino)-2-oxoethyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0751] Step D: tert-Butyl 2-(2-oxoethyl)-7-azaspiro[3.5]nonane-7-carboxylate

[0752] At 0 °C, a toluene solution of DABAI-H (1 M, 6.2 mL, 6.20 mmol) was added portionwise to a solution of tert-butyl 2-(2-(methoxy(methyl)amino)-2-oxoethyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.71 g, 5.24 mmol) in DCM (20 mL). The reaction mixture was stirred for 1 h at room temperature under N2. The reaction mixture was quenched by the addition of H2O (0.3 mL), an H2O solution of 15% NaOH (0.3 mL), and H2O (1 mL) and stirred for 10 min. The mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 10–60% EtOAc) to afford tert-butyl 2-(2-oxoethyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0753] Step E: tert-Butyl 2-(prop-2-yn-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0754] To a solution of Bestmann-Ohira reagent (1.0 g, 5.41 mmol) in MeOH (20 mL) was added K2CO3 (1.24 g, 9.02 mmol). The reaction mixture was stirred at room temperature for 20 min. 2-(2-Oxoethyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (1.21 g, 4.51 mmol) in MeOH (2 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by the addition of H2O (60 mL) and extracted with DCM (3 × 80 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 0 - 30% EtOAc) to afford tert-butyl 2-(prop-2-yn-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0755] Step F: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl)prop-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylate

[0756] To a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-(4-iodophenoxy)propyl]thiazole-4-carboxylate (160 mg, 225.16 μmol) and tert-butyl 2-prop-2-ynyl-7-azaspiro[3.5]nonane-7-carboxylate (89 mg, 337.74 μmol) in DMF (4 mL) was added Pd(PPh3)2Cl2 (15 mg, 21.10 μmol), DIEA (116 mg, 900.64 μmol, 4.0 equiv) and CuI (22 mg, 112.58 μmol). The resulting mixture was stirred at 100 °C under N2 for 5 h. H2O (30 mL) was added to the mixture, and the mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 10 - 60% EtOAc) to afford methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-(7-tert-butoxycarbonyl-7-azaspiro[3.5]nonan-2-yl)prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate. LC / MS: MS(ESI) m / z 846.3 [M+H] + 。

[0757] Step G: Methyl 5-(3-(4-(3-(7-azaspiro[3.5]nonan-2-yl)prop-1-yn-1-yl)phenoxy)propyl)-2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate

[0758] To a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-(7-tert-butoxycarbonyl-7-azaspiro[3.5]nonan-2-yl)prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate (140 mg, 165.47 μmol) in DCM (5 mL) was added FA (72 mg, 827.36 μmol). The resulting mixture was stirred at room temperature for 16 h. The solution was concentrated in vacuo to give methyl 5-[3-[4-[3-(7-azaspiro[3.5]nonan-2-yl)prop-1-ynyl]phenoxy]propyl]-2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]thiazole-4-carboxylate, which was used directly in the next step without purification.

[0759] Step H: 2-(2-(3-(4-(3-(2-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)prop-2-yn-1-yl)-7-azaspiro[3.5]nonan-7-yl)acetic acid

[0760] To a solution of methyl 5-[3-[4-[3-(7-azaspiro[3.5]nonan-2-yl)prop-1-yn-1-yl]phenoxy]propyl]-2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]thiazole-4-carboxylate (140 mg, 176.77 μmol, FA salt) and glyoxylic acid (26 mg, 353.55 μmol) in DCE (5 mL) was added NaBH3CN (375 mg, 1.77 mmol) and AcOH (32 mg, 530.32 μmol). The resulting mixture was stirred at room temperature for 16 h. The solid was removed and the solution was concentrated. The residue was purified by reverse-phase preparative HPLC (YMC-Actus Triart C18, 150*20 mm, 5um; 0.05% NH3H2O - 10 mmol / L NH4HCO3 - ACN, 48 - 68%, flow rate: 20 mL / min) to give 2-[2-[3-[4-[3-[2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]prop-2-yn-1-yl]-7-azaspiro[3.5]nonan-7-yl]acetic acid. LC / MS: MS(ESI) M / Z 804.4 [M+H] + 。

[0761] Step I: Methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethyl]-7-azaspiro[3.5]nonan-7-yl]prop-1-yn-1-yl]phenoxy]propyl]thiazole-4-carboxylate

[0762] To a solution of 2-[2-[3-[4-[3-[2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]prop-2-ynyl]-7-azaspiro[3.5]nonan-7-yl]acetic acid (80 mg, 99.50 μmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (56 mg, 119.41 μmol) in DMF (3 mL) was added HATU (56 mg, 149.26 μmol) and DIEA (39 mg, 298.51 μmol). The resulting mixture was stirred at room temperature for 2 h. H2O (20 mL) was added to the mixture and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to afford methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[7-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylaminocarbonyl]pyrrolidin-1-yl]-2,2-dimethyl-propyl]amino]-2-oxo-ethyl]-7-azaspiro[3.5]nonan-2-yl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate. LC / MS: MS (ESI) M / Z 608.9 [M / 2+H] + .

[0763] Step J: 2-(8-(Benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(7-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)aminocarbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-7-azaspiro[3.5]nonan-2-yl)prop-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylic acid

[0764] To a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[7-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-yl]carbonyl]-2,2-dimethylpropyl]amino]-2-oxoethyl]-7-azaspiro[3.5]nonan-2-yl]prop-1-yn-1-yl]phenoxy]propyl]thiazole-4-carboxylate (70 mg, 57.54 μmol) in MeOH (1 mL), THF (1 mL) and H2O (1 mL) was added LiOH.H2O (12 mg, 287.70 μmol). The resulting mixture was stirred at room temperature for 4 h. The pH of the resulting mixture was adjusted to 5 by using 0.5 M HCl and extracted with DCM (3 × 25 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18, 150*20 mm, 5um; 0.05% NH3H2O - 10 mmol / L NH4HCO3 - ACN, 56% - 76%; flow rate: 20 mL / min). The eluate was concentrated under reduced pressure and lyophilized to give 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(7-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-7-azaspiro[3.5]nonan-2-yl)prop-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ13.91(s,1H),9.81(s,1H),8.99(s,1H),8.61(t,J=6.4Hz,1H),8.04(d,J=7.6Hz,1H),7.80(d,J=8.0Hz,1H),7.68(d,J=7.2Hz,1H),7.50-7.35(m,9H),7.28(d,J=8.8Hz,2H),6.87(d,J=8.8Hz,2H),5.19(s,1H),4.84(s,2H),4.58-4.54(m,1H),4.47-4.38(m,3H),4.27-4.22(m,1H),3.98(t,J=6.4Hz,2H),3.74-3.69(m,3H),3.52-3.48(m,1H),3.17(t,J=7.2Hz,2H),3.04(t,J=5.6Hz,2H),2.48-2.45(m,5H),2.09-1.48(m,10H),1.31-1.18(m,9H),0.94(s,9H); LC / MS: MS(ESI) M / Z 1202.7 [M+H] + 。

[0765] Example 23: Compound 23

[0766]

[0767] Step A: 7-azaspiro[3.5]nonan-2-one hydrochloride

[0768] At 0 °C, HCl / dioxane (10.5 mL, 417.87 mmol, 4.0 M) was added dropwise to a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (5.01 g, 20.89 mmol) in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 h. The solution was concentrated in vacuo to afford crude 7-azaspiro[3.5]nonan-2-one hydrochloride (3.01 g, crude, HCl salt), which was used directly in the next step without purification.

[0769] Step B: Benzyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate

[0770] At 0 °C, Cbz-Cl (1.74 g, 10.25 mmol) was added dropwise to a solution of 7-azaspiro[3.5]nonan-2-one hydrochloride (1.02 g, 5.71 mmol) in THF (7 mL) and saturated NaHCO3 (5 mL). The resulting mixture was then stirred at 25 °C for 3 h. H2O (20 mL) was added and the mixture was extracted with EA (3 × 40 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: petroleum ether / 5 - 30% EtOAc) to afford benzyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate. LC / MS: MS (ESI) M / Z 274.3 [M+H] + .

[0771] Step C: Benzyl 2-(2-tert-butoxy-2-oxo-ethylidene)-7-azaspiro[3.5]nonane-7-carboxylate

[0772] At 0 °C, NaH (93 mg, 3.84 mmol, 60% purity) was added to a solution of benzyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, 2.56 mmol) and di-tert-butyl 2-diethoxyphosphorylacetate (969 mg, 3.84 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of H2O (20 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 10 - 30% EtOAc) to afford benzyl 2-(2-(tert-butoxy)-2-oxoethylidene)-7-azaspiro[3.5]nonane-7-carboxylate. LC / MS: MS (ESI) M / Z 394.4 [M+Na] + .

[0773] Step D: tert-Butyl 2-(7-azaspiro[3.5]nonan-2-yl)acetate

[0774] Under N2, Pd / C (500 mg, 50% purity) was added to a solution of benzyl 2-(2-tert-butoxy-2-oxo-ethylidene)-7-azaspiro[3.5]nonane-7-carboxylate (500 mg, 1.35 mmol) in MeOH (10 mL). The suspension was degassed under vacuum and purged with H2 several times. At room temperature, the resulting mixture was stirred under a H2 balloon for 2 h. The suspension was filtered through diatomaceous earth and the cake was washed with MeOH (3 × 20 mL). The combined filtrates were concentrated to afford tert-butyl 2-(7-azaspiro[3.5]nonan-2-yl)acetate.

[0775] Step E: tert-butyl 2-(7-(prop-2-yn-1-yl)-7-azaspiro[3.5]nonan-2-yl)acetate

[0776] At 0 °C, K2CO3 (173 mg, 1.25 mmol) was added to a solution of tert-butyl 2-(7-azaspiro[3.5]nonan-2-yl)acetate (250 mg, 1.04 mmol) and 3-bromoprop-1-yne (149 mg, 1.25 mmol) in DMF (5 mL). The resulting mixture was stirred at room temperature for 0.5 h. H2O (20 mL) was added to the mixture, and the mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 10 - 50% EtOAc) to give tert-butyl 2-(7-prop-2-ynyl-7-azaspiro[3.5]nonan-2-yl)acetate. LC / MS: MS (ESI) M / Z 278.2 [M + H - Boc] + .

[0777] Step F: 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethyl]-7-azaspiro[3.5]nonan-7-yl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid.

[0778] This compound was prepared according to a procedure similar to that described in Example 1. 1H-NMR (400 MHz, CD3OD) δ 8.82 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.70 - 7.67 (m, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.37 - 7.23 (m, 10H), 6.78 (d, J = 8.4 Hz, 2H), 4.82 - 4.77 (m, 3H), 4.54 - 4.52 (m, 1H), 4.46 - 4.39 (m, 3H), 4.26 - 4.23 (m, 1H), 4.10 (s, 2H), 3.91 (t, J = 5.4 Hz, 2H), 3.79 - 3.67 (m, 3H), 3.52 - 3.45 (m, 2H), 3.16 (t, J = 7.2 Hz, 2H), 2.99 - 2.90 (m, 4H), 2.58 - 2.54 (m, 1H), 2.37 (s, 3H), 2.31 - 2.27 (m, 2H), 2.14 - 1.88 (m, 7H), 1.70 - 1.52 (m, 5H), 0.92 (s, 9H). LC / MS: MS (ESI) M / Z 1224.6 [M+Na] + 。

[0779] Example 24: Compound 24

[0780]

[0781] Step A: tert-Butyl 3-ethynylazetidine-1-carboxylate

[0782] To a solution of tert-butyl 3-formylazetidine-1-carboxylate (5.0 g, 26.99 mmol) in MeOH (125 mL) was added 1-diazo-1-dimethoxyphosphoryl-prop-2-one (7.8 g, 40.49 mmol) and K2CO3 (5.6 g, 40.49 mmol). The resulting mixture was stirred at room temperature for 16 h. Then the reaction mixture was poured into H2O (100 mL) and extracted with EA (3 × 80 mL), washed with brine (2 × 50 mL). The organic layers were combined and concentrated. The obtained residue was purified by TLC (1 / 10 PE / EA) to afford tert-butyl 3-ethynylazetidine-1-carboxylate. LC / MS: MS (ESI) M / Z 181.1 [M+H] + 。

[0783] Step B: 3-Ethynylazetidine

[0784] At room temperature, a solution of tert-butyl 3-ethynylazetidine-1-carboxylate (3.7 g, 20.44 mmol) in FA (30 mL) was stirred for 3 h. The reaction mixture was concentrated in vacuo to afford 3-ethynylazetidine (1.5 g, 90.90%). LC / MS: MS (ESI) M / Z 81.1 [M+H] + .

[0785] Step C: tert-Butyl 3-(methoxymethylene)cyclobutanecarboxylate

[0786] At 0 °C, t-BuOK (3.7 g, 32.90 mmol) was added to a solution of methoxymethyl(triphenyl)-phosphane (9.5 g, 30.85 mmol) in THF (60 mL). The resulting mixture was stirred at 0 °C for 0.5 h. Then at 0 °C, a solution of tert-butyl 3-oxocyclobutanecarboxylate (3.5 g, 20.56 mmol) in anhydrous THF (10 mL) was added under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 10 min. The reaction mixture was stirred at 70 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched with saturated NH4Cl aqueous solution (50 mL). The resulting mixture was extracted with EA (3 × 50 mL). The organic layers were combined and washed with brine (2 × 35 mL). The residue obtained was purified by TLC (1:20 PE / EA) to afford tert-butyl 3-(methoxymethylene)cyclobutanecarboxylate. LC / MS: MS (ESI) M / Z 198.1 [M+H] + .

[0787] Step D: tert-Butyl 3-formylcyclobutanecarboxylate

[0788] At room temperature, TFA:H2O = 1:20 (25 mL) was added to a solution of tert-butyl 3-(methoxymethylene)cyclobutanecarboxylate (2.2 g, 11.10 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with DCM (3 × 50 mL). The organic layers were combined and washed with brine (2 × 35 mL). The residue obtained was purified by TLC (1:30 PE / EA) to afford tert-butyl 3-formylcyclobutanecarboxylate. LC / MS: MS (ESI) M / Z 184.1 [M+H] +

[0789] Step E: tert-Butyl 3-((3-ethynylazetidin-1-yl)methyl)cyclobutanecarboxylate

[0790] To a solution of tert-butyl 3-formylcyclobutanecarboxylate (1.1 g, 6.61 mmol) in DCM / MeOH = 1 / 1 (20 mL) was added NaBH3CN (1.55 g, 24.66 mmol), 3-ethynylazetidine (500 mg, 6.16 mmol) and AcOH (0.1 mL). The resulting mixture was stirred at 25 °C for 16 h. The reaction was quenched with H2O (10 mL). The resulting mixture was extracted with DCM (3 × 30 mL). The organic layers were combined and washed with brine (4 × 15 mL). The obtained residue was purified by TLC (1:50 DCM / MeOH) to afford tert-butyl 3-((3-ethynylazetidin-1-yl)methyl)cyclobutanecarboxylate. LC / MS: MS(ESI) M / Z 249.2 [M+H] +

[0791] Step F: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((1-((3-(tert-butoxycarbonyl)cyclobutyl)methyl)azetidin-3-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate

[0792] To a solution of tert-butyl 3-((3-ethynylazetidin-1-yl)methyl)cyclobutanecarboxylate (200 mg, 0.80 mmol) in DMF (6 mL) was added methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-(4-iodophenoxy)propyl]thiazole-4-carboxylate (570 mg, 0.80 mmol), Pd(PPh3)2Cl2 (56 mg, 0.08 mmol, 0.1 equiv), CuI (31 mg, 0.16 mmol) and DIEA (517 mg, 4.00 mmol). The resulting mixture was stirred at 60 °C for 4 h. The reaction was quenched with H2O (10 mL). The resulting mixture was extracted with EA (3 × 20 mL). The obtained residue was purified by TLC (1:50 DCM / MeOH) to afford methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((1-((3-(tert-butoxycarbonyl)cyclobutyl)methyl)azetidin-3-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate. LC / MS: MS(ESI) M / Z 847.3 [M+H] + 。

[0793] Step G: 3-((3-((4-(3-(2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)ethynyl)azetidin-1-yl)methyl)cyclobutanecarboxylic acid

[0794] At room temperature, a solution of methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((1-((3-(tert-butoxycarbonyl)cyclobutyl)methyl)azetidin-3-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate (200 mg, 0.24 mmol) in FA (10 mL) was stirred for 10 h. The reaction mixture was concentrated in vacuo to afford 3-((3-((4-(3-(2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)ethynyl)azetidin-1-yl)methyl)cyclobutanecarboxylic acid. LC / MS: MS (ESI) m / z 791.8 [M+H] + 。

[0795] Step H: methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((1-((3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)cyclobutyl)methyl)azetidin-3-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate

[0796] To a solution of 3-((3-((4-(3-(2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)ethynyl)azetidin-1-yl)methyl)cyclobutanecarboxylic acid (0.18 g, 0.22 mmol) in DMF (3 mL) was added (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (0.11 g, 0.23 mmol), HATU (0.19 g, 0.44 mmol) and DIEA (0.17 g, 1.10 mmol). The resulting mixture was stirred at 25 °C for 2 h. The reaction was quenched with H2O (5 mL). The resulting mixture was extracted with EA (3 × 15 mL). The obtained residue was purified by TLC (1:10 DCM / MeOH) to afford methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((1-((3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)cyclobutyl)methyl)azetidin-3-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate. LC / MS: MS(ESI) M / Z 1187.4 [M+H] + .

[0797] Step I: 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((1-((3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)cyclobutyl)methyl)azetidin-3-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylic acid

[0798] To a solution of 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((1-((3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)cyclobutyl)methyl)azetidin-3-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate (0.27 g, 0.23 mmol) in THF (3 mL) and MeOH (3 mL) was added LiOH.H2O (98.9 mg, 2.30 mmol) and H2O (3 mL). The resulting mixture was stirred at 25 °C for 4 h. The reaction was quenched with H2O (5 mL). The resulting mixture was extracted with EtOAc (3 × 15 mL). The organic layers were combined and washed with brine (4 × 15 mL). The residue obtained was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: aqueous solution of 10 mmol / L NH4HCO3 + 0.1% NH3.H2O, mobile phase B: CH3CN (15% to 45% in 11 min, 45% to 100% in 0.1 min, 100% to 100% in 2 min, 100% to 30% in 0.1 min, 30% to 30% in 1 min); detector, UV 254 nm, to afford 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((1-((3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)cyclobutyl)methyl)azetidin-3-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylic acid.1H-NMR (400 MHz, CD3OD) δ 8.89 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.45 - 7.37 (m, 7H), 7.34 - 7.25 (m, 3H), 6.83 - 6.77 (m, 2H), 5.00 - 4.88 (m, 3H), 4.64 - 4.09 (m, 9H), 3.99 - 3.76 (m, 7H), 3.24 (t, J = 7.4 Hz, 3H), 3.18 - 3.05 (m, 3H), 2.52 - 2.43 (m, 4H), 2.40 - 2.17 (m, 3H), 2.13 - 1.94 (m, 5H), 0.99 (s, 9H).

[0799] Example 25: Compound 25

[0800]

[0801] Step A: tert-Butyl 3-((3-(methoxycarbonyl)azetidin-1-yl)methyl)azetidine-1-carboxylate

[0802] To a solution of tert-butyl 3-formylazetidine-1-carboxylate (6.11 g, 32.98 mmol) and methyl azetidine-3-carboxylate (5.01 g, 32.98 mmol) in THF (100 mL) was added NaBH(OAc)3 (17.48 g, 82.46 mmol) and HOAc (5 mL). The mixture was stirred at 30 °C for 3 h. The reaction mixture was quenched by the addition of H2O (40 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 10 - 40% EtOAc) to afford tert-butyl 3-[(3-methoxycarbonylazetidin-1-yl)methyl]azetidine-1-carboxylate.

[0803] Step B: tert-Butyl 3-((3-(methoxycarbonyl)azetidin-1-yl)methyl)azetidine-1-carboxylate

[0804] At -78 °C, under N2, DIBAL-H (1 M, 14.07 mL) was added to a solution of tert-butyl 3-[(3-methoxycarbonylazetidin-1-yl)methyl]azetidine-1-carboxylate (2.00 g, 7.03 mmol) in DCM (40 mL). The mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched by adding sodium sulfate decahydrate (ca. 8 g) and stirred at -78 °C for 30 min. The reaction mixture was filtered through a pad of diatomaceous earth and the cake was washed with DCM (3 × 80 mL). The combined filtrates were concentrated to afford tert-butyl 3-[(3-formylazetidin-1-yl)methyl]azetidine-1-carboxylate.

[0805] Step C: tert-butyl 3-((3-ethynylazetidin-1-yl)methyl)azetidine-1-carboxylate

[0806] To a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (1.18 g, 6.13 mmol) in MeOH (8 mL) was added K2CO3 (848 mg, 6.13 mmol). The mixture was stirred at 30 °C for 0.5 h. Then tert-butyl 3-[(3-formylazetidin-1-yl)methyl]azetidine-1-carboxylate (1.31 g, 5.12 mmol) was added. The mixture was stirred at 30 °C for 15.5 h. The reaction mixture was quenched by adding H2O (60 mL), and extracted with EtOAc (2 × 80 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 0 - 50% EtOAc) to afford tert-butyl 3-[(3-ethynylazetidin-1-yl)methyl]azetidine-1-carboxylate.

[0807] Step D: 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[2-[1-[[1-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethylpropyl]amino]-2-oxoethyl]azetidin-3-yl]methyl]azetidin-3-yl]ethynyl]phenoxy]propyl]thiazole-4-carboxylic acid.

[0808] The compound was prepared according to a procedure similar to that described in Example 1. 1H-NMR (400 MHz, CD3OD) δ 8.84 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.47 - 7.24 (m, 10H), 6.84 - 6.77 (m, 2H), 4.86 - 4.86 (1H), 4.59 - 4.48 (m, 3H), 4.39 - 4.24 (m, 5H), 4.12 - 3.94 (m, 7H), 3.86 - 3.75 (m, 4H), 3.62 - 3.47 (m, 2H), 3.22 (t, J = 7.2 Hz, 2H), 3.16 - 3.11 (m, 1H), 3.08 - 2.93 (m, 2H), 2.44 (s, 3H), 2.38 - 1.97 (m, 4H), 1.44 - 1.18 (m, 4H), 1.02 (s, 9H). LC / MS: 1189.60 [M + H] + 。

[0809] Example 26: Compound 26

[0810]

[0811]

[0812] Step A: tert-Butyl 2-(3-(benzyloxy)cyclobutylidene)acetate

[0813] At 0 °C, NaH (1.36 g, 34.05 mmol, 60% purity) was added portionwise to a solution of tert-butyl 2-(diethoxyphosphoryl)acetate (5.00 g, 34.05 mmol) in THF (60 mL). The mixture was stirred at the same temperature for 20 min. Then, 3-(benzyloxy)cyclobutanone (5.01 g, 28.38 mmol) in THF (20 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by adding H2O (40 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (2 × 40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 0 - 20% EtOAc) to afford tert-butyl 2-(3-(benzyloxy)cyclobutylidene)acetate.

[0814] Step B: tert-Butyl 2-(3-hydroxycyclobutyl)acetate

[0815] Under N2, Pd / C (500 mg, 50% purity) was added to a solution of tert-butyl 2-(3-benzylidenyloxocyclobutyl)acetate (5.0 g, 18.22 mmol) in MeOH (70 mL). The suspension was degassed under vacuum and purged with H2 several times. At room temperature, under a H2 balloon, the mixture was stirred for 16 h. The suspension was filtered through celite and the cake was washed with MeOH (3 × 40 mL). The combined filtrates were concentrated to afford tert-butyl 2-(3-hydroxycyclobutyl)acetate.

[0816] Step C: tert-Butyl 2-(3-oxocyclobutyl)acetate

[0817] DMP (8.22 g, 19.36 mmol) was added to a solution of tert-butyl 2-(3-hydroxycyclobutyl)acetate (3.02 g, 16.14 mmol) in DCM (40 mL). The reaction mixture was stirred at room temperature for 2 h. Aqueous Na2S2O4 solution (40 mL) and NaHCO3 (50 mL) were added to the mixture, and it was extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (2 × 40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 0 - 30% EtOAc) to afford tert-butyl 2-(3-oxocyclobutyl)acetate.

[0818] Step D: tert-Butyl 2-(3-(3-ethynylazetidin-1-yl)cyclobutyl)acetate

[0819] AcOH (147 mg, 2.44 mmol) and NaBH3CN (101 mg, 1.63 mmol) were added to a solution of tert-butyl 2-(3-oxocyclobutyl)acetate (150 mg, 814.19 μmol) and 3-ethynylazetidine (125 mg, 977.03 μmol) in DCM (5 mL) and methanol (5 mL). The resulting mixture was stirred at room temperature for 3 h. Aqueous NaHCO3 solution (20 mL) was added to the mixture, and it was extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / 10 - 70% EtOAc) to afford tert-butyl 2-(3-(3-ethynylazetidin-1-yl)cyclobutyl)acetate.

[0820] Step E: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((1-(3-(2-(tert-butoxy)-2-oxoethyl)cyclobutyl)azetidin-3-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate

[0821] To a solution of methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-iodophenoxy)propyl)thiazole-4-carboxylate (160 mg, 225.16 μmol) and tert-butyl 2-[3-(3-ethynylazetidin-1-yl)cyclobutyl]acetate (141 mg, 562.90 μmol) in DMF (5 mL) were added Pd(PPh3)2Cl2 (92 mg, 112.58 μmol), CuI (21 mg, 112.58 μmol) and DIEA (116 mg, 900.64 μmol). The resulting mixture was stirred at 60 °C under N2 for 3 h. H2O (20 mL) was added to the mixture and the mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to afford methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[2-[1-[3-(2-tert-butoxy-2-oxo-ethyl)cyclobutyl]azetidin-3-yl]ethynyl]phenoxy]propyl]thiazole-4-carboxylate. LC / MS: MS(ESI) M / Z 832.3 [M+H] +

[0822] Step F: 2-(3-(3-((4-(3-(2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)ethynyl)azetidin-1-yl)cyclobutyl)acetic acid

[0823] At room temperature, a solution of methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((1-(3-(2-(tert-butoxy)-2-oxoethyl)cyclobutyl)azetidin-3-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate (150 mg, 180.28 μmol) in FA (3 mL) was stirred for 16 h. The solution was concentrated in vacuo to afford 2-[3-[3-[2-[4-[3-[2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]ethynyl]azetidin-1-yl]cyclobutyl]acetic acid (120 mg, crude, FA salt), which was used directly in the next step without purification. LC / MS: MS(ESI) M / Z 388.8 [M / 2+H] +

[0824] Step G: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((1-(3-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)cyclobutyl)azetidin-3-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate

[0825] To a solution of (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (85 mg, 182.49 μmol, HCl salt) and 2-[3-[3-[2-[4-[3-[2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]ethynyl]azetidin-1-yl]cyclobutyl]acetic acid (100 mg, 121.66 μmol) in DMF (2 mL) was added DIEA (63 mg, 486.64 μmol) and HATU (60 mg, 158.16 μmol). The resulting mixture was stirred at room temperature for 2 h. H2O (20 mL) was added to the mixture and the mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to afford methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[2-[1-[3-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylaminocarbonyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethyl]cyclobutyl]azetidin-3-yl]ethynyl]phenoxy]propyl]thiazole-4-carboxylate. LC / MS: MS(ESI) M / Z 595.0 [M / 2 + H] +

[0826] Example 27: Compound 27

[0827]

[0828] Step A: Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate

[0829] At 110 °C, a solution of ethyl 4-oxocyclohexanecarboxylate (800 g, 4.70 mol), TosOH (81 g, 0.47 mol), and ethylene glycol (350.08 g, 5.64 mol) in toluene (5500 mL) was refluxed for 16 h, and water was removed by a Dean-Stark trap. The mixture was cooled to room temperature, washed with saturated aqueous NaHCO3, and the organic layer was dried over Na2SO4 and concentrated in vacuo. The crude oil was purified by column chromatography using PE / EA = 30 / 1 to obtain ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate. LC / MS: MS (ESI) M / Z 215.2 [M+H] + 。

[0830] Step B: Diethyl 1,4-dioxaspiro[4.5]decane-8,8-dicarboxylate

[0831] At -78 °C, under a nitrogen atmosphere, n-BuLi (2.5 M, 729.03 mL) was slowly added dropwise to a solution of HTMP (257.44 g, 1.82 mol) in anhydrous THF (1500 mL), and the reaction mixture was stirred at -78 °C for 30 min. Then, at -78 °C, under a nitrogen atmosphere, a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (355 g, 1.66 mol) in anhydrous THF (1000 mL) was slowly added dropwise over 1.5 h, and then a solution of ethyl chloroformate (269.72 g, 2.49 mol) in anhydrous THF (500 mL) was slowly added dropwise, and the mixture was stirred for an additional 1 h. The mixture was quenched with saturated aqueous NH4Cl, extracted with EA (3 × 1000 mL), and the organic layer was dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography using PE / EA = 50 / 1 to obtain diethyl 1,4-dioxaspiro[4.5]decane-8,8-dicarboxylate.

[0832] Step C: 1,4-Dioxaspiro[4.5]decane-8,8-diyldimethanol

[0833] At 0 °C, under a nitrogen atmosphere, a solution of diethyl 1,4-dioxaspiro[4.5]decane-8,8-dicarboxylate (250 g, 873.15 mmol) in anhydrous THF (500 mL) was slowly added dropwise over 2 h to a solution of LiAlH4 (99.42 g, 2.62 mol) in anhydrous THF (1500 mL), and the reaction mixture was stirred for an additional 5 h at 0 - 10 °C. At 0 - 10 °C, the mixture was quenched with H2O (100 mL), 15% aqueous NaOH solution (100 mL), and H2O (300 mL), then Na2SO4 was added and the mixture was stirred at 10 °C for 15 min. The solid was filtered off, the filtrate was concentrated, and [8-(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-8-yl]methanol was obtained.

[0834] Step D: 2-[(2,4-Dimethoxyphenyl)methyl]-8,11-dioxa-2-azadispiro[3.2.4 7 .2 4 tridecane

[0835] At -40 to -30 °C, trifluoromethanesulfonic anhydride (Tf2O) (167.40 g, 593.33 mmol, 2.0 equiv) was added dropwise to a suspension of [8-(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-8-yl]methanol (60 g, 296.67 mmol) and DIEA (115.03 g, 890.00 mmol) in anhydrous CH3CN (1000 mL). The reaction mixture was stirred at -40 to -30 °C for 1 h. At -40 to -30 °C, DIEA (115.03 g, 890.00 mmol) was added in one portion to the resulting brown solution, and (3,4-dimethoxyphenyl)methanamine (49.60 g, 296.67 mmol) was added dropwise within 5 min. The flask containing the reaction mixture was transferred to an oil bath and stirred at 75 - 80 °C for 12 h. The reaction mixture was diluted with H2O (600 mL) and extracted with EA (2 × 600 mL). The combined organic layers were washed with brine (2 × 600 mL), dried over Na2SO4, and concentrated in vacuo to dryness. The residue was purified by column chromatography (silica gel, MeOH / DCM = 0 - 10%) to give 2-[(3,4-dimethoxyphenyl)methyl]-8,11-dioxa-2-azadispiro[3.2.4 7 .2 4 tridecane. LC / MS: MS(ESI) M / Z 334.3 [M + H] + .

[0836] Step E: 8,11-Dioxa-2-azadispiro[3.2.4 7 .2 4tert-Butyl tridecane-2-carboxylate

[0837] Under N2, to a solution of 2-[(2,4-dimethoxyphenyl)methyl]-8,11-dioxa-2-azadispiro[3.2.4 7 .2 4 tridecane (3 g, 9.00 mmol) and di-tert-butyl dicarbonate (3.93 g, 18.00 mmol) in MeOH (60 mL) was added TEA (2.73 g, 26.99 mmol), Pd / C (600.00 mg, 10% w / w). The suspension was degassed under vacuum and purged with H2 several times. At 60 °C, under H2, the mixture was stirred for 16 h. The suspension was filtered through Celite and the cake was washed with MeOH. The combined filtrates were concentrated and the crude oil was purified by column chromatography using PE / EA = 4 / 1 to give 8,11-dioxa-2-azadispiro[3.2.4 7 .2 4 tridecane-2-carboxylate tert-butyl ester.

[0838] Step F: tert-Butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate

[0839] To a solution of 8,11-dioxa-2-azadispiro[3.2.4 7 .2 4 tridecane-2-carboxylate tert-butyl ester (2.54 g, 8.96 mmol) in acetone (50 mL) and H2O (5 mL) was added TsOH·H2O (341.01 mg, 1.79 mmol), and the resulting mixture was stirred at 45 °C for 16 h. The mixture was cooled to room temperature, concentrated in vacuo, and the crude oil was purified by column chromatography using PE / EA = 4 / 1 to afford tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate.

[0840] Step G: tert-Butyl 7-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.5]nonane-2-carboxylate

[0841] At 0 °C, under a nitrogen atmosphere, NaH (768.88 mg, 19.22 mmol, 60% purity) was added portionwise to a solution of ethyl 2-diethoxyphosphorylacetate (3.23 g, 14.42 mmol) in anhydrous THF (50 mL), and the reaction mixture was stirred at 0 °C for 30 min. Then a solution of tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (2.3 g, 9.61 mmol, 1.0 equiv) in anhydrous THF (50 mL) was added and the mixture was stirred at 0 °C - 10 °C for another 3 h. Saturated aqueous NH4Cl solution was added to quench the solution, and the mixture was extracted with EA (2 × 100 mL). The organic layer was dried over Na2SO4 and concentrated to obtain tert-butyl 7-(2-ethoxy-2-oxo-ethylidene)-2-azaspiro[3.5]nonane-2-carboxylate (3.20 g, crude).

[0842] Step H: tert-Butyl 7-(2-ethoxy-2-oxoethyl)-2-azaspiro[3.5]nonane-2-carboxylate

[0843] Under N2, Pd / C (600.00 mg, 10% w / w) was added to a solution of tert-butyl 7-(2-ethoxy-2-oxo-ethylidene)-2-azaspiro[3.5]nonane-2-carboxylate (3 g, 9.70 mmol) in MeOH (150 mL). The suspension was degassed under vacuum and purged with H2 several times. At 20 °C, under H2, the mixture was stirred for 3 h. The suspension was filtered through diatomaceous earth and the filter cake was washed with MeOH (3 × 20 mL). The combined filtrates were concentrated, and the crude oil was purified by column chromatography using PE / EA = 4 / 1 to obtain tert-butyl 7-(2-ethoxy-2-oxo-ethyl)-2-azaspiro[3.5]nonane-2-carboxylate. LC / MS: MS(ESI) M / Z 256.2 [M+H-t-Bu] + .

[0844] Step I: tert-Butyl 7-(2-oxoethyl)-2-azaspiro[3.5]nonane-2-carboxylate

[0845] At -78 °C, under a nitrogen atmosphere, DIBAL-H (1 M, 4.82 mL) was added dropwise to a solution of tert-butyl 7-(2-ethoxy-2-oxo-ethyl)-2-azaspiro[3.5]nonane-2-carboxylate (1 g, 3.21 mmol) in anhydrous DCM (10 mL) over 30 min, and the mixture was stirred for another 30 min. The mixture was quenched with saturated aqueous NaHCO3 solution, extracted with DCM (3 × 50 mL), the organic layer was dried and concentrated to obtain tert-butyl 7-(2-oxoethyl)-2-azaspiro[3.5]nonane-2-carboxylate.

[0846] Step J: tert-Butyl 7-(prop-2-yn-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate

[0847] At room temperature, K2CO3 (930.46 mg, 6.73 mmol) was added to a solution of 1-diazo-1-dimethoxyphosphoryl-propan-2-one (862.24 mg, 4.49 mmol) in anhydrous MeOH (20 mL), and the reaction mixture was stirred at room temperature for 30 min. Then a solution of tert-butyl 7-(2-oxoethyl)-2-azaspiro[3.5]nonane-2-carboxylate (1.2 g, 4.49 mmol) in anhydrous MeOH (20 mL) was added and the mixture was stirred for another 16 h. The reaction mixture was concentrated and purified by column chromatography using PE / EA = 4 / 1 to obtain tert-butyl 7-prop-2-ynyl-2-azaspiro[3.5]nonane-2-carboxylate.

[0848] Step K: 2-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethyl]-2-azaspiro[3.5]nonan-7-yl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid

[0849] This compound was prepared according to a procedure similar to that described in Example 22. 1 H NMR (400 MHz, DMSO-d6) δ 12.96 (brs, 1H), 10.57 (s, 1H), 9.03 (s, 1H), 8.66 - 8.54 (m, 1H), 8.00 (d, J = 6.4 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 6.8 Hz, 1H), 7.47 - 7.29 (m, 8H), 7.22 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 4.85 (s, 2H), 4.51 (d, J = 8.4 Hz, 4H), 4.42 - 4.28 (m, 4H), 4.26 - 3.98 (m, 4H), 3.96 - 3.84 (m, 6H), 3.18 (s, 2H), 3.05 (s, 2H), 2.46 (s, 3H), 2.26 - 1.82 (m, 8H), 1.76 - 1.58 (m, 2H), 1.45 - 1.17 (m, 5H), 0.95 (s, 9H). LCMS: MS (ESI) M / Z: 1202.7 [M+H] + .

[0850] Example 28: Compound 28

[0851]

[0852] Step A: tert-Butyl 3-(2-(((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0853] To a solution of 10-{4-[3-(2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-4-(methoxycarbonyl)-1,3-thiazol-5-yl)propoxy]phenyl}dec-9-ynoic acid (300 mg, 0.400 mmol) in DMF (5 mL) was added (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (266.42 mg, 0.600 mmol), HATU (227.86 mg, 0.600 mmol), and DIEA (154.90 mg, 1.200 mmol). The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 mL). The mixture was extracted with EA (3 × 20 mL) and the resulting mixture was washed with 3 × 20 mL of water. The organic layer was dried over Na2SO4 and filtered. The organic layer was concentrated. The crude product was purified by silica gel column chromatography. The organic layer was concentrated under reduced pressure to afford methyl 2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-{3-[4-(9-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]aminocarbonyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]aminocarbonyl}non-1-yn-1-yl)phenoxy]propyl}-1,3-thiazole-4-carboxylate. LCMS: MS(ESI) M / Z: 1177 [M+H] + 。

[0854] Step B: tert-Butyl 3-(2-(((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0855] To a solution of methyl 2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-{3-[4-(9-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}non-1-yn-1-yl)phenoxy]propyl}-1,3-thiazole-4-carboxylate (300 mg, 0.255 mmol) in MeOH (2 mL) and THF (4 mL) was added aqueous NaOH solution (2 N, 2 mL). The mixture was stirred at 50 °C for 1 h. The mixture was concentrated under reduced pressure to remove MeOH. The pH of the solution was adjusted to 4 - 5 with 2 M HCl. The mixture was extracted with EA (10 mL × 2). The crude product was purified by preparative HPLC under the following conditions: column: XSelect CSH preparative C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 51% B to 71% B in 7 min, 71% B; wavelength: 254 nm; RT1 (min): 4.95; number of runs: 0. After lyophilization, methyl 2-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl}-5-{3-[4-(9-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}non-1-yn-1-yl)phenoxy]propyl}-1,3-thiazole-4-carboxylate was provided. 1HNMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.73 - 7.85 (m, 2H), 7.63 - 7.72 (m, 1H), 7.18 - 7.52 (m, 10H), 6.85 (d, J = 8.7 Hz, 2H), 4.75 - 5.00 (m, 4H), 4.48 - 4.56 (m, 1H), 4.36 - 4.48 (m, 1H), 4.23 - 4.33 (m, 1H), 3.95 (t, J = 6.3 Hz, 2H), 3.66 - 3.79 (m, 2H), 3.55 - 3.66 (m, 2H), 3.16 (t, J = 6.3 Hz, 2H), 3.03 (t, J = 6.3 Hz, 2H), 2.44 (s, 3H), 2.34 (t, J = 6.9 Hz, 2H), 2.18 - 2.32 (m, 1H), 2.07 - 2.17 (m, 1H), 1.93 - 2.06 (m, 3H), 1.72 - 1.86 (m, 1H), 1.43 - 1.59 (m, 4H), 1.32 - 1.43 (m, 5H), 1.19 - 1.32 (m, 4H), 0.93 (s, 9H). LCMS: MS (ESI) M / Z: 1163.45 [M+H] + 。

[0856] Example 29: Compound 29

[0857]

[0858]

[0859] Step A: tert-Butyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate

[0860] At -78 °C, a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 34.57 mL) was added to a solution of tert-butyl 4-oxocyclohexanecarboxylate (6.23 g, 31.42 mmol) in THF (65.43 mL). The mixture was stirred at -78 °C for 1 h, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (12.35 g, 34.57 mmol) was added, and the mixture was stirred at 28 °C for 16 h. The resulting solution was extracted with EA (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography, eluting with PE:EtOAc = 1:0 to give tert-butyl 4-(trifluoromethylsulfonyloxy)cyclohex-3-ene-1-carboxylate. 11H-NMR (400 MHz, CDCl3) δ 5.80 - 5.75 (m, 1H), 2.57 - 2.31 (m, 5H), 2.14 - 2.04 (m, 1H), 1.95 - 1.82 (m, 1H), 1.46 - 1.42 (m, 9H).

[0861] Step B: Benzyl 4-(4-(tert-butoxycarbonyl)cyclohex-1-en-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate

[0862] To a solution of tert-butyl 4-(trifluoromethylsulfonyloxy)cyclohex-3-ene-1-carboxylate (4 g, 12.11 mmol) in water (10 mL) and dioxane (80 mL) was added benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.91 g, 8.48 mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (1.00 g, 1.21 mmol), and potassium acetate (3.57 g, 36.33 mmol). The resulting mixture was stirred at 90 °C under N2 for 16 h. The resulting solution was extracted with EA (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by silica gel chromatography, eluting with PE:EtOAc = 20:1, to give benzyl 4-(4-tert-butoxycarbonylcyclohexen-1-yl)-3,6-dihydro-2H-pyridine-1-carboxylate. LCMS: MS (ESI) M / Z: 420.1 [M+Na] +

[0863] Step C: tert-Butyl 4-(piperidin-4-yl)cyclohexanecarboxylate

[0864] To a solution of benzyl 4-(4-tert-butoxycarbonylcyclohexen-1-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (3.23 g, 8.13 mmol) in MeOH (120 mL) was added Pd / C (2.16 g, 10% purity). The resulting mixture was stirred at 70 °C under H2 atmosphere for 16 h. The reaction mixture was concentrated to dryness, and the crude product was used in the next step without further purification.

[0865] Step D: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(4-(4-(tert-butoxycarbonyl)cyclohexyl)piperidin-1-yl)prop-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylate

[0866] To a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-(3-chloroprop-1-ynyl)phenoxy]propyl]thiazole-4-carboxylate (24.58 mg) and tert-butyl 4-(piperidin-4-yl)cyclohexanecarboxylate (20 mg, 74.79 μmol) in DMF (0.2 mL) was added cesium carbonate (73.11 mg, 224.38 μmol). The resulting mixture was stirred at 25 °C under a N2 atmosphere for 16 h. The reaction mixture was filtered and the crude product was purified by HPLC (mobile phase: 0.05% NH3H2O - 10 mmol / l NH4HCO3 - ACN; column: YMC-Actus Triart C18, 150*20 mm, 5um; flow rate (ml / min): 20; gradient (%): 46.2 - 66.2; run time (min): 14; retention time (min): 8.7) to give methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[4-(tert-butoxycarbonylcyclohexyl)-1-piperidinyl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate. LCMS: MS(ESI) M / Z: 888.6 [M+H] +

[0867] Step E: 4-(1-(3-(4-(3-(2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)prop-2-yn-1-yl)piperidin-4-yl)cyclohexanecarboxylic acid

[0868] At 25 °C, a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[4-(tert-butoxycarbonylcyclohexyl)-1-piperidinyl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate (177 mg, 199.29 μmol) in FA (3 mL) was stirred for 16 h. The reaction mixture was concentrated under reduced pressure to give 4-[1-[3-[4-[3-[2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]prop-2-ynyl]-4-piperidinyl]cyclohexanecarboxylic acid, which was used in the next step without further purification. LCMS: MS(ESI) M / Z: 832.50 [M+H] +

[0869] Step F: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(4-(4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)cyclohexyl)piperidin-1-yl)prop-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylate

[0870] At 25 °C, a solution of 4-[1-[3-[4-[3-[2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]prop-2-ynyl]-4-piperidinyl]cyclohexanecarboxylic acid (165.82 mg), HATU (90.93 mg, 239.15 μmol), DIEA (77.27 mg, 597.88 μmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (85.81 mg, 199.29 μmol) in anhydrous DMF (2 mL) was stirred for 16 h. The crude reaction mixture was filtered and purified by HPLC (mobile phase: 0.1% TFA-ACN; column: preparative fluoro-phenyl column (Prep Fluoro-Phenyl), 150*19 mm, 5um; flow rate (ml / min): 20; gradient (%): 72.5 - 85.5; run time (min): 15; elution time (min): 7.5) to give methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[4-[4-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylaminocarbonyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]aminocarbonyl]cyclohexyl]-1-piperidinyl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate. LCMS: MS (ESI) M / Z: 1244.89 [M+H] +

[0871] Step G: 2-(8-(Benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(4-(4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)cyclohexyl)piperidin-1-yl)prop-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylic acid

[0872] To a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[4-[4-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-carbonyl]-2,2-dimethyl-propyl]carbamoyl]cyclohexyl]-1-piperidinyl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylate (19 mg, 15.27 μmol) in dioxane:H2O (240.00 μL) was added NaOH (6.11 mg, 152.66 μmol), and the resulting mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by HPLC (mobile phase: 0.1% TFA-ACN; column: X select CSH preparative fluorophenyl column, 150*19 mm, 5 μm; flow rate (ml / min): 20; gradient (%): 55.2 - 75.2; run time (min): 11; elution time (min): 8.2) to give 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[4-[4-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-carbonyl]-2,2-dimethyl-propyl]carbamoyl]cyclohexyl]-1-piperidinyl]prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid. 11H-NMR (400 MHz, CD3OD) δ 8.94 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.46 - 7.39 (m, 10H), 6.88 (d, J = 8.8 Hz, 2H), 4.97 (t, J = 15.3 Hz, 4H), 4.65 - 4.46 (m, 5H), 4.36 - 4.29 (m, 1H), 4.25 - 4.20 (m, 2H), 4.04 - 3.97 (m, 2H), 3.88 - 3.78 (m, 4H), 3.69 (d, J = 11.8 Hz, 1H), 3.13 - 3.02 (m, 4H), 2.47 (d, J = 3.0 Hz, 3H), 2.29 - 2.02 (m, 7H), 1.93 - 1.78 (m, 2H), 1.66 - 1.26 (m, 10H), 1.01 (d, J = 9.3 Hz, 9H). LCMS: MS (ESI) M / Z: 1230.70 [M + H] +

[0873] Example 30: Compound 30

[0874]

[0875] Step A: tert-Butyl 9-(methoxymethylene)-3-azaspiro[5.5]undecane-3-carboxylate

[0876] At 25 °C, t-BuOK (608.56 mg, 5.42 mmol) was added to a solution of (methoxymethyl)triphenylphosphonium chloride (1.67 g, 4.86 mmol) in THF (20 mL), and the mixture was stirred for 30 min. A solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1 g, 3.74 mmol) in THF (20 mL) was added dropwise. The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered and the filtrate was diluted with EtOAc (80 mL). The organic layer was washed with H2O (15 mL). The aqueous layer was extracted with EtOAc (80 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 9-(methoxymethylene)-3-azaspiro[5.5]undecane-3-carboxylate, which was used in the next step without further purification.

[0877] Step B: tert-Butyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate

[0878] To a solution of tert-butyl 9-(methoxymethylene)-3-azaspiro[5.5]undecane-3-carboxylate (1.1 g) in THF (15 mL) was added aqueous HCl solution (1 M, 11.17 mL) and the mixture was stirred at 25 °C for 16 h. The mixture was diluted with aqueous sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to afford the title compound, which was used in the next step without further purification.

[0879] Step C: tert-butyl 9-ethynyl-3-azaspiro[5.5]undecane-3-carboxylate

[0880] At room temperature, potassium carbonate (1.44 g, 10.45 mmol) was added to a solution of 1-diazo-1-dimethoxyphosphoryl-propan-2-one (1.00 g) in methanol (15 mL) and the mixture was stirred for 30 min. A solution of tert-butyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate (735 mg, 2.61 mmol) in methanol (15 mL) was added dropwise. The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was filtered and the filtrate was diluted with EtOAc (15 mL). The organic layer was washed with H2O (30 mL). The aqueous layer was extracted with EtOAc (15 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc = 10:1 to afford tert-butyl 9-ethynyl-3-azaspiro[5.5]undecane-3-carboxylate. 1 1H-NMR (400 MHz, CDCl3) δ 3.40 - 3.33 (m, 4H), 2.04 (d, J = 2.5 Hz, 1H), 1.78 - 1.39 (m, 18H), 1.38 - 1.14 (m, 5H)

[0881] Step D: methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate

[0882] To a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-(4-iodophenoxy)propyl]thiazole-4-carboxylate (300 mg, 422.18 μmol) and tert-butyl 9-ethynyl-3-azaspiro[5.5]undecane-3-carboxylate (175.67 mg, 633.26 μmol) in THF (10 mL) was added CuI (16.08 mg, 84.44 μmol), TEA (213.60 mg, 2.11 mmol, 293.41 μL) and bis(triphenylphosphine)palladium(II) chloride (148.16 mg, 211.09 μmol). The resulting mixture was stirred at 60 °C under N2 atmosphere for 3 h. The reaction mixture was concentrated to dryness and the residue was purified by preparative TLC (SiO2, DCM:MeOH = 25:1) to afford methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[2-(3-tert-butoxycarbonyl-3-azaspiro[5.5]undecan-9-yl)ethynyl]phenoxy]propyl]thiazole-4-carboxylate. LCMS: MS (ESI) m / z: 860.60 [M+H] +

[0883] Step E: Methyl 5-(3-(4-(3-azaspiro[5.5]undecan-9-ylethynyl)phenoxy)propyl)-2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate

[0884] At 28 °C, a solution of methyl 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[2-(3-tert-butoxycarbonyl-3-azaspiro[5.5]undecan-9-yl)ethynyl]phenoxy]propyl]thiazole-4-carboxylate (400 mg, 465.07 μmol) in FA (2 mL) was stirred for 1 h. The reaction mixture was concentrated to dryness to afford the title compound, which was used in the next step without further purification. LCMS MS [ESI] m / z: 760.4 [M+H] +

[0885] Step F: 2-(9-((4-(3-(2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-(methoxycarbonyl)thiazol-5-yl)propoxy)phenyl)ethynyl)-3-azaspiro[5.5]undecan-3-yl)acetic acid

[0886] To a solution of methyl 5-[3-[4-[2-(3-azaspiro[5.5]undecan-9-yl)ethynyl]phenoxy]propyl]-2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]thiazole-4-carboxylate (353 mg), glyoxylic acid monohydrate (85.51 mg, 928.98 μmol), and acetic acid (139.46 mg, 2.32 mmol) in DMF (3 mL) was added sodium cyanoborohydride (87.57 mg, 1.39 mmol) and the mixture was stirred at room temperature for 5 min. The mixture was diluted with EtOAc (30 mL). The organic layer was washed with H2O (30 mL). The aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was filtered and purified by HPLC (mobile phase: 0.1% TFA-ACN; column: YMC-Actus Triart C18, 150*20 mm, 5um; flow rate (ml / min): 20; gradient (%): 43.5 - 63.5; run time (min): 12; retention time (min): 9.5) to afford 2-[9-[2-[4-[3-[2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]ethynyl]-3-azaspiro[5.5]undecan-3-yl]acetic acid. LCMS: MS(ESI) M / Z: 818.4 [M+H] +

[0887] Step G: Methyl 2-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((3-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-3-azaspiro[5.5]undecan-9-yl)ethynyl)phenoxy)propyl)thiazole-4-carboxylate

[0888] At room temperature, a solution of 2-[9-[2-[4-[3-[2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-4-methoxycarbonyl-thiazol-5-yl]propoxy]phenyl]ethynyl]-3-aza...

Claims

1. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, having the structure of formula (I-A): Wherein, o is 0, 1, 2 or 3; Y is S or CH=CH; Each R 1 is independently selected from halogen, nitro, cyano, -OR 2 , -N(R 2 )2, -SR 2 , -S(O)R 2 , -S(O)2R 2 , -S(O)2N(R 2 )2, -NR 2 S(O)2R 2 , -NR 2 S(O)2N(R 2 )2, -C(O)R 2 , -C(O)OR 2 , -OC(O)R 2 , -OC(O)OR 2 , -OC(O)N(R 2 )2, -NR 2 C(O)R 2 , -NR 2 C(O)OR 2 , -NR 2 C(O)N(R 2 )2, -C(O)N(R 2 )2, -P(O)(OR 2 )2, -P(O)(R 2 )2, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 2-6 alkyl, in which 1 to 2 -CH2- units are replaced by N, O or S, provided that two adjacent -CH2- units are not replaced simultaneously, optionally substituted C 3-12 carbocyclic group and optionally substituted 3 - to 12 - membered heterocyclic group; Each R 2 is independently hydrogen or an optionally substituted C 1-6 alkyl; or Two Rs 2 Together with the nitrogen atom to which they are attached, they may form an optionally substituted 3- to 6-membered heterocyclic group ring; V is a bond, -C≡C-, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted C 3-7 cycloalkyl or an optionally substituted heterocyclic group; or Together form a fused bicyclic aryl ring or a fused bicyclic heteroaryl ring, each of which is substituted with o R 1 instances; L is selected from a) C2-C 15 alkylene, b) C 2-15 alkylene in which one or more -CH2- units are replaced by O, provided that two O atoms are not adjacent, and c) -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*; Wherein, Ak 1 Selected from -(CR 3 R 4 ) k -; Ak 2 Selected from -(CR 3 R 4 ) m -; Ak 3 Selected from -(CR 3 R 4 ) n -; each of k, m and n is from 0 to 6; Each R 3 and R 4 are independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl and C3 cycloalkyl; or R 3 and R 4 together form an oxo group; Z 1 and Z 2 are each independently selected from a bond, -O-, a heteroarylene group, and a cycloalkylene group; wherein at least one of 1 and Z 2 is a heteroarylene group or a cycloalkylene group; wherein the bonding point to U is indicated by an asterisk, and U is a recruitment motif selected from VHL ligands.

2. The compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to claim 1, wherein: Y is S.

3. The compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to claim 1, wherein: Y is CH=CH.

4. The compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 1-3, wherein: Each R 1 is independently selected from halogen, nitro, cyano, -OR 2 , -N(R 2 )2, -SR 2 , -S(O)R 2 , -S(O)2R 2 , -S(O)2N(R 2 )2, -NR 2 S(O)2R 2 , -NR 2 S(O)2N(R 2 )2, -C(O)R 2 , -C(O)OR 2 , -OC(O)R 2 , -OC(O)OR 2 , -OC(O)N(R 2 )2, -NR 2 C(O)R 2 , -NR 2 C(O)OR 2 , -NR 2 C(O)N(R 2 )2, -C(O)N(R 2 )2, -P(O)(OR 2 )2, -P(O)(R 2 )2, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 2-6 alkyl in which 1 to 2 -CH2- units are replaced by N, O or S, provided that two adjacent -CH2- units are not simultaneously replaced, optionally substituted C 3-12 carbocyclic group and optionally substituted 3 - to 12 - membered heterocyclic group, wherein the alkyl, haloalkyl, alkoxy, carbocyclic group and heterocyclic group are independently optionally substituted by one or more R e substituents; Each R 2 is independently hydrogen or an optionally substituted C 1-6 alkyl group, wherein said alkyl group is optionally substituted by one or more R e substituents; or Two Rs 2 Together with the nitrogen atom to which they are attached, may form an optionally substituted 3- to 6-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more Rs e substituted; Each R e is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; or Two Rs attached to the same atom e together form an oxo group; V is a bond, -C≡C-, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted C 3-7 cycloalkyl or an optionally substituted heterocyclic group, wherein the heteroaryl, aryl, cycloalkyl or heterocyclic group is optionally substituted by one or more R V substituents; or Together form a fused bicyclic aryl ring or a fused bicyclic heteroaryl ring, each of which is substituted with o R 1 Examples of; and Each R V is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; or Two Rs attached to the same atom of a cycloalkyl or heterocyclic group V together form an oxo group.

5. The compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 1-4, wherein: Each R 1 is independently selected from optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-3 alkoxy, halogen, -N(R 2 )2, -OR 2 and cyano, wherein said alkyl, haloalkyl and alkoxy are each independently optionally substituted with one or more R e substituents; and Each R e is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; or Two Rs attached to the same atom e together form an oxo group.

6. The compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 1-5, wherein: Each R 1 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

7. The compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 1-6, wherein: Each R 1 is independently selected from -F, -Cl, -CH3, -CH2CH3, and -CF3.

8. The compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 1-6, wherein: Each R 1 is independently selected from -Cl, -CH3, -CH2CH3, and -CF3.

9. The compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 1-8, wherein: o is 0 or 1.

10. The compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 1-9, wherein: L is C 4-15 an alkylene group.

11. The compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 1-10, wherein: L is C 4-9 an alkylene group.

12. The compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 1-11, wherein: L is C 5-8 an alkylene group.

13. The compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 1-9, wherein: L is C 2-15 an alkylene group in which one or more -CH2- units are replaced by O and having the structure –(CH2) x -O–(CH2) y -*, where: x is from 0 to 10; y is from 1 to 10; wherein the bonding point to the recruitment motif is indicated by an asterisk; and wherein the sum of x and y does not exceed 14.

14. The compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to claim 13, wherein: x is from 0 to 7; and y is from 1 to 7.

15. The compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to claim 13 or claim 14, wherein: x is from 0 to 6; and y is from 1 to 6.

16. A compound as claimed in any one of claims 1-9 or 11-15, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: L is C 2-15 an alkylene group in which one or more -CH2- units are replaced by O and having a structure selected from the following:

17. A compound as claimed in any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: L is C 4-15 an alkylene group in which one or more -CH2- units are replaced by O and which has the structure –(CH2) j —O–(CH2) p -O–(CH2) v -*, where: j is from 0 to 10; p is from 1 to 10; v is from 1 to 10; wherein the bonding point to the recruitment motif is indicated by an asterisk; and wherein the sum of j, p and v does not exceed 13.

18. A compound as claimed in claim 17, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: j is from 0 to 4; p is from 1 to 5; and v is from 1 to 4.

19. A compound as claimed in claim 17 or claim 18, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: j is from 0 to 2; p is from 2 to 4; and v is from 1 to 3.

20. A compound as claimed in any one of claims 1-9 or 15-19, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: L is C 4-15 an alkylene group in which one or more -CH2- units are replaced by O and having a structure selected from the following:

21. A compound as claimed in any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*, having a structure selected from the following: X, X1 and X2 are each independently CH or N; k is from 0 to 6; m is from 0 to 6; n is from 0 to 6; and wherein the bonding point to the VHL ligand is indicated by an asterisk.

22. A compound as claimed in claim 21, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: Each R 3 and R 4 are independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl and C3 cycloalkyl.

23. A compound as claimed in any one of claims 1-9, 21 or 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*, having a structure selected from the following: X, X1 and X2 are each independently CH or N; k is from 0 to 6; m is from 0 to 6; n is from 0 to 6; and wherein the bonding point to the VHL ligand is indicated by an asterisk.

24. A compound as claimed in any one of claims 1-9 or 21-23, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*, having a structure selected from the following: X, X1 and X2 are each independently CH or N; k is from 0 to 6; m is from 0 to 6; n is from 0 to 6; and wherein the bonding point to the VHL ligand is indicated by an asterisk.

25. A compound as claimed in any one of claims 21-24, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: k is from 0 to 3; m is from 0 to 3; and n is from 0 to 2.

26. A compound as claimed in any one of claims 1-9 or 21-25, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*, having a structure selected from the following: and wherein the bonding point to the VHL ligand is indicated by an asterisk.

27. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*, having a structure selected from the following: X1, X2, X3 and X4 are each independently CH or N; k is from 0 to 6; m is from 0 to 6; n is from 0 to 6; and wherein the bonding point to the VHL ligand is indicated by an asterisk.

28. The compound according to claim 27 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: Each R 3 and R 4 are independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-3 alkyl and C3 cycloalkyl.

29. The compound according to any one of claims 1-9, 27 or 28 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*, having a structure selected from the following: X1, X2, X3 and X4 are each independently CH or N; k is from 0 to 6; m is from 0 to 6; n is from 0 to 6; and wherein the bonding point to the VHL ligand is indicated by an asterisk.

30. The compound according to any one of claims 27-29 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: k is 0 or 1; m is 0 or 1; and n is from 0 to 2.

31. The compound according to any one of claims 1-9 or 27-30 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*, having a structure selected from the following: ； and wherein the bonding point to the VHL ligand is indicated by an asterisk.

32. The compound according to any one of claims 1-31 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: V is a bond.

33. The compound according to any one of claims 1-31 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: V is an optionally substituted heteroaryl.

34. The compound according to claim 33 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: The heteroaryl group is pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidinyl or pyridazinyl, each of which is optionally substituted with one or more R V substituted; and Each R V is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl and C1-C6 heteroalkyl.

35. The compound according to claim 33 or claim 34 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: The heteroaryl is Each R V is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; and wherein the asterisk indicates the point of attachment to L.

36. The compound according to any one of claims 33-35 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: The heteroaryl is and wherein the asterisk indicates the point of attachment to L.

37. The compound according to any one of claims 1-31 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: V is an optionally substituted aryl.

38. The compound according to claim 37 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: The aryl is optionally substituted phenyl having one or more R V substituents; and Each R V is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl.

39. The compound according to claim 37 or claim 38 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: The aryl group is Each R V is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl and C1-C6 heteroalkyl; and wherein the asterisk indicates the point of attachment to L.

40. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 37 - 39, wherein: The aryl group is and Wherein the asterisk indicates the point of attachment to L.

41. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 1 - 31, wherein: V is an optionally substituted C 3-7 cycloalkyl group.

42. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to claim 41, wherein: The said C 3-7 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionally substituted with one or more R V substituents; and Each R V is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; or two Rs attached to the same atom V together form an oxo group.

43. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to claim 41 or claim 42, wherein: The said C 3-7 The naphthenyl group is Each R V is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; or two Rs attached to the same atom V together form an oxo group; and Wherein the asterisk indicates the point of attachment to L.

44. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 41 - 43, wherein: The said C 3-7 The naphthenyl group is and Wherein the asterisk indicates the point of attachment to L.

45. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 1 - 31, wherein: V is an optionally substituted heterocyclic group.

46. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to claim 45, wherein: The heterocyclic group is pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl, each of which is optionally substituted by one or more R V substituted; and Each R V is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl and C1-C6 heteroalkyl; or Two Rs attached to the same atom V together form an oxo group.

47. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to claim 45 or claim 46, wherein: The heterocyclic group is Each R V is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; or Two Rs attached to the same atom V together form an oxo group; and Wherein the asterisk indicates the point of attachment to L.

48. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 45 - 47, wherein: The heterocyclic group is and Wherein the asterisk indicates the point of attachment to L.

49. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 1 - 31, wherein: V is -C≡C-.

50. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 1 - 31, wherein: together form a fused bicyclic aryl ring or a fused bicyclic heteroaryl ring, each of which is substituted with o R 1 instances of.

51. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to claim 50, wherein: Together form a fused bicyclic aryl ring substituted with o R 1 instances.

52. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to claim 51, wherein: The fused bicyclic aryl ring is naphthyl substituted with o R 1 instances.

53. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to claim 51 or claim 52, wherein: The fused bicyclic aryl ring is and Wherein the asterisk indicates the point of attachment to L.

54. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to any one of claims 51 - 53, wherein: The fused bicyclic aryl ring is Wherein the asterisk indicates the point of attachment to L.

55. A compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof according to claim 50, wherein: Together form a fused bicyclic heteroaryl ring substituted with o R 1 instances of.

56. The compound according to claim 55 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: The fused bicyclic heteroaryl ring is quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl or indolyl, each of which is substituted with o R 1 instances of which are substituted.

57. The compound according to claim 55 or claim 56 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: The fused bicyclic heteroaryl ring is and wherein the asterisk indicates the point of attachment to L.

58. The compound according to any one of claims 55-57 or a pharmaceutically acceptable 5 salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: The fused bicyclic heteroaryl ring is and wherein the asterisk indicates the point of attachment to L.

59. The compound according to any one of claims 1-58 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: U is selected from 60. The compound according to any one of claims 1-59 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: U is selected from 61. The compound according to any one of claims 1-60 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: U is selected from 62. The compound according to any one of claims 1-61 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: U is 63. The compound according to any one of claims 1-61 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: U is 64. The compound according to claim 1 or claim 4 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound has a structure listed in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6 or Table 7.

65. A pharmaceutical composition comprising the compound according to any one of claims 1-64 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof.

66. The compound according to any one of claims 1-64 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof or the pharmaceutical composition according to claim 65, for use in a method of treating a human or animal body.

67. The compound according to any one of claims 1-64 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof or the pharmaceutical composition according to claim 65, for use in a method of treating cancer or a neoplastic disease.

68. Use of the compound according to any one of claims 1-64 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof in the manufacture of a medicament for treating cancer or a neoplastic disease.

69. A method of treating cancer in a patient in need thereof, comprising administering to the patient the compound according to any one of claims 1-64 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof or the pharmaceutical composition according to claim 65.

70. A method for treating a disease caused by senescent cells in a patient in need thereof, comprising administering to the patient a compound according to any one of claims 1-64 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof or a pharmaceutical composition according to claim 65.

71. The method according to claim 70, wherein the disease caused by senescent cells is an eye disease.

72. The method according to claim 71, wherein the eye disease is age-related macular degeneration (AMD) or diabetic macular edema (DME).

73. A compound according to any one of claims 1-64 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof or a pharmaceutical composition according to claim 65, for use in a method for treating a disease caused by senescent cells.

74. The compound according to claim 73, wherein the disease caused by senescent cells is an eye disease.

75. The compound according to claim 74, wherein the eye disease is age-related macular degeneration (AMD) or diabetic macular edema (DME).

76. Use of a compound according to any one of claims 1-64 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof in the manufacture of a medicament for treating a disease caused by senescent cells.

77. The use according to claim 76, wherein the disease caused by senescent cells is an eye disease.

78. The use according to claim 77, wherein the eye disease is age-related macular degeneration (AMD) or diabetic macular edema (DME).

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