EGFR-targeted proteolysis targeting chimera compounds, composition thereof and use thereof

Abstract

The present invention relates to proteolysis targeting chimera compounds of formula (I) having degradation and / or inhibitory activity on EGFR comprising a mutation thereof, and also relates to a pharmaceutical composition comprising same, and a preparation method therefor and the use thereof.

Description

Targeting egfr protein degradation targeting chimera compounds and compositions and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, in particular to protein degradation targeting chimera compounds having degradation and / or inhibitory activity against EGFR mutants, to pharmaceutical compositions comprising them, and to methods of preparation and uses thereof. BACKGROUND

[0002] Epidermal Growth Factor Receptor (EGFR, ErbB-1 or HER1) is a member of the transmembrane protein tyrosine kinase ErbB receptor family. The family includes HER1 (ErbB1, EGFR), HER2 (ErbB2, NEU), HER3 (ErbB3) and HER4 (ErbB4), which play important regulatory roles in cell physiology. EGFR is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes and other cells, and the EGFR signaling pathway plays an important role in cell growth, proliferation and differentiation.

[0003] Disorders caused by overexpression or mutation of EGFR are associated with many types of human cancer, including prostate cancer, breast cancer, kidney cancer, colorectal cancer, pancreatic cancer, glioma, head and neck cancer and lung cancer, especially non-small cell lung cancer (NSCLC). Mutations of EGFR are mainly located in the kinase domain of exons 18-21: among them, exon 19 deletion (Del19) and exon 21 858 codon missense mutation (L858R) are the main ones, which are usually referred to as typical sensitive mutations of EGFR, accounting for about 80-90% of EGFR mutations in NSCLC; among other EGFR mutations, exon 20 T790M point mutation usually develops into acquired resistance mutation to first or second generation EGFR tyrosine kinase inhibitors, exon 20 insertion mutation (ex20ins) accounts for about 10% of lung adenocarcinoma, and exon 20 C797S point mutation is usually resistant to third generation EGFR tyrosine kinase inhibitors.

[0004] Currently, multiple EGFR tyrosine kinase inhibitors (TKIs) have been marketed for the treatment of various cancers, which can be divided into three generations. The first generation of EGFR TKIs is reversible inhibitors, including Gefitinib, Erlotinib and Icotinib, mainly for Del19 and L858R mutations; however, most patients will develop resistance after 10-12 months of treatment, and about 50% of patients develop resistance due to the secondary mutation of T790M. The second generation is represented by Afatinib and Dacomitinib, which are irreversible covalent inhibitors, effective for EGFR typical sensitive mutations (Del19, L858R) and "moderately sensitive" mutations (G719X, S768I, L861Q) and some rare mutations; however, it cannot completely solve the T790M mutation resistance problem, and due to the lack of selectivity for wild-type EGFR, the compound toxicity is larger. The third generation of EGFR TKIs simultaneously targets EGFR sensitive mutations (Del19, L858R) and T790M resistance mutations, and the representative drugs are Osimertinib, Almonertinib and Furmonertinib; however, new resistance will occur after 9-14 months of use, and the resistance mechanisms include 20 exon C797S (20-40%) or other EGFR-dependent gene mutations such as L718Q, L792F / H / Y and C797G / N. If it is a cis mutation (T790M and C797S are located on the same allele, accounting for about 85%), the EGFR inhibitor alone or in combination is ineffective, and such patients face the state of no drug available. If it is a trans mutation (T790M and C797S are located on different alleles), the first and third generation inhibitors can be used in combination, but after use, cis mutation is prone to occur, and still faces the state of no drug available.

[0005] Currently, there is no approved EGFR inhibitor available for single mutation or mutation combination containing C787S mutation (e.g., EGFR C797S, Del19 / T790M / C797S or L858R / T790M / C797S mutation), which highlights the medical need for new therapies targeting EGFR.

[0006] The protein degradation targeting chimera (PROTAC) technology is a technology that chemically induces polyubiquitination of a target protein (POI) and degrades the target protein through the ubiquitin-proteasome system (UPS). The PROTAC compound is a bifunctional molecule formed by connecting a target protein ligand and an E3 ubiquitin ligase ligand through a proper connecting chain, which can simultaneously recruit the target protein and the E3 ligase to induce ubiquitination and degradation of the target protein, and has a wide application prospect and development space. The EGFR-targeting PROTAC can be used as a potential strategy to overcome drug resistance mediated by these mutants.

[0007] It is still a challenging work to find new compounds for treating EGFR kinase mutant diseases and tumors resistant to available inhibitors. Therefore, there is still a need in the art to develop new EGFR PROTAC compounds to improve the clinical value. The present application provides such compounds.

[0008] SUMMARY

[0009] The present application provides a novel protein degradation targeting chimera compound, a composition comprising the compound, and a preparation method and use thereof. The compound has degradation and / or inhibition activity on EGFR including mutations (such as Del19, L858R, T790M, C797S, etc.) or combinations of mutations (such as a combination of two or three mutations selected from Del19, L858R, T790M and C797S), blood-brain barrier permeability, high selectivity and / or excellent pharmacokinetic properties, and can be used for treating diseases and / or conditions including those mediated by mutant EGFR and metastasis thereof (especially brain metastasis or central nervous system metastasis).

[0010] To this end, the present application adopts the following technical solutions:

[0011] In one aspect, the present application relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0012] wherein,

[0013] represents a single bond or a double bond;

[0014] X is C(O) or N;

[0015] Ring A is C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R;

[0016] Ring B is C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R;

[0017] R1is H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3- 6cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R;

[0018] R2and R3are each independently H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R;

[0019] R4is H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R;

[0020] R5and R6are each independently H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl, or R5and R6together with the C atom to which they are attached form a C 3-6 cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R;

[0021] L is -S0-(L1) i -S1-(L2) j -S2-(L3) k -S3-;

[0022] wherein, i is 0 or 1, j is 0 or 1, k is 0 or 1; with the proviso that at least one of i, j and k is not 0;

[0023] S0is a bond, -O-, -S-, -NR a -, -NR a (CR b R c ) p -, -(CR b R c ) p NR a -, -C(O)-, -C(O)NR a (CR b Rc ) p -, -(CR b R c ) p C(O)NR a -, -C(O)(CR b R c ) p -, -(CR b R c ) p C(O)-, -NR a C(O)(CR b R c ) p -, -(CR b R c ) p NR a C(O)-, -(CR b R c ) p - or -(CR b R c CR b R c O) q - ;

[0024] S1, S2and S3are each independently a bond, -O-, -S-, -NR a -, -NR a (CR b R c ) p -, -(CR b R c ) p NR a -, -C(O)-, -C(O)NR a -, -NR a C(O)-, -C(O)NR a (CR b R c ) p -, -(CR b R c ) p C(O)NR a -, -C(O)(CR b R c ) p -, -(CR b R c ) p C(O)-, -NR a C(O)(CR b R c ) p -, -(CRb R c ) p NR a C(O)-, -S(O)2-, -S(O)2NR a -, a S(O)2-, -S(O)2NR a (CR b R c ) p -, b R c ) p S(O)2NR a -, b R c ) p -, b R c ) p S(O)2-, a S(O)2(CR b R c ) p -, b R c ) p NR a S(O)2-, b R c ) p - or -(CR b R c CR b R c O) q -;

[0025] each L1, L2and L3is each independently a bivalent radical selected from 3-6 membered monocyclic carbocyclic ring, 4-7 membered monocyclic heterocyclic ring, 6-10 membered fused carbocyclic ring, 6-10 membered fused heterocyclic ring, 6-10 membered bridged carbocyclic ring, 6-10 membered bridged heterocyclic ring, 6-9 membered spiro carbocyclic ring or 6-9 membered spiro heterocyclic ring; wherein the above radicals are optionally substituted with one or more R’;

[0026] or, when S0is a bond and i is 1, ring A shares two adjacent ring atoms and one bond with L1;

[0027] each R a is each independently H or C 1-6 alkyl;

[0028] each R b and R c is each independently H, D, -OH, -CN, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0029] p is 1, 2, 3, or 4;

[0030] q is 1, 2, or 3;

[0031] each R and R' is independently D, -CN, -OH, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl;

[0032] U is selected from the following formulae (U A ), formula (U B ), formula (U C ), formula (U D ), formula (U E ), formula (U F ), formula (U G ), formula (U H ), formula (U J ), formula (U K ), formula (U L ), formula (U M ), formula (U N ), formula (U O ), formula (U P ):

[0033] wherein,

[0034] represents a single or double bond;

[0035] each V is independently a bond, C(O), NH, O, S, C(O)NH, C(O)NH, or CH2;

[0036] each W is independently a bond, C(O), NH, O, S, C(O)NH, C(O)NH, or CH2;

[0037] each Q1is independently C(O) or C(R9)2;

[0038] each Q2is independently N or CH;

[0039] each Q3and Q4is independently N or CR9;

[0040] each K1, K2, and K3is independently N or CR9;

[0041] K4and K5are each independently N or C;

[0042] H1is N, C, or CR9;

[0043] H2and H3are each independently C(O), N, O, S, NR9, CR9, or C(R9)2;

[0044] H4is N or CR9;

[0045] H5, H6, and H7are each independently C(O), O, S, NR9, or C(R9)2;

[0046] each R7is independently H or C 1-6 alkyl;

[0047] each R8is independently D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; or two R8together with the atom to which they are attached form a C 3-7 cycloalkane or 4-7 membered heterocyclic ring;

[0048] each R9is independently H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; or two R9together with the atom to which they are attached form a C 3-7 cycloalkane, 4- to 7-membered heterocyclic ring, C 6-10 aromatic hydrocarbon or 5- to 10-membered heteroaromatic hydrocarbon;

[0049] each o is independently 0, 1, or 2;

[0050] each h is independently 0, 1, 2, 3, or 4;

[0051] each z is independently 0, 1, or 2;

[0052] each r, s, t, and u is independently 0, 1, 2, 3, or 4.

[0053] In another aspect, the present application relates to a compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0054] wherein,

[0055] represents a single or double bond;

[0056] X is C(O) or N;

[0057] Ring A is C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R;

[0058] Ring B is C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R;

[0059] R1is H, halo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3- 6cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R;

[0060] R2and R3are each independently H, halo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R;

[0061] R4is H, halo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R;

[0062] R5and R6are each independently H, halo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl, or R5and R6together with the C atom to which they are attached form a C 3-6 cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R;

[0063] L is -S0-(L1) i -S1-(L2) j -S2-(L3) k -S3-;

[0064] wherein, i is 0 or 1, j is 0 or 1, k is 0 or 1; provided that at least one of i, j and k is not 0;

[0065] S0is a bond, -O-, -S-, -NR a -, -NR a (CR b R c ) p -, -(CR b R c ) pNR a - C(O)-, -C(O)NR a (CR b R c ) p -, -(CR b R c ) p C(O)NR a -, -C(O)(CR b R c ) p -, -(CR b R c ) p C(O)-, -NR a C(O)(CR b R c ) p -, -(CR b R c ) p NR a C(O)-, -(CR b R c ) p - or -(CR b R c CR b R c O) q - ;

[0066] S1, S2and S3are each independently a bond, -O-, -S-, -NR a -, -NR a (CR b R c ) p -, -(CR b R c ) p NR a -, -C(O)-, -C(O)NR a -, -NR a C(O)-, -C(O)NR a (CR b R c ) p -, -(CR b R c ) p C(O)NR a -, -C(O)(CR b R c ) p -, -(CR b R c ) p C(O)-, -NRa C(O)(CR b R c ) p -,-(CR b R c ) p NR a C(O)-, -S(O)2-, -S(O)2NR a -,-NR a S(O)2-,-S(O)2NR a (CR b R c ) p -,-(CR b R c ) p S(O)2NR a -,-S(O)2(CR b R c ) p -,-(CR b R c ) p S(O)2-, -NR a S(O)2(CR b R c ) p -,-(CR b R c ) p NR a S(O)2-, -(CR b R c ) p -or-(CR) b R c CR b R c O) q -;

[0067] Each L1, L2, and L3 is independently a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocycles, 6-10 membered fused carbon rings, 6-10 membered fused heterocycles, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocycles, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R'.

[0068] Alternatively, when S0 is a chemical bond and i is 1, ring A and L1 share two adjacent ring atoms and one chemical bond;

[0069] Each R a Each independently is H or C 1-6 alkyl;

[0070] Each R b and Rc Each can be independently H, D, -OH, -CN, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0071] p is 1, 2, 3 or 4;

[0072] q is 1, 2, or 3;

[0073] Each R and R' is independently D, -CN, -OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups;

[0074] U is selected from the following formula (U) A ), formula (U B ), formula (U C ), formula (U D ), formula (U E ), formula (U F ), formula (U G ), formula (U H ) or formula (U J ):

[0075] in,

[0076] Indicates a single bond or a double bond;

[0077] Each V is an independent chemical bond, C(O), NH, O, S, C(O)NH, C(O)NH or CH2;

[0078] Each W is independently a chemical bond, C(O), NH, O, S, C(O)NH, C(O)NH or CH2;

[0079] Each Q1 is independently C(O) or C(R9)2;

[0080] Each Q2 is independently either N or CH;

[0081] Each Q3 and Q4 is independently either N or CR9;

[0082] Each of K1, K2 and K3 is independently either N or CR9;

[0083] K4 and K5 are each independently N or C;

[0084] H1 is N, C, or CR9;

[0085] H2and H3are each independently C(O), N, O, S, NR9, CR9, or C(R9)2;

[0086] each R7is independently H or C 1-6 alkyl;

[0087] each R8is independently D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R8together with the atoms to which they are attached form a C 3-7 cycloalkane or 4-7 membered heterocyclic ring;

[0088] each R9is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R9together with the atoms to which they are attached form a C 3-7 cycloalkane, 4- to 7- membered heterocyclic ring, C 6-10 arene or 5- to 10- membered heteroarene;

[0089] each o is independently 0, 1, or 2;

[0090] each h is independently 0, 1, 2, 3, or 4.

[0091] In certain embodiments, the compounds of the present application have at least one atom required to be substituted with the isotope D in an amount greater than the natural abundance of the isotope, i.e., enriched.

[0092] In certain embodiments, the compounds of the present application include one deuterium atom or multiple deuterium atoms. In specific embodiments, the deuterium isotope content at the deuterium substituted position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 99%.

[0093] In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present application or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable excipient. In specific embodiments, the present application is provided in an effective amount in the pharmaceutical composition. In specific embodiments, the compound of the present application is provided in a therapeutically effective amount. In specific embodiments, the compound of the present application is provided in a prophylactically effective amount.

[0094] In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present application or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable excipient. In a specific embodiment, the pharmaceutical composition further comprises another therapeutic agent. In a specific embodiment, the other therapeutic agent is another EGFR inhibitor, an EGFR antibody, a c-MET inhibitor, an immune checkpoint inhibitor, a RAF inhibitor, an ALK inhibitor, or a MEK inhibitor. In a specific embodiment, the other EGFR inhibitor is gefitinib, erlotinib, icotinib, afatinib, dacomitinib, neratinib, osimertinib, lazertinib, amuvatinib, or futibatinib. In a specific embodiment, the EGFR antibody is cetuximab, panitumumab, or necitumumab. In a specific embodiment, the c-MET inhibitor is capmatinib, tepotinib, cabozantinib, or savolitinib. In a specific embodiment, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, atezolizumab, durvalumab, ipilimumab, or tremelimumab. In a specific embodiment, the RAF inhibitor is sorafenib, vemurafenib, dabrafenib, or encorafenib. In a specific embodiment, the ALK inhibitor is crizotinib, ceritinib, alectinib, brigatinib, entrectinib, lorlatinib, or irlotukimab. In a specific embodiment, the MEK inhibitor is trametinib, selumetinib, or refametinib.

[0095] In another aspect, the present application provides a method of treating a mutant EGFR-mediated disease, comprising administering to a subject an effective amount of a compound of the present application or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a composition of the present application.

[0096] In another aspect, the present application provides a compound of the present application or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a composition of the present application, for use in the treatment of a mutant EGFR-mediated disease.

[0097] In another aspect, the present application provides the use of a compound of the present application or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a composition of the present application, in the manufacture of a medicament for the treatment of a mutant EGFR-mediated disease.

[0098] In another aspect, the present application provides the use of a compound of the present application or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a composition of the present application, in the treatment of a subject having a mutant EGFR-mediated disease.

[0099] In specific embodiments, the mutant EGFR is non-limitingly present in exon 18, exon 19, exon 20, or exon 21, or any combination thereof. In more specific embodiments, the mutant EGFR is non-limitingly selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L858R, or L861Q, or any combination thereof. In more specific embodiments, the mutant EGFR is Del19, L858R, T790M, C797S, L718Q, L792H, or L861Q, or any combination thereof. In more specific embodiments, the mutant EGFR is G119A, R531Q, V948R, or I941R. In more specific embodiments, the mutant EGFR comprises a combination mutation, wherein the combination comprises two mutations, three mutations, four mutations, or more mutations, which can optionally be selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R, or I941R.

[0100] In more specific embodiments, the mutant EGFR is L858R and one additional mutation, which can optionally be selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L861Q, G119A, R531Q, V948R, or I941R.

[0101] In more specific embodiments, the mutant EGFR is L858R and two additional mutations, which can optionally be selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L861Q, G119A, R531Q, V948R, or I941R.

[0102] In more specific embodiments, the mutant EGFR is a L858R mutation.

[0103] In more specific embodiments, the mutant EGFR is a T790M mutation.

[0104] In more specific embodiments, the mutant EGFR is a C797S mutation.

[0105] In more specific embodiments, the mutant EGFR is a L718Q mutation.

[0106] In more specific embodiments, the mutant EGFR is a L792H mutation.

[0107] In more specific embodiments, the mutant EGFR is a L861Q mutation.

[0108] In more specific embodiments, the mutant EGFR is a L858R / T790M double mutation.

[0109] In more specific embodiments, the mutant EGFR is a L858R / C797S double mutation.

[0110] In more specific embodiments, the mutant EGFR is a L858R / T790M / C797S triple mutation.

[0111] In particular embodiments, the mutant EGFR-mediated disease is cancer. In particular embodiments, the mutant EGFR-mediated disease is brain metastasis or central nervous system (CNS) metastasis. In more particular embodiments, the mutant EGFR-mediated disease is lung cancer, brain cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, colon cancer, rectal cancer, breast cancer, head and neck cancer, glioblastoma, pancreatic cancer, thyroid cancer, astrocytoma, esophageal cancer, uterine cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urothelial cancer, kidney cancer, stomach cancer, sarcoma, melanoma, endometrial cancer, testicular cancer, pancreatic cancer, prostate cancer, mesothelioma, and metastasis thereof, especially brain metastasis or CNS metastasis. In more particular embodiments, the mutant EGFR-mediated disease is lung cancer and metastasis thereof, especially brain metastasis or CNS metastasis. In more particular embodiments, the mutant EGFR-mediated disease is non-small cell lung cancer and metastasis thereof, especially brain metastasis or CNS metastasis.

[0112] Other objects and advantages of the application will become apparent to those skilled in the art from the subsequent detailed description, examples, and claims.

[0113] Definitions

[0114] Chemical Definitions

[0115] The definitions of specific functional groups and chemical terms are described in more detail below.

[0116] When a range of values is listed, it is intended to include each value and sub-range within the range. For example, "C 1-6 "alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl groups.

[0117] "C 1-6 alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group having from 1 to 6 carbon atoms, also referred to herein as "lower alkyl." In some embodiments, C 1-4 alkyl and C 1-3Alkyl is particularly preferred. Examples of alkyl groups include, but are not limited to, methyl (Ci), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), t-butyl (C4), sec-butyl (C4), i-butyl (C4), n-pentyl (C5), 3-pentyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), t-amyl (C5), and n-hexyl (C6). Each of the alkyl groups is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with the proviso that the alkyl is not modified as "substituted" unless otherwise indicated, with appropriate substituents as defined below.

[0118] "C 1-6 Alkylidene refers to =CRR, where R is H or C 1-5 Alkyl.

[0119] "C 2-6 Alkenyl refers to a straight or branched chain hydrocarbon group having from 2 to 6 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). In some embodiments, C 2-4 Alkenyl is particularly preferred. Examples of alkenyl groups include, but are not limited to, ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1 -butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Each of the alkenyl groups is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with the proviso that the alkenyl is not modified as "substituted" unless otherwise indicated, with appropriate substituents as defined below.

[0120] "C 2-6 Alkynyl refers to a straight or branched chain hydrocarbon group having from 2 to 6 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). In some embodiments, C 2-4 Alkynyl is particularly preferred. In some embodiments, the alkynyl group does not contain any double bonds. The one or more carbon triple bonds can be internal (e.g., in 2-butylynyl) or terminal (e.g., in 1-butylynyl). Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1 -propynyl (C3), 2-propynyl (C3), 1 -butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. Each of the alkynyl groups is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with the proviso that the alkynyl is not modified as "substituted" unless otherwise indicated, with appropriate substituents as defined below.

[0121] "C 1-6 "Aloxy" refers to the radical -OR, where R is a substituted or unsubstituted C 1-6 alkyl group. In some embodiments, C 1-4 alkoxy and C 1-3 alkoxy groups are particularly preferred. Specific examples of said alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0122] "Halo" or "halogen" refers to fluoro (F), chloro (CI), bromo (Br), and iodo (I). In some embodiments, the halo group is F, CI, or Br. In some embodiments, the halo group is F or CI. In some embodiments, the halo group is F.

[0123] Thus, "C 1-6 "Haloalkyl" and "C 1-6 haloalkoxy" refers to the above "C 1-6 alkyl" and "C 1-6 alkoxy" groups substituted with one or more halo groups. In some embodiments, C 1-4 haloalkyl groups are particularly preferred, more preferably C 1- 3haloalkyl and C 1-2 haloalkyl groups. In some embodiments, C 1-4 haloalkoxy groups are particularly preferred, more preferably C 1-3 haloalkoxy and C 1-2 haloalkoxy groups. Exemplary said haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CC13, -CH2CI, -CHC12, 2,2,2-trifluoro-l,l-dimethyl-ethyl, and the like. Exemplary said haloalkoxy groups include, but are not limited to: -OCH2F, -OCHF2, -OCF3, and the like.

[0124] "C 1-6 "Alkylene," "C 1-6 "Aloalkylene" and "C 1-6 "Aloalkylene" and "C 1-6 alkyl, C 1-6 alkenyl, and C 1-6 alkynyl groups. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-2 alkylene groups are preferred. In some embodiments, C 2-4 alkylene and C2alkenylene groups are preferred. In some embodiments, C2-4 Alkyneyl groups and C2 alkyneyl groups are preferred. Examples of the alkylene groups include, but are not limited to: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, and -CH2C(CH3). 2- Examples of the alkenyl group include, but are not limited to: -CH=CH-, -CH=CH-CH2-, -CH=C(CH3)-CH2-, -CH=CH-CH(CH3)-, -CH=CH-CH2-CH2-, -CH2-CH=CH-CH2-, and -CH2-CH=C(CH3)-CH2-. Examples of the alkyne group include, but are not limited to: -C≡C-, -C≡C-CH2-, -C≡C-CH(CH3)-, -C≡C-CH2-CH2-, -CH2-C≡C-CH2-, and -CH2-C≡C-CH(CH3)-. Regardless of whether the alkylene, alkenyl, and alkyne groups are modified with "substituted", each of the alkylene, alkenyl, and alkyne groups is optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0125] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-8 Cycloalkyl groups are preferred, C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-6 Cycloalkyl. Cycloalkyl can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic can be fused, spirocyclic, bridged, or a combination thereof. Bicyclic or polycyclic may include one or more aromatic rings, but the ring system as a whole is not aromatic, and in such cases, the number of carbons continues to indicate the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), bicyclo[1.1.1]pentyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), bicyclo[2.1.1]hexyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), etc. 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10), spiro[4.5]decyl (C 10 Each of the cycloalkyl groups, whether or not modified by "substituted," is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents being defined below.

[0126] "3-10 membered heterocyclyl" refers to a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. In some embodiments, 4-10 membered heterocyclyl is preferred, which is a 4- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, 3-7 membered heterocyclyl is preferred, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 3-6 membered heterocyclyl is particularly preferred, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably 5-6 membered heterocyclyl, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. The heterocyclyl group can be monocyclic, bicyclic, or polycyclic. The bicyclic or polycyclic can be fused, spiro, bridged, or a combination thereof, and can include one or more aromatic or heteroaromatic rings in the bicyclic or polycyclic ring system, but the overall ring system is non-aromatic; and in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Each of the heterocyclyl groups, whether or not modified by "substituted," is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents being defined below.

[0127] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, hexahydrotriazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0128] “C 6-14 Aryl” means a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthryl). In some embodiments, the aryl group has twelve ring carbon atoms (“C12aryl”; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). 10 Aryl” means a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthryl). In some embodiments, the aryl group has twelve ring carbon atoms (“C12aryl”; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). 14 Aryl” means a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthryl). In some embodiments, the aryl group has twelve ring carbon atoms (“C12aryl”; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). 6-10Aryl is particularly preferred, more preferably C6 aryl. Aryl also includes ring systems in which the above aryl ring is fused to one or more cycloalkyl or heterocyclyl rings, with the point of attachment being on the aryl ring, in which case the number of carbon atoms designates the number of carbon atoms in the aryl ring system. Each aryl group is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as defined below, whether or not modified by "substituted."

[0129] "5-10 membered heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl rings, with the point of attachment being on the heteroaryl ring, in which case the number of carbon atoms designates the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6 membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5 membered heteroaryl is particularly preferred, which is a 5 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Each heteroaryl group is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as defined below, whether or not modified by "substituted."

[0130] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0131] "Fused ring" means a polycyclic group in which rings share adjacent ring atoms and a chemical bond, and can contain one or more double or triple bonds, and can contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and oxidation states thereof. Typically, a fused ring is a 5-20 membered ring, or a 5-14 membered ring, or a 5-12 membered ring, or a 6-12 membered ring, or a 5-10 membered ring, or a 6-10 membered ring. Each of the fused rings is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate, with suitable substituents defined below, whether or not preceded by the term "substituted."

[0132] "Spirocycle" means a polycyclic group in which rings share a single carbon atom (termed a spiro atom), and can contain 0 or 1 double or triple bonds, and can contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and oxidation states thereof. Typically, a spirocycle is a 6-14 membered ring, or a 6-12 membered ring, or a 6-10 membered ring. Each of the spirocycles is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate, with suitable substituents defined below, whether or not preceded by the term "substituted."

[0133] "Bicyclic ring" means two rings sharing two non-adjacent ring atoms, can contain one or more double or triple bonds, can contain 0 to 5 heteroatoms selected from N, S, O, P, Si and oxidation states thereof. Typically bicyclic rings are 5-20 membered rings, or 5-14 membered rings, or 5-12 membered rings, or 6-12 membered rings, or 5-10 membered rings, or 6-10 membered rings. Each of the bicyclic rings is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below, whether or not modified by "substituted."

[0134] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb)2、-C(=O)NR bb SO2R aa -NR bb SO2R aa -SO2N(R) bb )2、-SO2R aa -SO2OR aa -OSO2R aa -S(=O)R aa -OS(=O)R aa 、-Si(R aa 3. -OSi(R) aa 3. -C(=S)N(R) bb )2、-C(=O)SR aa -C(=S)SR aa -SC(=S)SR aa -SC(=O)SR aa -OC(=O)SR aa -SC(=O)OR aa -SC(=O)R aa -P(=O)2R aa -OP(=O)2R aa -P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0135] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace;

[0136] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0137] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. ddGroup substitution;

[0138] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R groups. cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0139] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2Ree -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee 3. -OSi(R) ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0140] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0141] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R groups. ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0142] R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1- 6-alkyl), -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6Alkyl)3, -C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1- 6-alkyl, -SC(=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 carbocyclic, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0143] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. ccThe groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0144] "Deuterated" or "D" refers to the substitution of one or more hydrogen atoms in a compound or group by deuterium; deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted. The terms "one or more deuterated" and "one or more deuterated" are used interchangeably.

[0145] "Non-deuterated compounds" refer to compounds containing a deuterium atom ratio no higher than the natural deuterium isotope content (0.015%).

[0146] The content of deuterium isotopes at the deuterated position is at least 0.015% greater than the content of natural deuterium isotopes, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, and more preferably greater than 99%.

[0147] The term "pharmaceutically acceptable salt" refers to those salts that, within the bounds of reliable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Salts formed using methods conventional in the art are also included, such as ion exchange methods. Other pharmaceutically acceptable salts include: adipic acid salts, alginate salts, ascorbate salts, aspartate salts, benzenesulfonate salts, benzoate salts, bisulfate salts, borate salts, butyrate salts, camphorate salts, camphor sulfonate salts, citrate salts, cyclopentylpropionate salts, diglucuronate salts, dodecyl sulfate salts, ethanesulfonate salts, formate salts, fumarate salts, gluconate salts, glyceryl phosphate salts, glucuronate salts, hemisulfate salts, heptarate salts, hexanoate salts, hydroiodate salts, 2-hydroxy-ethanesulfonate salts, lactobionate salts, lactate salts, laurate salts, lauryl sulfate salts, malate salts, maleate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, oxalate salts, palmitate salts, dihydroxynaphthalate salts, pectin ester salts, persulfate salts, 3-phenylpropionate salts, phosphate salts, picrate salts, p-pentanoate salts, propionate salts, stearate salts, succinate salts, sulfate salts, tartrate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts, if appropriate, include non-toxic ammonium salts, quaternary ammonium salts, and amine cations that form with counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonates, and aryl sulfonates.

[0148] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0149] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0150] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0151] The term "combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, the compounds of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously with another therapeutic agent in a single unit dosage form. Detailed Implementation

[0152] compound

[0153] In this document, “compound of the present invention” refers to a compound of formula (I) (including subsets thereof), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0154] This invention provides compounds that specifically degrade mutant EGFR through targeted ubiquitination of the EGFR protein and subsequent proteasome degradation. The compounds of this invention bind to the universally expressed E3 ligase protein cereblon (CRBN) and alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, thereby leading to the recruitment and ubiquitination of mutant EGFR (specifically, for example, the EGFR L858R mutation, the L858R / T790M double mutation, and the L858R / T790M / C797S triple mutation).

[0155] The present invention provides compounds having the activity of inhibiting mutant EGFRs, wherein the mutant EGFRs are, for example, L858R mutation, T790M mutation, C797S mutation, L858R / T790M double mutation, L858R / C797S double mutation, T790M / C797S double mutation, or L858R / T790M / C797S triple mutation.

[0156] This invention provides compounds that selectively degrade EGFR (e.g., EGFR L858R mutation, L858R / T790M double mutation, and L858R / T790M / C797S triple mutation) in tumors that have metastasized to the brain or CNS and may have mutations or combinations of mutations.

[0157] In one embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0158] in,

[0159] Indicates a single bond or a double bond;

[0160] X is C(O) or N;

[0161] Ring A is C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally substituted by one or more R;

[0162] Ring B is C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally substituted by one or more R;

[0163] R1 is H, a halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3- A 6-cycloalkyl or 4-7-membered heterocyclic group; wherein the above groups are optionally substituted by one or more R;

[0164] R2 and R3 are each independently H, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1- 6-Haloalkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups; wherein the above groups are optionally substituted by one or more R;

[0165] R4 is H, a halogen, -CN, C 1-6 Alkyl, C 1-6Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups; wherein the above groups are optionally substituted by one or more R;

[0166] R5 and R6 are each independently H, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or R5 and R6 together with the C atoms they are attached to form C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups; wherein the above groups are optionally substituted by one or more R;

[0167] L is -S0-(L1) i -S1-(L2) j -S2-(L3) k -S3-;

[0168] Where i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0;

[0169] S0 is a chemical bond, -O-, -S-, -NR a -,-NR a (CR b R c ) p -,-(CR b R c ) p NR a -,-C(O)-,-C(O)NR a (CR b R c ) p -,-(CR b R c ) p C(O)NR a -,-C(O)(CR b R c ) p -,-(CR b R c ) p C(O)-, -NR a C(O)(CR b R c ) p -,-(CR b R c ) p NR a C(O)-, -(CR) b R c ) p -or-(CR)b R c CR b R c O) q -;

[0170] S1, S2 and S3 are each independently a chemical bond, -O-, -S-, -NR a -, -NR a (CR b R c ) p -, -(CR b R c ) p NR a -, -C(O)-, -C(O)NR a -, -NR a C(O)-, -C(O)NR a (CR b R c ) p -, -(CR b R c ) p C(O)NR a -, -C(O)(CR b R c ) p -, -(CR b R c ) p C(O)-, -NR a C(O)(CR b R c ) p -, -(CR b R c ) p NR a C(O)-, -S(O)2-, -S(O)2NR a -, -NR a S(O)2-, -S(O)2NR a (CR b R c ) p -, -(CR b R c ) p S(O)2NR a -, -S(O)2(CR b R c ) p -, -(CR b R c ) p S(O)2-, -NR a S(O)2(CRb R c ) p -,-(CR b R c ) p NR a S(O)2-, -(CR b R c ) p -or-(CR) b R c CR b R c O) q -;

[0171] Each L1, L2, and L3 is independently a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocycles, 6-10 membered fused carbon rings, 6-10 membered fused heterocycles, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocycles, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R'.

[0172] Alternatively, when S0 is a chemical bond and i is 1, ring A and L1 share two adjacent ring atoms and one chemical bond;

[0173] Each R a Each independently is H or C 1-6 alkyl;

[0174] Each R b and R c Each can be independently H, D, -OH, -CN, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0175] p is 1, 2, 3 or 4;

[0176] q is 1, 2, or 3;

[0177] Each R and R' is independently D, -CN, -OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups;

[0178] U is selected from the following formula (U) A ), formula (U B ), formula (U C ), formula (U D ), formula (U E ), formula (U F ), formula (U G), formula (U H ), formula (U J ), formula (U K ), formula (U L ), formula (U M ), formula (U N ), formula (U O ) and formula (U P ):

[0179] in,

[0180] Indicates a single bond or a double bond;

[0181] Each V is an independent chemical bond, C(O), NH, O, S, C(O)NH, C(O)NH or CH2;

[0182] Each W is independently a chemical bond, C(O), NH, O, S, C(O)NH, C(O)NH or CH2;

[0183] Each Q1 is independently C(O) or C(R9)2;

[0184] Each Q2 is independently either N or CH;

[0185] Each Q3 and Q4 is independently either N or CR9;

[0186] Each of K1, K2 and K3 is independently either N or CR9;

[0187] K4 and K5 are each independently N or C;

[0188] H1 is N, C, or CR9;

[0189] H2 and H3 are each independently C(O), N, O, S, NR9, CR9 or C(R9)2;

[0190] H4 is either N or CR9;

[0191] H5, H6 and H7 are each independently C(O), O, S, NR9 or C(R9)2;

[0192] Each R7 is independently either H or C. 1-6 alkyl;

[0193] Each R8 is independently D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R8 atoms together with the atoms they are attached to form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0194] Each R9 is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R9s together with the atoms they are attached to form C. 3-7 Cycloalkanes, 4- to 7-membered heterocycles, C 6-10 Aromatic hydrocarbons or 5- to 10-membered heteroaromatic hydrocarbons;

[0195] Each 'o' can be 0, 1, or 2 independently;

[0196] Each h can be independently 0, 1, 2, 3 or 4;

[0197] Each z can be 0, 1, or 2 independently;

[0198] Each r, s, t, and u is independently 0, 1, 2, 3, or 4.

[0199] In another embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0200] in,

[0201] Indicates a single bond or a double bond;

[0202] X is C(O) or N;

[0203] Ring A is C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally substituted by one or more R;

[0204] Ring B is C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally substituted by one or more R;

[0205] R1 is H, a halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3- A 6-cycloalkyl or 4-7-membered heterocyclic group; wherein the above groups are optionally substituted by one or more R;

[0206] R2 and R3 are each independently H, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1- 6-Haloalkoxy, C 3-6Cycloalkyl or 4-7 membered heterocyclic groups; wherein the above groups are optionally substituted by one or more R;

[0207] R4 is H, a halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups; wherein the above groups are optionally substituted by one or more R;

[0208] R5 and R6 are each independently H, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or R5 and R6 together with the C atoms they are attached to form C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups; wherein the above groups are optionally substituted by one or more R;

[0209] L is -S0-(L1) i -S1-(L2) j -S2-(L3) k -S3-;

[0210] Where i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0;

[0211] S0 is a chemical bond, -O-, -S-, -NR a -,-NR a (CR b R c ) p -,-(CR b R c ) p NR a -,-C(O)-,-C(O)NR a (CR b R c ) p -,-(CR b R c ) p C(O)NR a -,-C(O)(CR b R c ) p -,-(CR b R c ) p C(O)-, -NR a C(O)(CR b R c ) p -,-(CR b Rc ) p NR a C(O)-, -(CR b R c ) p - or -(CR b R c CR b R c O) q -;

[0212] S1, S2 and S3 are each independently a chemical bond, -O-, -S-, -NR a -, -NR a (CR b R c ) p -, -(CR b R c ) p NR a -, -C(O)-, -C(O)NR a -, -NR a C(O)-, -C(O)NR a (CR b R c ) p -, -(CR b R c ) p C(O)NR a -, -C(O)(CR b R c ) p -, -(CR b R c ) p C(O)-, -NR a C(O)(CR b R c ) p -, -(CR b R c ) p NR a C(O)-, -S(O)2-, -S(O)2NR a -, -NR a S(O)2-, -S(O)2NR a (CR b R c ) p -, -(CR b R c ) p S(O)2NR a -, -S(O)2(CR b Rc ) p -,-(CR b R c ) p S(O)2-, -NR a S(O)2(CR b R c ) p -,-(CR b R c ) p NR a S(O)2-, -(CR b R c ) p -or-(CR) b R c CR b R c O) q -;

[0213] Each L1, L2, and L3 is independently a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocycles, 6-10 membered fused carbon rings, 6-10 membered fused heterocycles, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocycles, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R'.

[0214] Alternatively, when S0 is a chemical bond and i is 1, ring A and L1 share two adjacent ring atoms and one chemical bond;

[0215] Each R a Each independently is H or C 1-6 alkyl;

[0216] Each R b and R c Each can be independently H, D, -OH, -CN, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0217] p is 1, 2, 3 or 4;

[0218] q is 1, 2, or 3;

[0219] Each R and R' is independently D, -CN, -OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups;

[0220] U is selected from the following formula (U) A ), formula (UB ), formula (U C ), formula (U D ), formula (U E ), formula (U F ), formula (U G ), formula (U H ) or formula (U J ):

[0221] in,

[0222] Indicates a single bond or a double bond;

[0223] Each V is an independent chemical bond, C(O), NH, O, S, C(O)NH, C(O)NH or CH2;

[0224] Each W is independently a chemical bond, C(O), NH, O, S, C(O)NH, C(O)NH or CH2;

[0225] Each Q1 is independently C(O) or C(R9)2;

[0226] Each Q2 is independently either N or CH;

[0227] Each Q3 and Q4 is independently either N or CR9;

[0228] Each of K1, K2 and K3 is independently either N or CR9;

[0229] K4 and K5 are each independently N or C;

[0230] H1 is N, C, or CR9;

[0231] H2 and H3 are each independently C(O), N, O, S, NR9, CR9 or C(R9)2;

[0232] Each R7 is independently either H or C. 1-6 alkyl;

[0233] Each R8 is independently D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R8 atoms together with the atoms they are attached to form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0234] Each R9 is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R9s together with the atoms they are attached to form C. 3-7Cycloalkanes, 4- to 7-membered heterocycles, C 6-10 Aromatic hydrocarbons or 5- to 10-membered heteroaromatic hydrocarbons;

[0235] Each 'o' can be 0, 1, or 2 independently;

[0236] Each h can be independently 0, 1, 2, 3, or 4.

[0237] In another embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein ring A is phenyl or a 5-6 membered heteroaryl group.

[0238] In another embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein ring A is phenyl or a 6-membered heteroaryl group.

[0239] In one embodiment of ring A, ring A is a phenyl group.

[0240] In another embodiment of ring A, ring A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0241] In another embodiment of ring A, ring A is pyridyl.

[0242] In another embodiment of ring A, ring A is a pyrimidinyl group.

[0243] In another embodiment of ring A, ring A is pyrazinyl.

[0244] In another embodiment of ring A, ring A is pyridazine-based.

[0245] In another embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein ring B is a 5-6 membered heteroaryl group.

[0246] In one embodiment of cycloB, cycloB is a 5-membered heteroaryl group.

[0247] In another embodiment of ring B, ring B is a thiazolyl, pyrazolyl, or imidazolel group.

[0248] In another embodiment of ring B, ring B is a thiazolyl group.

[0249] In another embodiment of ring B, ring B is a pyrazolyl group.

[0250] In another embodiment of ring B, ring B is an imidazole group.

[0251] In another embodiment of cycloB, cycloB is a 6-membered heteroaryl group.

[0252] In another embodiment of ring B, ring B is pyridinyl or pyrimidinyl.

[0253] In another embodiment of ring B, ring B is pyridyl.

[0254] In another embodiment of cyclic B, cyclic B is a pyrimidinyl group.

[0255] In another embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of formula (II) or (III):

[0256] Where Y is CH or N, and R1, R2, R3, R4, R5, R6, L and U are as defined above.

[0257] In another embodiment, the present invention relates to compounds of formula (I), formula (II) or formula (III), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, which are compounds of formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII):

[0258] Where Y is CH or N, and R4, R5, R6, L and U are as defined above.

[0259] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R4 is H or a halogen.

[0260] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R4 is H.

[0261] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R4 is a halogen.

[0262] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R4 is F.

[0263] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein R5 and R6 are H or C. 1-6 alkyl.

[0264] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R5 and R6 are H.

[0265] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R5 and R6 are C 1-6 alkyl.

[0266] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R5 and R6 are methyl, ethyl, n-propyl or isopropyl.

[0267] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R5 and R6 are methyl groups.

[0268] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R5 and R6 together with the C atoms to which they are attached form cyclopropane.

[0269] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein,

[0270] L is -S0-(L1) i -S1-(L2) j -S2-(L3) k -S3-;

[0271] Where i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0; preferably, i is 1;

[0272] S0 is a chemical bond, -(CR) b R c ) p -,-NR a (CR b R c ) p -or-(CR) b R c ) p NR a -;

[0273] S1, S2, and S3 are each an independent chemical bond, -NR a (CR b R c ) p -,-(CR b R c ) p NR a -,-C(O)-,-C(O)NR a -,-NR aC(O)-,-C(O)NR a (CR b R c ) p -,-(CR b R c ) p C(O)NR a -,-C(O)(CR b R c ) p -,-(CR b R c ) p C(O)-, -NR a C(O)(CR b R c ) p -,-(CR b R c ) p NR a C(O)-, -S(O)2-, -S(O)2NR a -,-NR a S(O)2-,-S(O)2NR a (CR b R c ) p -,-(CR b R c ) p S(O)2NR a -,-S(O)2(CR b R c ) p -,-(CR b R c ) p S(O)2-, -NR a S(O)2(CR b R c ) p -,-(CR b R c ) p NR a S(O)2- or -(CR) b R c ) p -;

[0274] Each L1, L2, and L3 is independently a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocycles, 6-10 membered fused carbon rings, 6-10 membered fused heterocycles, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocycles, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R'.

[0275] Alternatively, when S0 is a chemical bond and i is 1, ring A and L1 share two adjacent ring atoms and one chemical bond;

[0276] Each R a Independently H or C 1-6 alkyl;

[0277] Each R b and R c Each can be independently H, D, -OH, -CN, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0278] p is 1, 2, 3 or 4;

[0279] Each R' is independently D, -CN, -OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0280] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein,

[0281] L is -S0-(L1) i -S1-(L2) j -S2-(L3) k -S3-;

[0282] Where i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0; preferably, i is 1;

[0283] S0 is a chemical bond, -CH2-, -NHCH2- or -CH2NH-;

[0284] S1, S2, and S3 are each an independent chemical bond, -NHCH2-, -CH2NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)NHCH2-, -CH2C(O)NH-, -C(O)CH2-, -CH2C(O)-, -NHC(O)CH2-, -CH2NHC(O)O-, -S(O)2-, -S(O)2NH-, -NHS(O)2-, -S(O)2NHCH2-, -CH2S(O)2NH-, -S(O)2CH2-, -CH2S(O)2-, -NHS(O)2CH2-, -CH2NHS(O)2-, or -CH2-;

[0285] Each L1, L2, and L3 is independently a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocycles, 6-10 membered fused carbon rings, 6-10 membered fused heterocycles, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocycles, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R'.

[0286] Alternatively, when S0 is a chemical bond and i is 1, ring A and L1 share two adjacent ring atoms and one chemical bond;

[0287] Each R' is independently D, -CN, -OH, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0288] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein,

[0289] L is -L1-S1-(L2) j -S2-(L3) k -S3-;

[0290] Where j is 0 or 1, and k is 0 or 1;

[0291] Ring A and L1 share two adjacent ring atoms and one chemical bond;

[0292] S1, S2, and S3 are each an independent chemical bond, -NHCH2-, -CH2NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)NHCH2-, -CH2C(O)NH-, -C(O)CH2-, -CH2C(O)-, -NHC(O)CH2-, -CH2NHC(O)O-, -S(O)2-, -S(O)2NH-, -NHS(O)2-, -S(O)2NHCH2-, -CH2S(O)2NH-, -S(O)2CH2-, -CH2S(O)2-, -NHS(O)2CH2-, -CH2NHS(O)2-, or -CH2-;

[0293] Each L1, L2, and L3 is independently a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocycles, 6-10 membered fused carbon rings, 6-10 membered fused heterocycles, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocycles, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R'.

[0294] Each R' is independently D, -CN, -OH, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0295] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein,

[0296] L is -S0-(L1) i -S1-(L2) j -S2-(L3) k -S3-;

[0297] Where i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0; preferably, i is 1;

[0298] S0 is a chemical bond, -CH2-, -NHCH2- or -CH2NH-;

[0299] S1, S2 and S3 are independently chemical bonds, -C(O)-, -C(O)CH2-, -CH2C(O)-, -S(O)2-, -S(O)2CH2-, -CH2S(O)2- or -CH2-;

[0300] Each L1, L2, and L3 is independently a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R's.

[0301] Alternatively, when S0 is a chemical bond and i is 1, ring A and L1 share two adjacent ring atoms and one chemical bond;

[0302] Each R' is independently D, -CN, -OH, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0303] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein,

[0304] L is -L1-S1-(L2) j -S2-(L3)k -S3-;

[0305] Where j is 0 or 1, and k is 0 or 1;

[0306] Ring A and L1 share two adjacent ring atoms and one chemical bond;

[0307] S1, S2 and S3 are independently chemical bonds, -C(O)-, -C(O)CH2-, -CH2C(O)-, -S(O)2-, -S(O)2CH2-, -CH2S(O)2- or -CH2-;

[0308] Each L1, L2, and L3 is independently a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R's.

[0309] Each R' is independently D, -CN, -OH, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0310] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein,

[0311] L is -S0-(L1) i -S1-(L2) j -S2-(L3) k -S3-;

[0312] Where i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0; preferably, i is 1;

[0313] S0 is a chemical bond or -CH2-;

[0314] S1, S2 and S3 are independently chemical bonds, -C(O)-, -C(O)CH2-, -CH2C(O)-, -S(O)2-, -S(O)2CH2-, -CH2S(O)2- or -CH2-;

[0315] Each L1, L2, and L3 is independently a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R's.

[0316] Alternatively, when S0 is a chemical bond and i is 1, ring A and L1 share two adjacent ring atoms and one chemical bond;

[0317] Each R' is independently D, -CN, -OH, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0318] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein,

[0319] L is -L1-S1-(L2) j -S2-(L3) k -S3-;

[0320] Where j is 0 or 1, and k is 0 or 1;

[0321] Ring A and L1 share two adjacent ring atoms and one chemical bond;

[0322] S1, S2 and S3 are independently chemical bonds, -C(O)-, -C(O)CH2-, -CH2C(O)-, -S(O)2-, -S(O)2CH2-, -CH2S(O)2- or -CH2-;

[0323] Each L1, L2, and L3 is independently a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R's.

[0324] Each R' is independently D, -CN, -OH, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0325] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein,

[0326] L is -S0-L1-S1-(L2) j -;

[0327] Where j is 0 or 1;

[0328] S0 is a chemical bond, -CH2-, -NHCH2- or -CH2NH-;

[0329] S1 is a chemical bond, -C(O)-, -C(O)CH2-, -CH2C(O)-, -S(O)2-, -S(O)2CH2-, -CH2S(O)2- or -CH2-;

[0330] L1 and L2 are independently divalent groups selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R'.

[0331] Alternatively, when S0 is a chemical bond, ring A and L1 share two adjacent ring atoms and one chemical bond;

[0332] Each R' is independently D, -CN, -OH, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0333] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein,

[0334] L is -L1-S1-(L2) j -;

[0335] Where j is 0 or 1;

[0336] Ring A and L1 share two adjacent ring atoms and one chemical bond;

[0337] S1 is a chemical bond, -C(O)-, -C(O)CH2-, -CH2C(O)-, -S(O)2-, -S(O)2CH2-, -CH2S(O)2- or -CH2-;

[0338] L1 and L2 are independently divalent groups selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R'.

[0339] Each R' is independently D, -CN, -OH, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0340] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein L is:

[0341] In this embodiment, the aforementioned groups are optionally substituted by one or more R'.

[0342] Each R' is independently D, -CN, -OH, F, Cl, Br, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0343] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein,

[0344] L is -S0-L1-C(O)-CH2-L2-;

[0345] Wherein, S0 is a chemical bond or -CH2-;

[0346] L1 and L2 are independently divalent groups selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R'.

[0347] Each R' is independently D, -CN, -OH, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0348] In one implementation of L, L1 is:

[0349] In this embodiment, the aforementioned groups are optionally substituted by one or more R's; each R' is independently D, -CN, -OH, F, Cl, Br, C. 1-3 Alkyl or C 1-3 Halogenated alkyl groups; * indicates connection to S0, and * indicates connection to -C(O)-.

[0350] In another implementation of L, L2 is:

[0351] In this embodiment, the aforementioned groups are optionally substituted by one or more R's; each R' is independently D, -CN, -OH, F, Cl, Br, C. 1-3 Alkyl or C 1-3 Halogenated alkyl groups; * indicates connection to CH2, and * indicates connection to U.

[0352] In another implementation of L, L2 is in, * indicates connection to CH2, and * indicates connection to U.

[0353] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein L is -SO-L1-C(O)-CH2-L2-;

[0354] Wherein, S0 is a chemical bond;

[0355] L1 is It may be replaced by one or more R's; wherein, * indicates connection to S0, and * indicates connection to -C(O)-.

[0356] L2 is a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R's.

[0357] Each R' is independently D, -CN, -OH, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0358] In one implementation of L, L2 is:

[0359] In this embodiment, the above-mentioned groups are optionally replaced by one or more R';

[0360] Each R' is independently D, -CN, -OH, F, Cl, Br, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0361] * indicates connection to CH2, and * indicates connection to U.

[0362] In another implementation of L, L2 is

[0363] in, * indicates connection to CH2, and * indicates connection to U.

[0364] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is selected from the following formula (U A1 ), formula (U B1 ), formula (U C1 ), formula (U D1 ), formula (U E1 ), formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U F1 ), formula (U G1 ) or formula (U H1 ):

[0365] in,

[0366] Indicates a single bond or a double bond;

[0367] V represents a chemical bond;

[0368] Each W is independently a chemical bond, C(O), NH, O, S, C(O)NH, C(O)NH or CH2;

[0369] Each Q1 is independently C(O) or C(R9)2;

[0370] Each Q2 is independently either N or CH;

[0371] Each Q3 and Q4 is independently either N or CR9;

[0372] Each R7 is independently either H or C. 1-6 alkyl;

[0373] Each R8 is independently D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R8 atoms together with the atoms they are attached to form C 3-7 cycloalkyl or 4-7 membered heterocyclic groups;

[0374] Each R9 is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R9s together with the atoms they are attached to form C. 3-7 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0375] Each h can be independently 0, 1, 2, 3 or 4;

[0376] Each k' is independently 0, 1, 2, 3, or 4.

[0377] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0378] in,

[0379] Q3 is either N or CR9;

[0380] Each R9 is independently H, D, or halogen;

[0381] Each k' is independently either 0 or 1.

[0382] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is selected from the following formula (U E8 ) or formula (U E9 ):

[0383] in,

[0384] V represents a chemical bond;

[0385] Each Q2 is independently either N or CH;

[0386] Each R8 is independently D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R8 atoms together with the atoms they are attached to form C 3-7 cycloalkyl or 4-7 membered heterocyclic groups;

[0387] Each R9 is independently H, D, halogen, C 1-6 Alkyl or C1-6 Halogenated alkyl; or two R9s together with the atoms they are attached to form C. 3-7 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0388] Each h can be independently 0, 1, 2, 3 or 4;

[0389] Each k' is independently 0, 1, 2, 3, or 4.

[0390] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0391] in,

[0392] Each R9 is independently H, D, or halogen;

[0393] Each k' is independently either 0 or 1.

[0394] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is selected from the following formula (U K1 ), formula (U K2 ), formula (U L1 ), formula (U L2 ), formula (U M1 ), formula (U N1 ), formula (U O1 ) or formula (U P1 ):

[0395] in,

[0396] Each V is an independent chemical bond;

[0397] Each W is independently a chemical bond, C(O), NH, O, S, C(O)NH, C(O)NH or CH2;

[0398] Each Q1 is independently C(O) or C(R9)2;

[0399] Each Q2 is independently either N or CH;

[0400] Each R8 is independently D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R8 atoms together with the atoms they are attached to form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0401] Each R9 is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R9s together with the atoms they are attached to form C. 3-7 Cycloalkanes, 4- to 7-membered heterocycles, C 6-10 Aromatic hydrocarbons or 5- to 10-membered heteroaromatic hydrocarbons;

[0402] Each z can be 0, 1, or 2 independently;

[0403] Each h can be independently 0, 1, 2, 3 or 4;

[0404] Each k' is independently 0, 1, 2, 3 or 4;

[0405] Each r, s, t, and u is independently 0, 1, 2, 3, or 4.

[0406] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0407] in,

[0408] Each R9 is independently H, D, or halogen;

[0409] Each k' is independently either 0 or 1.

[0410] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0411] in,

[0412] Each R9 is independently H, D, or halogen;

[0413] Each k' is independently either 0 or 1.

[0414] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0415] in,

[0416] Each R9 is independently H, D, or halogen;

[0417] Each k' is independently either 0 or 1.

[0418] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0419] in,

[0420] R9 is H, D, or a halogen;

[0421] k' is 0 or 1.

[0422] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0423] in,

[0424] R9 is H, D, or a halogen;

[0425] k' is 0 or 1.

[0426] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0427] in,

[0428] Q3 is either N or CR9;

[0429] Each R9 is independently H, D, or halogen;

[0430] k' is independently 0 or 1.

[0431] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0432] in,

[0433] R9 is H, D, or a halogen;

[0434] k' is 0 or 1.

[0435] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0436] in,

[0437] R9 is H, D, or a halogen;

[0438] k' is 0 or 1.

[0439] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0440] in,

[0441] Each R9 is independently H, D, or halogen;

[0442] Each k' is independently either 0 or 1.

[0443] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0444] in,

[0445] R9 is H, D, or a halogen;

[0446] k' is 0 or 1.

[0447] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0448] in,

[0449] Each R9 is independently H, D, or halogen;

[0450] Each k' is independently either 0 or 1.

[0451] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0452] in,

[0453] Each R9 is independently H, D, or halogen;

[0454] Each k' is independently either 0 or 1.

[0455] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein U is:

[0456] in,

[0457] Each R9 is independently H, D, or halogen;

[0458] Each k' is independently either 0 or 1.

[0459] In another embodiment, the present invention relates to a compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, isotopic variant, hydrate, or solvate thereof, wherein the compound is selected from:

[0460] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0461] "Tautomers" refer to compounds in which one functional group changes its structure to become another functional group isomer, and can rapidly interconvert to each other, becoming two isomers in dynamic equilibrium. These two isomers are called tautomers.

[0462] Those skilled in the art will understand that organic compounds can form complexes with solvents, react in the solvent, or precipitate or crystallize out of the solvent. These complexes are called "solvates." When the solvent is water, the complex is called a "hydrate." This invention covers all solvates of the compounds of this invention.

[0463] The term "solvent" refers to a compound or its salt that is bound to a solvent and formed typically by a solvent decomposition reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0464] The term "hydrate" refers to a compound that is bound to water. Typically, it is determined by the ratio of the number of water molecules contained in the hydrate to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0465] The compounds of this invention can be in amorphous or crystalline forms (crystalline or polymorphic). Furthermore, the compounds of this invention can exist in one or more crystalline forms. Therefore, this invention encompasses all amorphous or crystalline forms of the compounds of this invention within its scope. The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates) with a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

[0466] The present invention also includes isotopically labeled compounds that are equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e.14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0467] Furthermore, prodrugs are also included in the context of this invention. As used herein, the term "prodrug" refers to a compound which is converted in vivo, for example, by hydrolysis in the blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series, Vol. 14; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; and D. Fleisher, S. Ramon, and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs," Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated herein by reference.

[0468] A prodrug is any covalently bonded compound of the present invention that, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in a manner that allows the modification to produce the parent compound through conventional operation or in vivo cleavage. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or thiol group is bonded to any group, which, when administered to a patient, can cleave to form a hydroxyl, amino, or thiol group. Thus, representative examples of prodrugs include (but are not limited to) acetate / amide, formate / amide, and benzoate / amide derivatives of formula (I) with hydroxyl, thiol, and amino functional groups. Additionally, in the case of carboxylic acids (-COOH), esters, such as methyl esters, ethyl esters, etc., can be used. The ester itself may be active and / or hydrolyzable under in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that readily decompose in the body to release the parent acid or its salt.

[0469] Pharmaceutical compositions, formulations and kits

[0470] In another aspect, the present invention provides pharmaceutical compositions comprising the compound of the present invention (also referred to as the "active ingredient") and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the active ingredient.

[0471] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0472] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0473] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0474] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0475] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0476] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0477] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to rapidly increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active ingredient, while a bolus dose delivered directly to a vein (e.g., via IV infusion) allows for a more rapid delivery, causing the concentration of the active ingredient in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV infusion, thereby providing a steady-state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0478] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, the compositions are provided in unit dose form for the purpose of precise dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients useful for forming the desired dosage form, as well as processing aids.

[0479] For oral dosage, a typical regimen is one to five oral doses daily, particularly two to four oral doses, typically three oral doses. Using these dosage regimens, each dose provides approximately 0.01 to approximately 20 mg / kg of the compound of the invention, with preferred doses each providing approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0480] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0481] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0482] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[0483] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0484] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and generally include other components to enhance stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of this invention.

[0485] The compounds of this invention can also be administered via transdermal devices. Therefore, transdermal drug delivery can be achieved using reservoirs or porous membrane types, or patches with various solid matrices.

[0486] The above-described components for oral, injectable, or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0487] The compounds of this invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[0488] This invention also relates to pharmaceutically acceptable formulations of the compounds of this invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfonyl ether substituted groups. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0489] Indications

[0490] On the other hand, the use of the compound of formula (I) disclosed in this invention (including all individual embodiments and subsets thereof disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvent compounds as a medicine.

[0491] In one embodiment, the present invention provides compounds that specifically degrade mutant EGFR through targeted ubiquitination of the EGFR protein and subsequent proteasome degradation. The compounds of the present invention bind to the universally expressed E3 ligase protein cereblon (CRBN) and alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, thereby leading to the recruitment and ubiquitination of mutant EGFR (specifically, for example, the EGFR L858R mutation, the L858R / T790M double mutation, and the L858R / T790M / C797S triple mutation).

[0492] In another embodiment, the present invention provides a compound having the activity of inhibiting mutant EGFR, wherein the mutant EGFR is, for example, L858R mutation, T790M mutation, C797S mutation, L858R / T790M double mutation, L858R / C797S double mutation, T790M / C797S double mutation or L858R / T790M / C797S triple mutation.

[0493] In another embodiment, the compounds of the present invention can be used to treat diseases mediated by mutated EGFR, wherein EGFR has been mutated from the wild-type. In another embodiment, the compounds of the present invention are used to treat EGFR-mediated cancers that have metastasized to the brain or central nervous system (CNS), such as metastases to the peripheral nervous system, cerebrospinal fluid, spinal cord, pia mater, epidural space, and / or dura mater, wherein EGFR has been mutated from the wild-type. EGFR mutations are possible in many ways. In one specific embodiment, the EGFR mutation is not limited to being present in exon 18, exon 19, exon 20, or exon 21, or any combination thereof. In a more specific implementation, the EGFR mutation is not limited to positions E709, L718, G719, G724, Del19, L747, D761, M766, S768, T790, L792, G796, C797, ex20ins, G834, V843, L844, T854, L858, or L861, or any combination thereof. In one more specific embodiment, the EGFR mutation is non-restricted and selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L858R, or L861Q, or any combination thereof. In another more specific embodiment, the EGFR mutation is Del19, L858R, T790M, C797S, L718Q, L792H, or L861Q, or any combination thereof. In another, more specific embodiment, the EGFR mutation is an exon 19 deletion mutation (Del19) or an exon 20 insertion mutation (ex20ins), wherein the exon 19 deletion mutation includes, without limitation, the deletion of amino acid LREA (L747-A750) or amino acid ELREA (E746-A750). In another, more specific embodiment, the EGFR mutation is not an exon 18, exon 19, exon 20, or exon 21 mutation. In another, more specific embodiment, the non-exon 18, non-exon 19, exon 20, or exon 21 mutation is, without limitation, selected from G119A, R531Q, V948R, or I941R.

[0494] In another specific embodiment, the mutated EGFR includes a combination of mutations, wherein the combination includes two, three, four or more mutations, optionally selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R or I941R.

[0495] In another, more specific embodiment, the mutated EGFR is the L858R mutation and an additional mutation, which may optionally be selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L861Q, G119A, R531Q, V948R, or I941R.

[0496] In another, more specific embodiment, the mutated EGFR is the L858R mutation and two additional mutations, which may optionally be selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L861Q, G119A, R531Q, V948R, or I941R.

[0497] In another, more specific embodiment, the mutated EGFR is the L858R mutation and three additional mutations, which may optionally be selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L861Q, G119A, R531Q, V948R, or I941R.

[0498] In another, more specific embodiment, the mutated EGFR is the T790M mutation and an additional mutation, which may optionally be selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R, or I941R.

[0499] In another, more specific embodiment, the mutated EGFR is the T790M mutation and two additional mutations, which may optionally be selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R, or I941R.

[0500] In another, more specific embodiment, the mutated EGFR is the T790M mutation and three additional mutations, which may optionally be selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R, or I941R.

[0501] In another, more specific embodiment, the mutated EGFR is the C797 mutation and an additional mutation, which may optionally be selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R, or I941R.

[0502] In another, more specific embodiment, the mutated EGFR is the C797 mutation and two additional mutations, which may optionally be selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R, or I941R.

[0503] In another, more specific embodiment, the mutated EGFR is the C797 mutation and three additional mutations, which may optionally be selected from E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R, or I941R.

[0504] In another specific implementation, the EGFR mutation is an E709 mutation, such as E709A, E709G, E709K, or E709V.

[0505] In another specific implementation, the EGFR mutation is an L718 mutation, such as L718Q or L718V.

[0506] In another specific implementation, the EGFR mutation is a G719 mutation, such as G719C, G719S, G719A, or G719D.

[0507] In another specific implementation, the EGFR mutation is a deletion mutation of one or more exon 18.

[0508] In another specific implementation, the EGFR mutation is an insertion mutation of one or more exon 19 and / or one or more exon 20.

[0509] In another specific implementation, the EGFR mutation is the L861Q mutation.

[0510] In another specific implementation, the EGFR mutation is the L858R mutation.

[0511] In another specific implementation, the EGFR mutation is the T790M mutation.

[0512] In another specific implementation, the EGFR mutation is the C797 mutation.

[0513] In another specific implementation, the EGFR mutation is the C797S mutation.

[0514] In another specific implementation, the EGFR mutation is the C797G mutation.

[0515] In another specific implementation, the EGFR mutation is the C797N mutation.

[0516] In another specific implementation, the EGFR mutation is the L792 mutation.

[0517] In another specific implementation, the EGFR mutation is the L792F mutation.

[0518] In another specific implementation, the EGFR mutation is the L792H mutation.

[0519] In another specific implementation, the EGFR mutation is the L792V mutation.

[0520] In another specific implementation, the EGFR mutation is the L718Q mutation.

[0521] In another specific implementation, the EGFR mutation is the L858R / T790M combined mutation.

[0522] In another specific implementation, the EGFR mutation is the L858R / C797 combined mutation.

[0523] In another specific implementation, the EGFR mutation is the L858R / C797S combined mutation.

[0524] In another specific implementation, the EGFR mutation is the L858R / L718Q combined mutation.

[0525] In another specific implementation, the EGFR mutation is the L858R / L792H combined mutation.

[0526] In another specific implementation, the EGFR mutation is a T790M / C797 combined mutation.

[0527] In another specific implementation, the EGFR mutation is a T790M / C797S combined mutation.

[0528] In another specific implementation, the EGFR mutation is a combined L858R / T790M / C797 mutation.

[0529] In another specific implementation, the EGFR mutation is a combined L858R / T790M / C797S mutation.

[0530] In another embodiment, the compounds of the present invention are used to treat diseases in which escape mutations (one or more mutations) have developed after treatment with at least one EGFR inhibitor, said inhibitor being a non-covalent inhibitor (including, but not limited to, gefitinib, erlotinib, lapatinib, or vandetanib) or a covalent inhibitor (including, but not limited to, afatinib, osimertinib, or dacomitinib). In another embodiment, the compounds of the present invention are used to treat diseases in which escape mutations (one or more mutations) have developed after treatment with an antibody, said antibody being non-limitingly included in the categories of cetuximab, panitumumab, or nexituzumab. In another embodiment, the compounds of the present invention are used to treat diseases with intrinsic resistance to EGFR mutations or non-EGFR mutations, such as somatic exon 20 insertions, MET amplification, somatic PIK3CA mutations, PTEN loss of expression, or KRAS mutations.

[0531] In another embodiment, the compounds of the present invention are used to treat cancers that are resistant to or have acquired resistance to at least one EGFR inhibitor, such as diseases resistant to or have acquired resistance to first-generation EGFR inhibitors such as gefitinib, erlotinib, and / or icotinib. In one specific embodiment, the compounds of the present invention are used to treat diseases resistant to or have acquired resistance to first-generation EGFR inhibitors such as gefitinib, erlotinib, and / or icotinib. In another specific embodiment, the compounds of the present invention are used to treat diseases resistant to or have acquired resistance to second-generation EGFR inhibitors such as afatinib and / or dacomitinib. In another specific embodiment, the compounds of the present invention are used to treat diseases resistant to or have acquired resistance to third-generation EGFR inhibitors such as osimertinib.

[0532] In another embodiment, the compounds of the present invention are used to treat EGFR-mediated and metastatic diseases (especially brain and CNS metastases), said diseases being cancer or proliferative disorders.

[0533] In one specific implementation, the cancers include, but are not limited to: squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, salivary gland cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, and thyroid cancer.

[0534] In another embodiment, the compounds of the present invention are used to treat lung cancer, which is not limited to small cell lung cancer and non-small cell lung cancer, each of which can be primary or metastatic (especially brain metastases and CNS metastases).

[0535] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer and its metastases (especially brain metastases or CNS metastases), such as non-small cell lung cancer and its metastases (especially brain metastases or CNS metastases) having L861Q, L858R, T790M, C797S / G / N, L792F / H / V or L718Q mutations, or any combination of mutations thereof.

[0536] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the L858R mutation and its metastases (especially brain metastases or CNS metastases).

[0537] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the T790M mutation and its metastases (especially brain metastases or CNS metastases).

[0538] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with C797 mutations and its metastases (especially brain metastases or CNS metastases).

[0539] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with C797S mutation and its metastases (especially brain metastases or CNS metastases).

[0540] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the C797G mutation and its metastases (especially brain metastases or CNS metastases).

[0541] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the C797N mutation and its metastases (especially brain metastases or CNS metastases).

[0542] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the L858R / T790M combined mutation and its metastases (especially brain metastases or CNS metastases).

[0543] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the L858R / C797 combined mutation and its metastases (especially brain metastases or CNS metastases).

[0544] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the L858R / C797S combined mutation and its metastases (especially brain metastases or CNS metastases).

[0545] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the T790M / C797 combined mutation and its metastases (especially brain metastases or CNS metastases).

[0546] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the T790M / C797S combined mutation and its metastases (especially brain metastases or CNS metastases).

[0547] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the L858R / T790M / C797 combined mutation and its metastases (especially brain metastases or CNS metastases).

[0548] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the L858R / T790M / C797S combined mutation and its metastases (especially brain metastases or CNS metastases).

[0549] In another embodiment, the compounds of the present invention are used to treat colorectal cancer and its metastases (especially brain metastases or CNS metastases).

[0550] In another embodiment, the compounds of the present invention are used to treat head and neck cancer and its metastases (especially brain metastases or CNS metastases).

[0551] In another embodiment, the compounds of the present invention are used to treat breast cancer and its metastases (especially brain metastases or CNS metastases), such as HER-2 positive breast cancer, ER+ (estrogen-positive) breast cancer, PR+ (progesterone-positive) breast cancer, or triple-negative breast cancer.

[0552] In another embodiment, the compounds of the present invention are used to treat gliomas and their metastases (especially brain metastases or CNS metastases).

[0553] In another embodiment, the compounds of the present invention are used to treat squamous cell carcinoma and its metastases (especially brain metastases or CNS metastases).

[0554] In another embodiment, the compounds of the present invention are used to treat prostate cancer and its metastases (especially brain metastases or CNS metastases).

[0555] In another embodiment, the compounds of the present invention are used to treat gastric cancer and its metastases (especially brain metastases or CNS metastases).

[0556] In another embodiment, the compounds of the present invention are used to treat esophageal cancer and its metastases (especially brain metastases or CNS metastases).

[0557] In another embodiment, the compounds of the present invention are used to treat pancreatic cancer and its metastases (especially brain metastases or CNS metastases).

[0558] In another embodiment, the compounds of the present invention are used to treat thyroid cancer and its metastases (especially brain metastases or CNS metastases).

[0559] In another embodiment, the compounds of the present invention are used to treat ovarian cancer and its metastases (especially brain metastases or CNS metastases).

[0560] In another embodiment, the compounds of the present invention are used to treat uterine cancer and its metastases (especially brain metastases or CNS metastases).

[0561] In another embodiment, the compounds of the present invention are used to treat cervical cancer and its metastases (especially brain metastases or CNS metastases).

[0562] In another embodiment, the compounds of the present invention are used to treat liver cancer and its metastases (especially brain metastases or CNS metastases).

[0563] In another embodiment, the compounds of the present invention are used to treat renal cell carcinoma and its metastases (especially brain metastases or CNS metastases).

[0564] In another embodiment, the compounds of the present invention are used to treat bladder cancer and its metastases (especially brain metastases or CNS metastases).

[0565] In another embodiment, the compounds of the present invention are used to treat melanoma and its metastases (especially brain metastases or CNS metastases).

[0566] In another implementation, EGFR-mediated disease is abnormal cell proliferation, including but not limited to solid or blood cancers.

[0567] In one specific implementation plan, hematologic malignancies include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphoblastic T-cell leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, and acute megakaryoblastic leukemia. Diseases, promyelocytic leukemia, mixed spectrum leukemia (MLL), erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Myc and B-cell leukemia (BCL) 2 and / or CL6 rearrangement / overexpression [double and triple hit lymphomas], myelodyplastic / myeloproliferative neoplasms, mantle cell lymphoma (including bortezomib-resistant mantle cell lymphoma).

[0568] In another specific implementation, solid cancers include, but are not limited to, lung cancer (including small cell lung cancer and non-small cell lung cancer), breast cancer (including inflammatory breast cancer, ER-positive breast cancer, and triple-negative breast cancer), colon cancer, midline cancer, liver cancer, kidney cancer, prostate cancer (including castration-resistant prostate cancer), brain cancer (including glioma, glioblastoma, neuroblastoma, and medulloblastoma (including MYC-amplified medulloblastoma)), colorectal cancer, nephroblastoma, and Ewing's sarcoma. Tumors, rhabdomyosarcomas, ependymomas, head and neck cancers, melanomas, squamous cell carcinomas, ovarian cancers, pancreatic cancers (including pancreatic ductal carcinomas and pancreatic neuroendocrine tumors), osteosarcomas, giant cell tumors of bone, thyroid cancers, bladder cancers, urothelial carcinomas, vulvar cancers, cervical cancers, endometrial cancers, mesotheliomas, esophageal cancers, salivary gland cancers, gastric cancers, nasopharyngeal carcinomas, buccal cancers, oral cancers, gastrointestinal stromal tumors, NUT-midline carcinomas, testicular cancers, squamous cell carcinomas, hepatocellular carcinomas, MYCN-driven solid tumors, and NUT-midline carcinomas.

[0569] In another embodiment, the compounds of the present invention are used to treat inflammation, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis and other arthritis, neuroinflammatory diseases, allergic reactions, pain, neuropathic pain, fever, lung diseases, pneumonia, adult respiratory distress syndrome, chronic inflammatory lung disease and chronic obstructive pulmonary disease (COPD), liver disease and nephritis, gastrointestinal diseases, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, and ulcerative diseases. Gastric ulcers, autoimmune diseases, graft-host reactions and allogeneic graft rejection, cancer, leukemia, lymphoma, brain cancer, bone cancer, epithelial cell carcinoma (epithelial carcinoma), basal cell carcinoma, gastrointestinal cancer, lip cancer, oral cancer, esophageal cancer, small bowel cancer, bladder cancer, cervical cancer, skin cancer, renal cell carcinoma and other known cancers affecting epithelial cells throughout the body, angiogenesis (including tumor formation, metastasis, central nervous system disorders), central nervous system disorders with inflammatory or apoptotic components, peripheral neuropathy, or B-cell lymphoma.

[0570] In another embodiment, the compounds of the present invention are used to treat autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immune-mediated diseases.

[0571] Based on the foregoing, the present invention also provides a method for preventing or treating any of the aforementioned diseases or conditions in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of the compound as described herein, or its enantiomers, diastereomers, or stereoisomers, or pharmaceutically acceptable salts, hydrates, or solvates thereof. For any of the above uses, the required dosage will vary depending on the method of administration, the specific patient to be treated, and the desired effect.

[0572] combination therapy

[0573] The compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof may be used alone or in combination with another compound of the present invention or another bioactive agent or a second therapeutic agent to treat subjects, such as subjects with EGFR-mediated disorders, including but not limited to those described herein.

[0574] The term "bioactive agent" or "additional active agent" is used to describe pharmaceutical agents other than those selected according to the invention, which can be used in combination with or alternately with the compounds of the invention to achieve a desired therapeutic outcome. In one embodiment, the compounds and bioactive agents of the invention are administered in a manner that allows them to be active in vivo during overlapping time periods, such as time periods with overlapping Cmax, Tmax, AUC, or other pharmacokinetic parameters. In another embodiment, the compounds and bioactive agents of the invention are administered to a subject in need who does not have overlapping pharmacokinetic parameters, but whose therapeutic effect is influenced by the other drug.

[0575] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with another EGFR inhibitor, said other EGFR inhibitor including, but not limited to, gefitinib, erlotinib, icotinib, afatinib, dacomitinib, neratinib, osimertinib, lazatinib, ametinib, vormetinib, lapatinib, vandetanib, omamotinib, befotinib, or brigatinib. In another specific embodiment, the EGFR inhibitor is a first-generation EGFR inhibitor such as gefitinib, erlotinib, or icotinib. In another specific embodiment, the EGFR inhibitor is a second-generation EGFR inhibitor such as afatinib and / or dacomitinib. In another specific embodiment, the EGFR inhibitor is a third-generation EGFR inhibitor such as osimertinib, ametinib, or vormetinib.

[0576] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with an EGFR antibody. In another specific embodiment, the EGFR antibody is cetuximab. In another specific embodiment, the EGFR antibody is panitumumab. In another specific embodiment, the EGFR antibody is nexituzumab.

[0577] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with a c-MET inhibitor. In yet another specific embodiment, the c-MET inhibitor is terpoxtinib, carmatinib, cevotinib, gumetinib, or beritinib.

[0578] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with an immunomodulator, said immunomodulator including, but not limited to, immune checkpoint inhibitors or antibodies. In another specific embodiment, the immunomodulator is an immune checkpoint inhibitor, such as a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, T-cell activation V-domain Ig inhibitor inhibitor inhibitor, small molecule, peptide, nucleotide, or other inhibitor. In yet another more specific embodiment, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pildizumab, atezolizumab, durvalumab, ipilimumab, or trimemumab.

[0579] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with an ALK inhibitor. In yet another specific embodiment, the ALK inhibitor is crizotinib, ceritinib, alectinib, brigatinib, ensartinib, loratinib, or ilurac.

[0580] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with a BTK inhibitor. In another specific embodiment, the BTK inhibitor is ibrutinib, acomitinib, zanubrutinib, tabrutinib, or obrutinib or pitutinib.

[0581] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with a MEK inhibitor. In yet another specific embodiment, the MEK inhibitor is trametinib, selmetinib, or refatinib.

[0582] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with a RAF inhibitor. In yet another specific embodiment, the RAF inhibitor is sorafenib, vemurafenib, dabrafenib, or encofenib.

[0583] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with an optional selection of HER-2 inhibitors, CD20 inhibitors, JAK3 inhibitors, BCL-2 inhibitors, PI3K inhibitors, SYK inhibitors, AKT inhibitors, mTOR inhibitors, RAS inhibitors or HSP inhibitors, or any combination thereof.

[0584] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapy agent, or an immunosuppressant.

[0585] Example

[0586] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, parts and percentages are parts by weight and weight percentages.

[0587] Typically, in the preparation process, each reaction is carried out in an inert solvent at room temperature to reflux temperature (e.g., 0°C to 100°C, preferably 0°C to 80°C). The reaction time is usually 0.1-60 hours, preferably 0.5-24 hours.

[0588] The abbreviations used in this article have the following meanings: Pd(dppf)Cl2: [1,1'-bis(triphenylphosphine)ferrocene]palladium dichloride; Pd2(dba)3: tris(dibenzylacetone)palladium; Pd(PPh3)4: tetra(triphenylphosphine)palladium; Pd(PPh3)2Cl2: bis(triphenylphosphine)palladium dichloride; Ruphos Pd G3: methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) NBS: N-bromosuccinimide; AIBN: Azobisisobutyronitrile; PTSA: p-Toluenesulfonic acid; HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate; DMAP: 4-dimethylaminopyridine; B2Pin2: pinacol diboronate; t-BuXphos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; Dess-Martin: (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodo-3(1H)-one; DAST: diethylaminosulfuric acid; NaBH3CN: sodium cyanoborohydride. uI: Cuprous iodide TBAF: Tetrabutylammonium fluoride TBAB: Tetrabutylammonium bromide TEA: Triethylamine DIEA: N,N-Diisopropylethylamine DME: Ethylene glycol dimethyl ether TFA: Trifluoroacetic acid HCOOH: Formic acid AcOH: Acetic acid Cs2CO3: Cesium carbonate KOAc: Potassium acetate DCM: Dichloromethane THF: Tetrahydrofuran DMF: N,N-Dimethylformamide CDI: N,N'-Carbonyldiimidazolium KSCN: Potassium thiocyanate SeO2: Selenium dioxide i-PrOH: Isopropanol LDA: Lithium diisopropylaminodimethyl DMSO: Dimethyl sulfoxide TBAI: Tetrabutylammonium iodide Xphos Pd-G3: Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) Brettphos Pd-G3: Methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0589] Example 1 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-1)

[0590] The synthesis is performed using the following route:

[0591] Step 1: Synthesis of compound (S)-2-(3-ethoxy-3-oxopropionyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0592] BOC-L-proline (8.6 g, 40.0 mmol), potassium monoethyl malonate (7.48 g, 44.0 mmol), CDI (6.5 g, 40.0 mmol), anhydrous magnesium chloride (7.6 g, 80.0 mmol), and 80 mL of acetonitrile were added to a reaction flask. The mixture was heated to 50 °C under nitrogen protection and stirred for 4–6 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the residue was purified by column chromatography and vacuum dried to obtain 9.35 g of a pale yellow oily liquid, with a yield of 82%. LC-MS (APCI): m / z = 286.2 (M+1) + .

[0593] Step 2: Synthesis of compound (S)-3-oxo-3-(pyrrolidone-2-yl)propionate ethyl hydrochloride

[0594] Add (S)-2-(3-ethoxy-3-oxopropionyl)pyrrolidine-1-carboxylic acid tert-butyl ester (9.35 g, 32.8 mmol) and 4N ethyl hydrogen chloride solution (30 mL, 120.0 mmol) to the reaction flask. Stir the mixture at room temperature for 2–4 hours. After the reaction is complete, monitor the concentration by TLC and then directly add the solution to the next step of the reaction. LC-MS (APCI): m / z = 186.4 (M+1) + .

[0595] Step 3: Synthesis of compound 2-(3-thio-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethyl acetate

[0596] Compound (S)-3-oxo-3-(pyrrolidone-2-yl)propionate ethyl hydrochloride and potassium thiocyanate (7.97 g, 82.0 mmol) were added to a reaction flask and dissolved in 60 mL of ethanol. The mixture was heated to reflux and stirred overnight under nitrogen protection. The reaction was monitored by TLC until completion. The reaction was quenched by adding saturated ammonium chloride aqueous solution. The mixture was extracted 3-4 times with ethyl acetate. The combined organic phases were washed 3 times with saturated brine. The organic phase was separated, concentrated, and purified by silica gel column chromatography to give 4.82 g of a pale yellow solid. The two-step yield was 65%. LC-MS (APCI): m / z = 227.2 (M+1) + .

[0597] Step 4: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)ethyl acetate

[0598] Ethyl 2-(3-thio-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl) (4.82 g, 21.3 mmol) was added to a reaction flask and dissolved in 20 mL of acetic acid. The mixture was cooled to 0 °C under nitrogen protection, and 30% hydrogen peroxide (48.3 mL, 42.6 mmol) was slowly added dropwise. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. Excess sodium thiosulfate solution was added to quench the reaction. The mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.94 g of an off-white solid, 47% yield. LC-MS (APCI): m / z = 195.6 (M+1) + .

[0599] Step 5: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxoethyl acetate

[0600] To a reaction flask, 1.94 g (10.0 mmol) of ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) compound, 2.22 g (20.0 mmol) of selenium dioxide, and 25 mL of anhydrous 1,4-dioxane were added. The mixture was heated to 80 °C and stirred overnight under nitrogen protection. After the reaction was complete, excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.27 g of a yellow solid, in 61% yield. LC-MS (APCI): m / z = 209.2 (M+1) + .

[0601] Step 6: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(hydroxyimino)ethyl acetate

[0602] To a reaction flask, ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxoethyl acetate (1.27 g, 6.1 mmol), hydroxylamine hydrochloride (466 mg, 6.71 mmol), sodium acetate (1.0 g, 12.2 mmol), and 10 mL of ethanol were added. The mixture was heated to 80 °C and reacted for 4–5 hours. The reaction was confirmed to be complete by TLC. After concentration, the reaction solution was purified by silica gel column chromatography to obtain 1.13 g of product, with a yield of 83%. LC-MS (APCI): m / z = 224.7 (M+1) + .

[0603] Step 7: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-aminoethyl acetate hydrochloride

[0604] To a reaction flask, 1.13 g (5.07 mmol) of ethyl acetate 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(hydroxyimino) was added, along with 10 mL of ethanol, a catalytic amount of palladium on carbon, and hydrochloric acid. Hydrogen gas was purged three times, and the mixture was then filled with a hydrogen balloon and heated to 50 °C with stirring overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the catalyst was removed by filtration. The filtrate was concentrated to give 1.06 g of a pale yellow solid, which was directly added to the next reaction step without further purification. LC-MS (APCI): m / z = 210.5 (M+1) + .

[0605] Step 8: Synthesis of compound 2-methyl-3-fluoro-5-iodobenzoic acid

[0606] 2-Methyl-3-fluorobenzoic acid (3.08 g, 20 mmol) was added to a reaction flask and dissolved in 30 mL of concentrated sulfuric acid. The mixture was cooled to 0 °C in an ice bath. 1,3-Diiodo-5,5-dimethylhydantoin (9.12 g, 24 mmol) was added in portions. After the addition was complete, the mixture was brought to room temperature and stirred for 3–5 hours. The reaction was monitored by TLC until complete. The reaction solution was slowly added dropwise to ice water, precipitating a yellow solid. The solid was filtered, and the filter cake was dried under vacuum to obtain 3.7 g of yellow solid, with a yield of 66%. LC-MS (APCI): m / z = 280.9 (M+1) + .

[0607] Step 9: Synthesis of compound methyl 2-methyl-3-fluoro-5-iodobenzoate

[0608] 2-Methyl-3-fluoro-5-iodobenzoic acid (3.7 g, 13.2 mmol) was added to a reaction flask and dissolved in 20 mL of DMF. Potassium carbonate (3.65 g, 26.4 mmol) and iodomethane (2.8 g, 19.8 mmol) were added sequentially. After addition, the mixture was stirred at room temperature for 4–6 hours. The reaction was monitored by TLC until complete. Excess water was added for dilution, and the mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 3.53 g of a yellow solid, with a yield of 91%. LC-MS (APCI): m / z = 294.9 (M+1) + .

[0609] Step 10: Synthesis of compound methyl 2-bromomethyl-3-fluoro-5-iodobenzoate

[0610] 3.53 g (12.0 mmol) of methyl 2-methyl-3-fluoro-5-iodobenzoate was added to a reaction flask and dissolved in 60 mL of anhydrous trifluorotoluene. Under nitrogen protection, NBS (2.35 g, 13.2 mmol) and AIBN (0.98 g, 6.0 mmol) were added, and the mixture was heated to 100 °C and stirred for 48 hours. The reaction was monitored by LC-MS until completion. The dissolved solids were removed by concentration, and the residue was purified by silica gel column chromatography to give 3.35 g of a pale yellow solid, with a yield of 75%. LC-MS (APCI): m / z = 372.7 (M+1) + .

[0611] Step 11: Synthesis of compound 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0612] 4-Bromoiodobenzene (2.82 g, 10 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (2.97 g, 15 mmol), Pd2(dba)3 (458 mg, 0.5 mmol), and t-BuXphos (425 mg, 1.0 mmol) were added to the reaction flask. Nitrogen gas was purged three times. 20 mL of 1,4-dioxane was added, and the mixture was heated to 100 °C and stirred overnight under nitrogen protection. The reaction was monitored by TLC until completion. The dissolved solids were removed by concentration, and the residue was purified by silica gel column chromatography to give 2.39 g of a yellow solid, with a yield of 68%. LC-MS (APCI): m / z = 353.3 (M+1) + .

[0613] Step 12: Synthesis of compound 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0614] Compound 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2.39 g, 6.8 mmol), pinacol diborate (3.45 g, 13.6 mmol), Pd(dppf)Cl2 (544 mg, 0.34 mmol), potassium acetate (1.67 g, 17.0 mmol), and 25 mL of 1,4-dioxane were added to a reaction flask. Nitrogen gas was bubbled for 5 minutes, and the mixture was heated to 90 °C for 5–7 hours. After the reaction was complete as detected by TLC, the mixture was concentrated and purified by silica gel column chromatography to obtain 1.9 g of product, with a yield of 70%. LC-MS (APCI): m / z = 401.1 (M+1) + .

[0615] Step 13: Synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione

[0616] 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 10.0 mmol) and 4-piperidinol (1.38 g, 12.0 mmol) were added to a reaction flask and dissolved in 20 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was added, and the mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. The reaction was completed by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 2.48 g of a yellow solid, with a yield of 67%. LC-MS (APCI): m / z = 372.3 (M+1) + .

[0617] Step 14: Synthesis of compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-carboxaldehyde

[0618] Compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione (2.48 g, 6.7 mmol) was added to a reaction flask and dissolved in 20 mL of dichloromethane. Dess-Martin oxidant (4.27 g, 10.1 mmol) was added in portions, and the mixture was stirred at room temperature for 1–2 hours. The reaction was complete by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.2 g of a pale yellow solid, in 49% yield. LC-MS (APCI): m / z = 370.6 (M+1) + .

[0619] Step 15: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)ethyl acetate

[0620] Compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-aminoethyl ethyl hydrochloride (1.06 g, 4.32 mmol) and compound methyl 2-bromomethyl-3-fluoro-5-iodobenzoate (1.61 g, 4.32 mmol) were added to a reaction flask and dissolved in 15 mL of anhydrous DMF. Triethylamine (1.32 g, 13 mmol) was added, and the mixture was heated to 60 °C under nitrogen protection with stirring for 4–6 hours. The reaction was monitored by TLC until completion. Excess water was added for dilution, and the mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.68 g of an off-white solid, in 83% yield. LC-MS (APCI): m / z = 470.2 (M+1) + .

[0621] Step 16: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)acetic acid

[0622] Add ethyl acetate (1.68 g, 3.58 mmol), 10 mL tetrahydrofuran, 10 mL purified water, and lithium hydroxide (86 mg, 3.58 mmol) of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl) to the reaction flask. Stir the mixture at room temperature for 1–3 hours. After the reaction is complete as monitored by TLC, concentrate the solution to remove the solvent. No further purification is required; the solution can be directly added to the next reaction step. LC-MS (APCI): m / z = 442.3 (M+1) + .

[0623] Step 17: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)-N-(thiazol-2-yl)acetamide

[0624] The compound obtained in the previous step, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindololin-2-yl)acetic acid, 2-aminothiazole (537 mmol, 5.37 mmol), HATU (2.04 g, 5.37 mmol), DIEA (925 mg, 7.16 mmol), and 15 mL of anhydrous DMF were added to the reaction flask. The mixture was stirred overnight under nitrogen protection. After the reaction was completed, excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.2 g of an off-white solid. The two-step yield was 64%. LC-MS (APCI): m / z = 524.6 (M+1) + .

[0625] Step 18: Synthesis of compound 6-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0626] Add the following compounds to the reaction flask: 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindololin-2-yl)-N-(thiazolyl-2-yl)acetamide (1.2 g, 2.29 mmol), 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-2,6-diazaspiro[3,3]heptane-2-carboxylic acid tert-butyl ester (1.1 g, 2.75 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (183 mg, 0.11 mmol), sodium carbonate (485 mg, 4.58 mmol), and 10 ml of [amount not specified]. The reaction was carried out under DMF and nitrogen bubbling for 5 minutes, then microwaved to 90°C for 1 hour. The reaction was monitored by TLC until completion. Excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 1.03 g of a pale yellow solid, with a yield of 67%. LC-MS (APCI): m / z = 670.4 (M+1) + .

[0627] Step 19: Synthesis of compound 2-(6-(4-(2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindoline-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazolyl-2-yl)acetamide hydrochloride

[0628] Compound 6-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (100 mg, 0.15 mmol) and 4N 1,4-dioxane hydrochloride solution (3 mL, 12.0 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1-2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. No purification was required before proceeding to the next step of the reaction. LC-MS (APCI): m / z = 570.3 (M+1) + .

[0629] Step 20: Synthesis of compound T-1

[0630] The compound 2-(6-(4-(2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindoline-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazo-2-yl)acetamide hydrochloride, compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (77.5 mg, 0.21 mmol), and 0.5 mL of acetic acid were added to the reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added in portions. The mixture was stirred overnight. The reaction was monitored by TLC until it was complete. After cooling to room temperature, the mixture was concentrated to remove the solvent. The solid was purified by silica gel column chromatography to give 87 mg of off-white solid, with a yield of 63%. LC-MS (APCI): m / z = 923.4 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.67(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.21(m,4H),7.16(d,J=8.9Hz,2H ),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H), 4.02–3.44(m,12H),3.26–2.98(m,4H),2.67–2.20(m,6H),1.58–1.25(m,5H).

[0631] Example 2 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazo-2-yl)acetamide (compound T-2)

[0632] The synthesis is performed using the following route:

[0633] Step 1: Synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azacyclobutane-1-yl)isoindoline-1,3-dione

[0634] 2-(2,6-dioxadiazine-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 10.0 mmol) and 3-azacyclobutane methanol hydrochloride (1.48 g, 12.0 mmol) were added to a reaction flask and dissolved in 20 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was added, and the mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. The reaction was completed by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.71 g of a yellow solid, with a yield of 50%. LC-MS (APCI): m / z = 344.1 (M+1) + .

[0635] Step 2: Synthesis of compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-carboxaldehyde

[0636] Compound 2-(2,6-dioxadiazin-3-yl)-5-(3-(hydroxymethyl)azacyclobutan-1-yl)isoindoline-1,3-dione (1.71 g, 5.0 mmol) was added to a reaction flask and dissolved in 20 mL of dichloromethane. Dess-Martin oxidant (4.27 g, 10.1 mmol) was added in portions, and the mixture was stirred at room temperature for 1–2 hours. The reaction was monitored by TLC until complete. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.12 g of a pale yellow solid, in 66% yield. LC-MS (APCI): m / z = 342.4 (M+1) + .

[0637] Step 3: Synthesis of compound T-2

[0638] Compound 2-(6-(4-(2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindoline-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazo-2-yl)acetamide hydrochloride (91 mg, 0.15 mmol) and compound 1-(2-(2,6-dioxopiperidin-3-yl)-1 3-Dioxoisoindoline-5-yl)azacyclobutane-3-carboxaldehyde (71.6 mg, 0.21 mmol) and 0.5 mL of acetic acid were dissolved in 5 mL of methanol. The solution was heated to 50 °C, and sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added in portions. The mixture was stirred overnight. After the reaction was complete, it was cooled to room temperature, concentrated to remove the solvent, and purified by silica gel column chromatography to give 96 mg of an off-white solid, with a yield of 72%. LC-MS (APCI): m / z = 895.3 (M+1) + . 1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),10.67(s,1H),8.29(s,1H),8.01(d,J =8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.21(m,4H),7.16(d,J=8.7Hz, 2H),6.89(d,J=8.7Hz,2H),5.86(s,1H),4.87(m,1H),4.26(s,2H),4.14(m, 2H),4.02–3.44(m,12H),3.26–2.96(m,4H),2.81–2.35(m,6H),1.37(m,1H).

[0639] Example 3 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)phenyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-3) and its isomers T-3-1, T-3-2 and T-3-3

[0640] The synthesis is performed using the following route:

[0641] Step 1: Synthesis of compound 5-(4-bromophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

[0642] 4-Bromoiodobenzene (2.82 g, 10 mmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylate (3.18 g, 15 mmol), Pd2(dba)3 (458 mg, 0.5 mmol), and t-BuXphos (425 mg, 1.0 mmol) were added to a reaction flask. The mixture was purged with nitrogen three times. 20 mL of 1,4-dioxane was added, and the mixture was heated to 100 °C and stirred overnight under nitrogen protection. The reaction was monitored by TLC until completion. The dissolved solids were removed by concentration, and the residue was purified by silica gel column chromatography to give 2.67 g of a yellow solid, with a yield of 73%. LC-MS (APCI): m / z = 367.5 (M+1) + .

[0643] Step 2: Synthesis of compound 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid tert-butyl ester

[0644] Compounds 5-(4-bromophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (2.49 g, 6.8 mmol), pinacol diboronate (3.45 g, 13.6 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (544 mg, 0.34 mmol), potassium acetate (1.67 g, 17.0 mmol), and 25 mL of 1,4-dioxane were added to a reaction flask. The mixture was bubbled under nitrogen for 5 minutes and heated to 90 °C for 5–7 hours. After the reaction was complete as detected by TLC, the mixture was concentrated and purified by silica gel column chromatography to obtain 1.52 g of product, with a yield of 54%. LC-MS (APCI): m / z = 415.1 (M+1) + .

[0645] Step 3: Synthesis of compound 5-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

[0646] Add the following compounds to the reaction flask: 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindololin-2-yl)-N-(thiazo-2-yl)acetamide (1.2 g, 2.29 mmol), 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (1.14 g, 2.75 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (183 mg, 0.11 mmol), sodium carbonate (485 mg, 4.58 mmol), and 10 ml of [amount not specified]. The reaction was carried out under DMF and nitrogen bubbling for 5 minutes, then microwaved to 90°C for 1 hour. The reaction was monitored by TLC until complete. Excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 1.06 g of a pale yellow solid, with a yield of 68%. LC-MS (APCI): m / z = 684.7 (M+1) + .

[0647] Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-(4-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)phenyl)-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide hydrochloride in step 4

[0648] Compound 5-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (102 mg, 0.15 mmol) and 4N 1,4-dioxane hydrogen chloride solution (3 mL, 12.0 mmol) were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. No purification was required before proceeding to the next reaction step. LC-MS (APCI): m / z = 584.3 (M+1) + .

[0649] Step 5: Synthesis of compound T-3

[0650] The compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-(4-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)phenyl)-1-oxoisoindoline-2-yl)-N-(thiazo-2-yl)acetamide hydrochloride, compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (77.5 mg, 0.21 mmol), and 0.5 mL of acetic acid were added to the reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added in portions. The mixture was stirred overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated to remove the solvent. The solid was purified by silica gel column chromatography to give 77 mg of off-white solid, with a yield of 55%. LC-MS (APCI): m / z = 937.8 (M+1) + . 1 HNMR(400MHz,DMSO-d6)δ11.09(s,1H),10.65(s,1H),8.26(s,1H),8.00(d,J= 8.0Hz,1H),7.88(s,1H),7.59(s,1H),7.50–7.23(m,4H),7.18(d,J=8.3Hz,2H ),6.89(d,J=8.3Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H), 4.02–3.44(m,12H),3.26–2.98(m,4H),2.68–2.17(m,6H),1.57–1.23(m,7H).

[0651] Step 5: Preparation of compounds T-3-1, T-3-2, and T-3-3

[0652] Compound T-3 was separated by reversed-phase preparative chromatography to obtain target products T-3-1 (retention time: 10.15 min, relative content: 19.5%), T-3-2 (retention time: 11.22 min, relative content: 8.1%), and T-3-3 (retention time: 9.45 min, relative content: 72.4%).

[0653] Chromatographic separation conditions:

[0654] Pillar: Waters, Prep C18 OBD TM 150×19mm, 5μm

[0655] Column temperature: 30℃

[0656] Flow rate: 1.0 mL / min

[0657] UV detection wavelength: 220nm

[0658] Mobile phase: 0.1% TFA water:acetonitrile = 35:65

[0659] Example 4 Preparation of 5-(4-((6-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridinecarboxamide (compound T-4)

[0660] The synthesis is performed using the following route:

[0661] Step 1: Synthesis of compound methyl 5-(4-(hydroxymethyl)piperidin-1-yl)pyridinecarboxylate

[0662] 1.55 g (10.0 mmol) of 5-fluoropyridinecarboxylate and 1.38 g (12.0 mmol) of 4-piperidinemethanol were added to a reaction flask and dissolved in 15 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was then added. The mixture was heated to 80 °C and stirred for 10 hours under nitrogen protection. The reaction was complete by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 2.27 g of a pale yellow solid, with a yield of 91%. LC-MS (APCI): m / z = 251.2 (M+1) + .

[0663] Step 2: Synthesis of compound 5-(4-(hydroxymethyl)piperidin-1-yl)pyridinecarboxylic acid

[0664] To a reaction flask, methyl 5-(4-(hydroxymethyl)piperidin-1-yl)pyridinecarboxylate (2.27 g, 9.1 mmol), lithium hydroxide monohydrate (1.9 g, 45.4 mmol), 10 mL tetrahydrofuran, and 10 mL water were added. The mixture was stirred at room temperature for 1–2 hours. The reaction was monitored by TLC until complete. The pH was adjusted to weakly acidic with 1 N dilute hydrochloric acid. The mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.8 g of a pale yellow solid, in 84% yield. LC-MS (APCI): m / z = 237.3 (M+1) + .

[0665] Step 3: Synthesis of compound N-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyridinecarboxamide

[0666] Compounds 5-(4-(hydroxymethyl)piperidin-1-yl)pyridinecarboxylic acid (1.8 g, 7.6 mmol), 3-amino-2,6-piperidinedione (1.5 g, 11.4 mmol), HATU (5.8 g, 15.2 mmol), and DIEA (2.9 g, 22.8 mmol) were added to a reaction flask and dissolved in 20 mL of anhydrous DMF under nitrogen protection. The mixture was stirred overnight at room temperature. After the reaction was complete, excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.66 g of a yellow solid, in 63% yield. LC-MS (APCI): m / z = 347.4 (M+1) + .

[0667] Step 4: Synthesis of compound N-(2,6-dioxopiperidin-3-yl)-5-(4-formylpiperidin-1-yl)pyridinecarboxamide

[0668] N-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyridinecarboxamide (1.66 g, 4.8 mmol) was added to a reaction flask and dissolved in 20 mL of dichloromethane. Dess-Martin oxidant (4.27 g, 10.1 mmol) was added in portions, and the mixture was stirred at room temperature for 1–2 hours. The reaction was complete by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.06 g of a pale yellow solid, in 64% yield. LC-MS (APCI): m / z = 345.5 (M+1) + .

[0669] Step 5: Synthesis of compound T-4

[0670] Compound 2-(6-(4-(2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindoline-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazo-2-yl)acetamide hydrochloride (84.7 mg, 0.14 mmol), compound N-(2,6-dioxopiperidin-3-yl)-5-(4-formylpiperidin-1-yl)pyridinecarboxamide (72.2 mg, 0.21 mmol), and 0.5 mL of acetic acid were added to a reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added in portions. The mixture was stirred overnight, and the reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 50 mg of off-white solid, with a yield of 40%. LC-MS (APCI): m / z = 898.6 (M+1) + . 1 HNMR(400MHz,DMSO-d6)δ11.06(s,1H),10.65(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.24(m,4H),7.21(d,J=8.9Hz,2H ),6.84(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H), 4.05–3.45(m,12H),3.26–2.98(m,4H),2.67–2.07(m,6H),1.60–1.24(m,5H).

[0671] Example 5 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-5)

[0672] The synthesis is performed using the following route:

[0673] Step 1: Synthesis of compound 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0674] 7-Bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (2.27 g, 10 mmol) was added to a reaction flask and dissolved in 20 mL of anhydrous DMF. The mixture was cooled to 0 °C in an ice bath, and 60% sodium hydride (1.2 g, 30 mmol) was added in portions under nitrogen protection. Then, 3-bromopiperidin-2,6-dione (5.76 g, 30 mmol) was added. After the addition was complete, the mixture was cooled to room temperature and stirred overnight. The reaction was quenched with excess water. The mixture was extracted 3-4 times with ethyl acetate, and the organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.11 g of a yellow solid, in 33% yield. LC-MS (APCI): m / z = 338.4 (M+1) + .

[0675] Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-(4-(6-(prop-2-yn-1-yl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)isoindoline-2-yl)-N-(thiazol-2-yl)acetamide in step 2

[0676] Compound 2-(6-(4-(2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindoline-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazolyl-2-yl)acetamide hydrochloride (121 mg, 0.2 mmol), methanesulfonic acid-2-propyn-1-ol (40.2 mg, 0.3 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of dichloromethane were added to a reaction flask. The mixture was stirred at room temperature for 3–4 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration, and the product was purified by silica gel column chromatography to obtain 98.5 mg of a pale yellow oily liquid, with a yield of 81%. LC-MS (APCI): m / z = 608.2 (M+1) )+ .

[0677] Step 3: Synthesis of compound T-5

[0678] Compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-(4-(6-(prop-2-yn-1-yl)-2,6-diazaspiro[3,3]heptane-2-yl)phenyl)isoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (98.5 mg, 0.16 mmol) and compound 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[ [d]Imidazol-1-yl)piperidin-2,6-dione (82 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF were added. The mixture was heated to 70 °C and stirred for 5–7 hours under nitrogen protection. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to give 70 mg of a pale yellow solid, with a yield of 51%. LC-MS (APCI): m / z = 865.5 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),10.67(s,1H),8.26(s,1H),8.01(d,J=8.6 Hz,1H),7.88(s,1H),7.57(s,1H),7.51–7.23(m,4H),7.16(d,J=8.9Hz,2H),6.90 (d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H),4.05–3.4 4(m,12H),3.37(s,3H),3.26–2.98(m,4H),2.68–2.22(m,6H),1.61–1.27(m,5H).

[0679] Example 6 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)prop-2-yn-1-yl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-6)

[0680] The synthesis is performed using the following route:

[0681] Compounds 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-(4-(6-(prop-2-yn-1-yl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)isoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (98.5 mg, 0.16 mmol) and 3-(4-bromo-1-oxoisoindoline-2-yl)piperidine were added to the reaction flask. 2,6-Diketone (78 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF were added. The mixture was heated to 70 °C and stirred for 5–7 hours under nitrogen protection. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to obtain 90 mg of a pale yellow solid, with a yield of 66%. LC-MS (APCI): m / z = 850.3 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),10.68(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.89(s,1H),7.57(s,1H),7.50–7.21(m,4H),7.16(d,J=8.5Hz,2H ),6.89(d,J=8.5Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H), 4.02–3.44(m,12H),3.26–3.01(m,6H),2.67–2.20(m,6H),1.58–1.26(m,5H).

[0682] Example 7 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-(4-(1-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)piperazin-1-yl)methyl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-7) and its isomers T-7-1, T-7-2 and T-7-3

[0683] The synthesis is performed using the following route:

[0684] Step 1: Synthesis of compound 4-(4-ethynylbenzyl)piperazine-1-carboxylic acid tert-butyl ester

[0685] 4-Alynylbenzaldehyde (1.3 g, 10 mmol) and piperazine-1-carboxylic acid tert-butyl ester (2.2 g, 12 mmol) were added to a reaction flask and dissolved in 15 mL of dichloromethane. Sodium cyanoborohydride (754 mg, 12 mmol) was added in portions at room temperature, and the mixture was stirred overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 2.55 g of an off-white solid, in 85% yield. LC-MS (APCI): m / z = 301.4 (M+1) + .

[0686] Step 2: Synthesis of compound 1-(4-ethynylbenzyl)piperazine hydrochloride

[0687] Add 2.55 g (8.5 mmol) of compound 4-(4-ethynylbenzyl)piperazine-1-carboxylic acid tert-butyl ester and 10 mL (40.0 mmol) of 4N 1,4-dioxane hydrogen chloride solution to the reaction flask. Stir the mixture at room temperature for 1–2 hours. After the reaction is complete as monitored by TLC, concentrate the solution to remove the solvent. No purification is required; the solution is directly added to the next reaction step. LC-MS (APCI): m / z = 201.3 (M+1) + .

[0688] Step 3: Synthesis of compound 3-(4-(4-ethynylbenzyl)piperazin-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0689] Compound 1-(4-ethynylbenzyl)piperazine hydrochloride and tert-butyl 3-oxozylate-1-carboxylate (2.18 g, 12.8 mmol) were added to a reaction flask and dissolved in 15 mL of methanol. Sodium cyanoborohydride (754 mg, 12 mmol) was added in portions at room temperature, and the mixture was stirred overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the solvent was removed by concentration, and the solution was purified by silica gel column chromatography to give 1.72 g of an off-white solid, in 57% yield. LC-MS (APCI): m / z = 356.7 (M+1) + .

[0690] Step 4: Synthesis of compound 1-(azacyclobutane-3-yl)-4-(4-ethynylbenzyl)piperazine hydrochloride

[0691] Add 1.72 g (4.8 mmol) of compound 3-(4-(4-ethynylbenzyl)piperazin-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester and 10 mL (40.0 mmol) of 4N 1,4-dioxane hydrogen chloride solution to the reaction flask. Stir the mixture at room temperature for 1–2 hours. After the reaction is complete, monitor the reaction by TLC. Concentrate to remove the solvent. No purification is required; the mixture can be directly added to the next reaction step. LC-MS (APCI): m / z = 256.6 (M+1) + .

[0692] Step 5: Synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-ethynylbenzyl)piperazin-1-yl)azacyclobutane-1-yl)isoindoline-1,3-dione

[0693] Compound 1-(azacyclobutane-3-yl)-4-(4-ethynylbenzyl)piperazine hydrochloride, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (1.38 g, 5.0 mmol), 20 mL DMF, and triethylamine (2.02 g, 20.0 mmol) were added to a reaction flask. The mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. The reaction was completed by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 0.96 g of a yellow solid, with a yield of 39%. LC-MS (APCI): m / z = 512.1 (M+1) + .

[0694] Step 6: Synthesis of compound T-7

[0695] Compound 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-ethynylbenzyl)piperazin-1-yl)azacyclobutane-1-yl)isoindoline-1,3-dione (82 mg, 0.16 mmol) and compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl) were added to the reaction flask. Acetamide (84 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF were added. The mixture was heated to 70 °C and stirred for 5–7 hours under nitrogen protection. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to give 41 mg of an off-white solid, with a yield of 28%. LC-MS (APCI): m / z = 907.3 (M+1) + . 1H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.67(s,1H),8.26(s,1H),8.01(d,J=8.2Hz,1H),7.90(s,1H),7.57(s,1H),7.50–7.21(m,4H),7.16(d,J= 8.9Hz,2H),6.89(d,J=8.9Hz,2H),5.84(s,1H),4.87(m,1H),4.26(s,2H) ,4.14(m,2H),4.02–3.46(m,12H),3.26–2.99(m,5H),2.57–2.18(m,6H).

[0696] Step 7: Preparation of compounds T-7-1, T-7-2, and T-7-3

[0697] Compound T-7 was separated by reversed-phase preparative chromatography to obtain the target products T-7-1 (retention time: 9.69 min, relative content: 21.4%), T-7-2 (retention time: 10.77 min, relative content: 11.3%), and T-7-3 (retention time: 8.45 min, relative content: 67.3%).

[0698] Chromatographic separation conditions:

[0699] Pillar: Waters, Prep C18 OBD TM 150×19mm, 5μm

[0700] Column temperature: 30℃

[0701] Flow rate: 1.0 mL / min

[0702] UV detection wavelength: 220nm

[0703] Mobile phase: 0.1% TFA water: acetonitrile = 30:70

[0704] Example 8 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)piperidin-1-yl)methyl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-8)

[0705] The synthesis is performed using the following route:

[0706] Step 1: Synthesis of compound 3-(1-(4-ethynylbenzyl)piperidin-4-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0707] 4-Alynylbenzaldehyde (1.3 g, 10 mmol) and tert-butyl 3-(piperidin-4-yl)azacyclobutane-1-carboxylic acid (2.9 g, 12 mmol) were added to a reaction flask and dissolved in 20 mL of dichloromethane. Sodium cyanoborohydride (754 mg, 12 mmol) was added in portions at room temperature, and the mixture was stirred overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 2.62 g of an off-white solid, in 74% yield. LC-MS (APCI): m / z = 355.3 (M+1) + .

[0708] Step 2: Synthesis of compound 4-(azacyclobutane-3-yl)-1-(4-ethynylbenzyl)piperidine hydrochloride

[0709] Add 2.62 g (7.4 mmol) of compound 3-(1-(4-ethynylbenzyl)piperidin-4-yl)azacyclobutane-1-carboxylic acid tert-butyl ester and 10 mL (40.0 mmol) of 4N 1,4-dioxane hydrogen chloride solution to the reaction flask. Stir the mixture at room temperature for 1–2 hours. After the reaction is complete, monitor the reaction by TLC. Concentrate to remove the solvent. No purification is required; the mixture can be directly added to the next reaction step. LC-MS (APCI): m / z = 255.3 (M+1) + .

[0710] Step 3: Synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-5-(3-(1-(4-ethynylbenzyl)piperidin-4-yl)azacyclobutane-1-yl)isoindoline-1,3-dione

[0711] Compound 4-(azacyclobutane-3-yl)-1-(4-ethynylbenzyl)piperidine hydrochloride (2.76 g, 10.0 mmol), dissolved in 20 mL of DMF, and triethylamine (2.02 g, 20.0 mmol) were added to a reaction flask. The mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. The reaction was completed by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.51 g of a yellow solid, with a yield of 40%. LC-MS (APCI): m / z = 511.1 (M+1) + .

[0712] Step 4: Synthesis of compound T-8

[0713] Compound 2-(2,6-dioxopiperidin-3-yl)-5-(3-(1-(4-ethynylbenzyl)piperidin-4-yl)azacyclobutane-1-yl)isoindoline-1,3-dione (82 mg, 0.16 mmol) and compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl) were added to the reaction flask. Acetamide (84 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF were added. The mixture was heated to 70 °C and stirred for 5–7 hours under nitrogen protection. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to give 59 mg of an off-white solid, with a yield of 41%. LC-MS (APCI): m / z = 906.4 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.71(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.89(s,1H),7.58(s,1H),7.50–7.21(m,4H),7.16(d,J=8.9Hz,2H ),6.84(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H) ,4.02–3.44(m,8H),3.26–2.98(m,4H),2.67–2.20(m,6H),1.58–1.25(m,5H).

[0714] Example 9 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)piperidin-1-yl)methyl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-9)

[0715] The synthesis is performed using the following route:

[0716] Step 1: Synthesis of compound 4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)piperazine-1-carboxylic acid benzyl ester

[0717] N-tert-butyloxycarbonyl-4-piperidinone (1.99 g, 10 mmol) and benzyl piperazine-1-carboxylate (2.64 g, 12 mmol) were added to a reaction flask and dissolved in 30 mL of dichloromethane. Sodium cyanoborohydride (754 mg, 12 mmol) was added in portions at room temperature, and the mixture was stirred overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 2.54 g of an off-white solid, in 63% yield. LC-MS (APCI): m / z = 404.1 (M+1) + .

[0718] Step 2: Synthesis of compound 4-(piperazin-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0719] Compound 4-(1-(tert-butyloxycarbonyl)piperidin-4-yl)piperazine-1-carboxylic acid benzyl ester (2.54 g, 6.3 mmol) was added to a reaction flask, dissolved in 25 mL of tetrahydrofuran, and 10% palladium on carbon was added as a catalyst. The mixture was purged with hydrogen gas three times, and the mixture was stirred at room temperature for 4–6 hours. The reaction was monitored by TLC until completion. The catalyst was removed by filtration, and the concentrated filtrate was directly added to the next reaction step without further purification. LC-MS (APCI): m / z = 270.3 (M+1) + .

[0720] Step 3: Synthesis of compound 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)piperidin-1-carboxylic acid tert-butyl ester

[0721] The compound 4-(piperazin-1-yl)piperidin-1-carboxylic acid tert-butyl ester and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 10.0 mmol) obtained in the previous step were added to a reaction flask and dissolved in 20 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was added, and the mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. The reaction was completed by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.49 g of a yellow solid, with a yield of 45%. LC-MS (APCI): m / z = 526.5 (M+1) + .

[0722] Step 4: Synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-yl)piperazin-1-yl)isoindoline-1,3-dione hydrochloride

[0723] Add 1.49 g (2.8 mmol) of compound 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)piperidin-1-carboxylic acid tert-butyl ester and 5 mL (20.0 mmol) of 4N 1,4-dioxane hydrochloride solution to the reaction flask. Stir the mixture at room temperature for 1–2 hours. After the reaction is complete, monitor the reaction by TLC. Concentrate the mixture to remove the solvent. No purification is required; the mixture can be directly added to the next reaction step. LC-MS (APCI): m / z = 426.3 (M+1) + .

[0724] Step 5: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-((4-formylphenyl)ethynyl)-1-oxoisoindoline-2-yl)-N-(thiazol-2-yl)acetamide

[0725] 4-Alynylbenzaldehyde (26 mg, 0.2 mmol), compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (105 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF were added to a reaction flask. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to obtain 81 mg of an off-white solid, with a yield of 77%. LC-MS (APCI): m / z = 526.4 (M+1) + .

[0726] Step 6: Synthesis of compound T-9

[0727] Compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-((4-formylphenyl)ethynyl)-1-oxoisoindoline-2-yl)-N-(thiazol-2-yl)acetamide (81 mg, 0.15 mmol) and compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-yl)piperazin-1-yl)isoindoline-1,3-dione hydrochloride (106.5 mg, 0.23 mmol) were added to a reaction flask and dissolved in 5 mL of methanol. Sodium cyanoborohydride (14.5 mg, 0.23 mmol) was added in portions at room temperature, and the mixture was stirred overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to give 67 mg of an off-white solid, with a yield of 48%. LC-MS (APCI): m / z = 935.4 (M+1)+ . 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.67(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.21(m,4H),7.18(d,J=8.9Hz,2H ),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H), 4.02–3.44(m,12H),3.27–2.96(m,4H),2.62–2.17(m,6H),1.58–1.25(m,5H).

[0728] Example 10 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-10)

[0729] The synthesis is performed using the following route:

[0730] Step 1: Synthesis of compound 4-(4-((trimethylsilyl)ethynyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0731] 1-tert-Butoxycarbonyl-4-(4-bromophenyl)piperazine (1.7 g, 5.0 mmol), trimethylsilylacetylene (737 mg, 7.5 mmol), Pd(PPh3)2Cl2 (175 mg, 0.25 mmol), cuprous iodide (95 mg, 0.5 mmol), triethylamine (1.27 g, 12.5 mmol), and 5 mL of anhydrous THF were added to a reaction flask. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.41 g of an off-white solid, yield 79%. LC-MS (APCI): m / z = 359.2 (M+1) + .

[0732] Step 2: Synthesis of compound 4-(4-ethynylphenyl)piperazine-1-carboxylic acid tert-butyl ester

[0733] 1.41 g (3.95 mmol) of 4-(4-((trimethylsilyl)ethynyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester was added to a reaction flask and dissolved in 15 mL of tetrahydrofuran. A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (4.74 mL, 4.74 mmol) was added at room temperature. The mixture was stirred under nitrogen protection for 1–2 hours. After TLC monitoring, the reaction was completed. Excess water was added for dilution, and the mixture was extracted 3–4 times with ethyl acetate. The combined organic phases were washed 2–3 times with saturated brine. The concentrated organic phase was purified by silica gel column chromatography to give 0.85 g of a pale yellow solid (75% yield). LC-MS (APCI): m / z = 287.2 (M+1) + .

[0734] Step 3: Synthesis of compound 4-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0735] Compound 4-(4-ethynylphenyl)piperazine-1-carboxylic acid tert-butyl ester (57.2 mg, 0.2 mmol), compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)-N-(thiazol-2-yl)acetamide (105 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF were added to a reaction flask. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to give 93 mg of an off-white solid, with a yield of 68%. LC-MS (APCI): m / z = 682.5 (M+1) + .

[0736] Step 4: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(piperazin-1-yl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide hydrochloride

[0737] Compound 4-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (93 mg, 0.14 mmol) and a 4N solution of 1,4-dioxane hydrogen chloride (3 mL, 12.0 mmol) were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. No purification was required before proceeding to the next step of the reaction. LC-MS (APCI): m / z = 582.3 (M+1) + .

[0738] Step 5: Synthesis of compound T-10

[0739] The compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(piperazin-1-yl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide hydrochloride obtained in the previous step and compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (106.5 mg, 0.23 mmol) were added to the reaction flask and dissolved in 5 mL of methanol. Sodium cyanoborohydride (14.5 mg, 0.23 mmol) was added in portions at room temperature and the mixture was stirred overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to give 47 mg of off-white solid, with a yield of 36%. LC-MS (APCI): m / z = 935.5 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.67(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.21(m,4H),7.16(d,J=8.9Hz,2H ),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H), 4.02–3.44(m,12H),3.26–2.98(m,4H),2.67–2.20(m,6H),1.58–1.25(m,5H).

[0740] Example 11 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-11)

[0741] The synthesis is performed using the following route:

[0742] Step 1: Synthesis of compound 4-(4-((trimethylsilyl)ethynyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

[0743] N-tert-butoxycarbonyl-4-(4-bromophenyl)piperidine (1.7 g, 5.0 mmol), trimethylsilylacetylene (737 mg, 7.5 mmol), Pd(PPh3)2Cl2 (175 mg, 0.25 mmol), cuprous iodide (95 mg, 0.5 mmol), triethylamine (1.27 g, 12.5 mmol), and 5 mL of anhydrous THF were added to a reaction flask. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to obtain 1.05 g of an off-white solid, with a yield of 59%. LC-MS (APCI): m / z = 358.6 (M+1) + .

[0744] Step 2: Synthesis of compound 4-(4-ethynylphenyl)piperidine-1-carboxylic acid tert-butyl ester

[0745] 1.05 g (2.95 mmol) of 4-(4-((trimethylsilyl)ethynyl)phenyl)piperidin-1-carboxylic acid tert-butyl ester was added to a reaction flask and dissolved in 15 mL of tetrahydrofuran. A 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (4.4 mL, 4.4 mmol) was added at room temperature. The mixture was stirred under nitrogen protection for 1–2 hours. After TLC monitoring, the reaction was completed. Excess water was added for dilution, and the mixture was extracted 3–4 times with ethyl acetate. The combined organic phases were washed 2–3 times with saturated brine. The concentrated organic phase was purified by silica gel column chromatography to give 0.68 g of a pale yellow solid, with a yield of 81%. LC-MS (APCI): m / z = 286.2 (M+1) + .

[0746] Step 3: Synthesis of compound 4-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

[0747] To a reaction flask, compound 4-(4-ethynylphenyl)piperidin-1-carboxylic acid tert-butyl ester (57 mg, 0.2 mmol), compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (105 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF were added. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to give 102 mg of an off-white solid, yield 75%. LC-MS (APCI): m / z = 681.4 (M+1) + .

[0748] Step 4: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(piperidin-4-yl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide hydrochloride

[0749] Compound 4-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)phenyl)piperidin-1-carboxylic acid tert-butyl ester (102 mg, 0.15 mmol) and 4N 1,4-dioxane hydrogen chloride solution (3 mL, 12.0 mmol) were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. No purification was required before proceeding to the next reaction step. LC-MS (APCI): m / z = 581.6 (M+1) + .

[0750] Step 5: Synthesis of compound T-11

[0751] The compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(piperidin-4-yl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide hydrochloride and compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (106.5 mg, 0.23 mmol) obtained in the previous step were added to the reaction flask and dissolved in 5 mL of methanol. Sodium cyanoborohydride (14.5 mg, 0.23 mmol) was added in portions at room temperature and the mixture was stirred overnight. The reaction was monitored by TLC until it was complete. After cooling to room temperature, the mixture was concentrated to remove the solvent and purified by silica gel column chromatography to give 41 mg of off-white solid, with a yield of 29%. LC-MS (APCI): m / z = 934.7 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.69(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.21(m,4H),7.16(d,J=8.9Hz,2H ),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.18(m,2H) ,4.02–3.50(m,7H),3.26–2.95(m,4H),2.67–2.20(m,6H),1.60–1.17(m,9H).

[0752] Example 12 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)piperidin-4-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-12)

[0753] The synthesis is performed using the following route:

[0754] Compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(piperidin-4-yl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide hydrochloride (92 mg, 0.15 mmol), compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-carboxaldehyde (71.6 mg, 0.21 mmol), and 0.5 mL of acetic acid were added to a reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added in portions. The mixture was stirred overnight, and the reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to give 69 mg of an off-white solid, with a yield of 51%. LC-MS (APCI): m / z = 907.3 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.66(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.62(s,1H),7.50–7.21(m,4H),7.16(d,J=8.6Hz,2H ),6.89(d,J=8.6Hz,2H),5.78(s,1H),4.87(m,1H),4.27(s,2H),4.14(m,2H) ,4.02–3.49(m,8H),3.26–2.98(m,4H),2.68–2.20(m,6H),1.63–1.29(m,5H).

[0755] Example 13 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)azacyclobutane-3-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-13)

[0756] The synthesis is performed using the following route:

[0757] Step 1: Synthesis of compound 3-(4-bromophenyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0758] 4-Bromophenylboronic acid (1.41 g, 7.0 mmol), 1-tert-butoxycarbonyl-3-iodoazacyclobutane (2.12 g, 7.5 mmol), nickel iodide (219 mg, 0.7 mmol), sodium bis(trimethylsilyl)amino (14.0 mL, 14.0 mmol), and 15 mL of isopropanol were added to a reaction flask. The mixture was heated to 70 °C and stirred overnight under nitrogen protection. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.55 g of an off-white solid, with a yield of 71%. LC-MS (APCI): m / z = 312.2 (M+1) + .

[0759] Step 2: Synthesis of compound 3-(4-((trimethylsilyl)ethynyl)phenyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0760] To a reaction flask, tert-butyl 3-(4-bromophenyl)azacyclobutane-1-carboxylic acid (1.55 g, 5.0 mmol), trimethylsilylacetylene (737 mg, 7.5 mmol), Pd(PPh3)2Cl2 (175 mg, 0.25 mmol), cuprous iodide (95 mg, 0.5 mmol), triethylamine (1.27 g, 12.5 mmol), and 5 mL of anhydrous THF were added. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.15 g of an off-white solid, in 70% yield. LC-MS (APCI): m / z = 330.3 (M+1) + .

[0761] Step 3: Synthesis of compound 3-(4-(ethynyl)phenyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0762] 1.15 g (3.5 mmol) of tert-butyl 3-(4-((trimethylsilyl)ethynyl)phenyl)azacyclobutane-1-carboxylic acid was added to a reaction flask and dissolved in 15 mL of tetrahydrofuran. A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (4.5 mL, 4.5 mmol) was added at room temperature. The mixture was stirred under nitrogen protection for 1–2 hours. After TLC monitoring, the reaction was completed. Excess water was added for dilution, and the mixture was extracted 3–4 times with ethyl acetate. The combined organic phases were washed 2–3 times with saturated brine. The concentrated organic phase was purified by silica gel column chromatography to give 0.61 g of a pale yellow solid, in 68% yield. LC-MS (APCI): m / z = 258.2 (M+1) + .

[0763] Step 4: Synthesis of compound 3-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)phenyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0764] Compound 3-(4-(ethynyl)phenyl)azacyclobutane-1-carboxylic acid tert-butyl ester (51 mg, 0.2 mmol), compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)-N-(thiazol-2-yl)acetamide (105 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF were added to a reaction flask. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to give 81 mg of an off-white solid, with a yield of 62%. LC-MS (APCI): m / z = 653.5 (M+1) + .

[0765] Step 5: Synthesis of compound 2-(6-((4-(azacyclobutane-3-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazolyl-2-yl)acetamide hydrochloride

[0766] Compound 3-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)phenyl)azacyclobutane-1-carboxylic acid tert-butyl ester (81 mg, 0.12 mmol) and 4N 1,4-dioxane hydrogen chloride solution (3 mL, 12.0 mmol) were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. No purification was required before proceeding to the next reaction step. LC-MS (APCI): m / z = 553.6 (M+1) + .

[0767] Step 6: Synthesis of compound T-13

[0768] The compound 2-(6-((4-(azacyclobutane-3-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazo-2-yl)acetamide hydrochloride, compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (106.5 mg, 0.23 mmol) and 0.5 mL of acetic acid were added to the reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (14.5 mg, 0.23 mmol) was added in portions. The mixture was stirred and reacted overnight. The reaction was monitored by TLC until it was complete. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to give 40 mg of an off-white solid, with a yield of 37%. LC-MS (APCI): m / z = 906.8 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.67(s,1H),8.29(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.21(m,4H),7.16(d,J=8.9Hz,2H ),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H), 4.02–3.44(m,12H),3.26–2.98(m,4H),2.68–2.24(m,6H),1.59–1.25(m,5H).

[0769] Example 14 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)piperazin-1-yl)methyl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-14)

[0770] The synthesis is performed using the following route:

[0771] Step 1: Synthesis of compound 4-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)benzyl)piperazine-1-carboxylic acid tert-butyl ester

[0772] Compound 4-(4-ethynylbenzyl)piperazine-1-carboxylic acid tert-butyl ester (60 mg, 0.2 mmol), compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)-N-(thiazol-2-yl)acetamide (105 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF were added to a reaction flask. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to give 97 mg of an off-white solid, with a yield of 70%. LC-MS (APCI): m / z = 696.6 (M+1) + .

[0773] Step 2: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(piperazin-1-ylmethyl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide hydrochloride

[0774] Compound 4-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)benzyl)piperazine-1-carboxylic acid tert-butyl ester (97 mg, 0.14 mmol) and a 4N solution of 1,4-dioxane hydrogen chloride (3 mL, 12.0 mmol) were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. After the reaction was complete, the solvent was removed by TLC. The mixture was then directly added to the next reaction step without purification. LC-MS (APCI): m / z = 596.5 (M+1) + .

[0775] Step 3: Synthesis of compound T-14

[0776] The compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(piperazin-1-ylmethyl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide hydrochloride, compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-carboxaldehyde (78.4 mg, 0.23 mmol) and 0.5 mL of acetic acid were added to the reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (14.5 mg, 0.23 mmol) was added in portions. The mixture was stirred overnight, and the reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to give 58 mg of an off-white solid, with a yield of 45%. LC-MS (APCI): m / z = 921.2(M+1) + . 1 HNMR(400MHz,DMSO-d6)δ11.06(s,1H),10.64(s,1H),8.26(s,1H),8.01(d, J=8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.27(m,4H),7.16(d,J=8.9Hz ,2H),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.84(m,1H),4.26(s,2H),4.14(m, 2H),4.02–3.44(m,12H),3.26–2.98(m,4H),2.67–2.21(m,6H),1.69(m,1H).

[0777] Example 15 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-15)

[0778] The synthesis is performed using the following route:

[0779] Compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(piperazin-1-ylmethyl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide hydrochloride (95 mg, 0.15 mmol), compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (77.5 mg, 0.21 mmol), and 0.5 mL of acetic acid were added to a reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added in portions. The mixture was stirred overnight, and the reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to give 40 mg of an off-white solid, with a yield of 28%. LC-MS (APCI): m / z = 949.1 (M+1) + . 1 HNMR(400MHz,DMSO-d6)δ11.08(s,1H),10.67(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.59(s,1H),7.50–7.21(m,4H),7.16(d,J=8.9Hz,2H ),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.32(s,2H),4.14(m,2H), 4.02–3.44(m,12H),3.26–2.98(m,4H),2.72–2.26(m,6H),1.59–1.27(m,5H).

[0780] Example 16 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)azacyclobutane-3-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-16) and its isomers T-16-1 and T-16-2

[0781] The synthesis is performed using the following route:

[0782] Step 1: Synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)pyrrolidone-1-yl)isoindoline-1,3-dione

[0783] 2-(2,6-dioxadiazine-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 10.0 mmol) and 3-hydroxymethylpyrrolidine hydrochloride (1.64 g, 12.0 mmol) were added to a reaction flask and dissolved in 20 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was added, and the mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. The reaction was completed by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 2.07 g of a yellow solid, with a yield of 58%. LC-MS (APCI): m / z = 358.6 (M+1) + .

[0784] Step 2: Synthesis of compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-carboxaldehyde

[0785] Compound 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)pyrrolidone-1-yl)isoindoline-1,3-dione (2.07 g, 5.8 mmol) was added to a reaction flask and dissolved in 20 mL of dichloromethane. Dess-Martin oxidant (4.27 g, 10.1 mmol) was added in portions, and the mixture was stirred at room temperature for 1–2 hours. The reaction was complete as determined by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 0.91 g of a pale yellow solid, in 44% yield. LC-MS (APCI): m / z = 356.4 (M+1) + .

[0786] Step 3: Synthesis of compound T-16

[0787] Compound 2-(6-((4-(azacyclobutane-3-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazo-2-yl)acetamide hydrochloride (82.3 mg, 0.14 mmol) and compound 1-(2-(2,6-dioxopiperidin-3-yl)-1 3-Dioxoisoindololin-5-yl)pyrrolidine-3-carboxaldehyde (74.5 mg, 0.21 mmol) and 0.5 mL acetic acid were dissolved in 5 mL methanol. The solution was heated to 50 °C, and sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added in portions. The mixture was stirred overnight. After the reaction was complete, it was cooled to room temperature, concentrated to remove the solvent, and purified by silica gel column chromatography to give 81 mg of an off-white solid, in 65% yield. LC-MS (APCI): m / z = 892.4 (M+1) + . 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.69(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.59(s,1H),7.50–7.21(m,4H),7.16(d,J=8.9Hz,2H ),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.16(m,2H) ,4.02–3.44(m,8H),3.26–2.98(m,4H),2.67–2.21(m,6H),1.58–1.25(m,3H).

[0788] Step 4: Preparation of compounds T-16-1 and T-16-2

[0789] Compound T-16 was separated by reversed-phase preparative chromatography to obtain target products T-16-1 (retention time: 11.96 min, relative content: 23.2%) and T-16-2 (retention time: 11.05 min, relative content: 76.8%).

[0790] Chromatographic separation conditions:

[0791] Pillar: Waters, Prep C18 OBD TM 150×19mm, 5μm

[0792] Column temperature: 30℃

[0793] Flow rate: 1.0 mL / min

[0794] UV detection wavelength: 220nm

[0795] Mobile phase: 0.1% TFA water: acetonitrile = 30:70

[0796] Example 17 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)methyl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-17)

[0797] The synthesis is performed using the following route:

[0798] Compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(piperazin-1-ylmethyl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide hydrochloride (88.3 mg, 0.14 mmol), compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-carboxaldehyde (74.5 mg, 0.21 mmol), and 0.5 mL of acetic acid were added to a reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added in portions. The mixture was stirred overnight, and the reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to give 67 mg of an off-white solid, with a yield of 51%. LC-MS (APCI): m / z = 935.3 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.68(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.54–7.21(m,4H),7.16(d,J=8.9Hz,2H ),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H), 4.02–3.44(m,10H),3.26–2.98(m,4H),2.67–2.21(m,6H),1.55–1.30(m,3H).

[0799] Example 18 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)pyrrolidine-1-yl)methyl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-18) and its isomers T-18-1, T-18-2 and T-18-3

[0800] The synthesis is performed using the following route:

[0801] Step 1: Synthesis of compound 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-carboxylic acid tert-butyl ester

[0802] 2-(2,6-dioxadiazin-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 10.0 mmol) and tert-butyl piperazine-1-carboxylate (2.23 g, 12.0 mmol) were added to a reaction flask and dissolved in 20 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was added, and the mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. The reaction was completed by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 2.87 g of a yellow solid, with a yield of 65%. LC-MS (APCI): m / z = 443.2 (M+1) + .

[0803] Step 2: Synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride

[0804] Add compound 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 2.26 mmol) and a 4N solution of 1,4-dioxane hydrogen chloride (8 mL, 32.0 mmol) to a reaction flask. Stir the mixture at room temperature for 1–2 hours. After the reaction is complete, monitor the reaction by TLC. Concentrate the mixture to remove the solvent. No purification is required; the mixture can be directly added to the next reaction step. LC-MS (APCI): m / z = 343.5 (M+1) + .

[0805] Step 3: Synthesis of compound 3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0806] The compound 2-(2,6-dioxadiazin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride and 1-tert-butoxycarbonyl-3-pyrrolidinecarboxaldehyde (675 mg, 3.4 mmol) obtained in the previous step were added to a reaction flask and dissolved in 15 mL of methanol. The mixture was heated to 50 °C, and sodium cyanoborohydride (214 mg, 3.4 mmol) was added in portions. The mixture was stirred overnight, and the reaction was monitored by TLC until completion. After cooling to room temperature, the solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to give 759 mg of an off-white solid, with a yield of 64%. LC-MS (APCI): m / z = 526.1 (M+1) + .

[0807] Step 4: Synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-(pyrrolidone-3-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione hydrochloride

[0808] Compound 3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (73.5 mg, 0.14 mmol) and 4N 1,4-dioxane hydrochloride solution (3 mL, 12.0 mmol) were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. After the reaction was complete, the solvent was removed by TLC. The solution was then directly added to the next reaction step without purification. LC-MS (APCI): m / z = 426.5 (M+1) + .

[0809] Step 5: Synthesis of compound T-18

[0810] The compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-(pyrrolidin-3-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione hydrochloride, compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-((4-formylphenyl)ethynyl)-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (121 mg, 0.23 mmol) and acetic acid (0.5 mL) were added to the reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (14.5 mg, 0.23 mmol) was added in portions. The mixture was stirred overnight, and the reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 25 mg of off-white solid, with a yield of 19%. LC-MS (APCI): m / z = 935.3 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.67(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.21(m,4H),7.16(d,J=8.9Hz,2H ),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H), 4.02–3.44(m,12H),3.26–2.98(m,4H),2.67–2.20(m,6H),1.58–1.25(m,3H).

[0811] Step 6: Preparation of compounds T-18-1, T-18-2, and T-18-3

[0812] Reversed-phase preparative chromatography was used to separate the target products T-18 to obtain T-18-1 (retention time: 9.22 min, relative content: 8.9%), T-18-2 (retention time: 8.37 min, relative content: 24.7%) and T-18-3 (retention time: 7.58 min, relative content: 66.4%).

[0813] Chromatographic separation conditions:

[0814] Pillar: Waters, Prep C18 OBD TM 150×19mm, 5μm

[0815] Column temperature: 30℃

[0816] Flow rate: 1.0 mL / min

[0817] UV detection wavelength: 220nm

[0818] Mobile phase: 0.1% TFA water: acetonitrile = 30:70

[0819] Example 19 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-((5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazo-2-yl)acetamide (compound T-19) and its isomers T-19-1 and T-19-2

[0820] The synthesis is performed using the following route:

[0821] Step 1: Compound 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)hexahydropyrrolo

[0822] Synthesis of [3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

[0823] 2-(2,6-dioxadiidine-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 10.0 mmol) and tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.55 g, 12.0 mmol) were added to a reaction flask and dissolved in 20 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was added, and the mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. The reaction was completed by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 2.2 g of a yellow solid, with a yield of 47%. LC-MS (APCI): m / z = 469.4 (M+1) + .

[0824] Step 2: Synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-5-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)isoindoline-1,3-dione hydrochloride

[0825] Add 70 mg (0.15 mmol) of 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester and 3 mL (12.0 mmol) of 4N hydrogen chloride solution to the reaction flask. Stir the mixture at room temperature for 1–2 hours. After the reaction is complete as monitored by TLC, concentrate the solution to remove the solvent. No purification is required; the solution is directly added to the next reaction step. LC-MS (APCI): m / z = 369.5 (M+1) + .

[0826] Step 3: Synthesis of compound T-19

[0827] The compound 2-(2,6-dioxopiperidin-3-yl)-5-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)isoindoline-1,3-dione hydrochloride, compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-((4-formylphenyl)ethynyl)-1-oxoisoindoline-2-yl)-N-(thiazo-2-yl)acetamide (121 mg, 0.23 mmol) and acetic acid (0.5 mL) were added to the reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (14.5 mg, 0.23 mmol) was added in portions. The mixture was stirred overnight, and the reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to give 20 mg of off-white solid, with a yield of 15%. LC-MS (APCI): m / z = 878.2(M+1) + . 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.67(s,1H),8.26(s,1H),7.98(d,J=8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.51–7.23(m,4H),7.18(d,J= 8.9Hz,2H),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H) ,4.14(m,2H),4.02–3.44(m,10H),3.26–2.99(m,4H),2.55–2.18(m,4H).

[0828] Step 4: Preparation of compounds T-19-1 and T-19-2

[0829] Compound T-19 was separated by reversed-phase preparative chromatography to obtain target products T-19-1 (retention time: 9.27 min, relative content: 13.5%) and T-19-2 (retention time: 8.36 min, relative content: 86.5%).

[0830] Chromatographic separation conditions:

[0831] Pillar: Waters, Prep C18 OBD TM 150×19mm, 5μm

[0832] Column temperature: 30℃

[0833] Flow rate: 1.0 mL / min

[0834] UV detection wavelength: 220nm

[0835] Mobile phase: 0.1% TFA water: acetonitrile = 40:60

[0836] Example 20 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-((6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,6-diazaspiro[3.3]heptane-2-yl)methyl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazo-2-yl)acetamide (compound T-20)

[0837] The synthesis is performed using the following route:

[0838] Step 1: Synthesis of compound 6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0839] 2-(2,6-dioxadiazin-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 10.0 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (2.35 g, 12.0 mmol) were added to a reaction flask and dissolved in 20 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was added, and the mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. The reaction was completed by TLC. The solvent was removed by concentration, and the solid was purified by silica gel column chromatography to obtain 1.32 g of yellow solid, with a yield of 29%. LC-MS (APCI): m / z = 455.1 (M+1) + .

[0840] Step 2: Synthesis of compound 2-(2,6-dioxadiazin-3-yl)-5-(2,6-diazaspiro[3.3]heptane-2-yl)isoindoline-1,3-dione hydrochloride

[0841] Compound 6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (68 mg, 0.15 mmol) and 4N 1,4-dioxane hydrogen chloride solution (3 ml, 12.0 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1-2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. No purification was required before proceeding to the next step of the reaction. LC-MS (APCI): m / z = 355.2 (M+1) + .

[0842] Step 3: Synthesis of compound T-20

[0843] The compound 2-(2,6-dioxopiperidin-3-yl)-5-(2,6-diazaspiro[3.3]heptane-2-yl)isoindoline-1,3-dione hydrochloride, compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-((4-formylphenyl)ethynyl)-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (121 mg, 0.23 mmol) and 0.5 ml of acetic acid were added to the reaction flask. The mixture was dissolved in 5 ml of methanol, heated to 50 °C, and sodium cyanoborohydride (14.5 mg, 0.23 mmol) was added in portions. The mixture was stirred overnight, and the reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 14 mg of off-white solid, with a yield of 11%. LC-MS (APCI): m / z = 864.5 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.67(s,1H),8.29(s,1H),8.00(d,J=8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.21(m,4H),7.16(d,J= 8.5Hz,2H),6.89(d,J=8.5Hz,2H),5.82(s,1H),4.87(m,1H),4.29(s,2H ),4.14(m,2H),4.02–3.44(m,8H),3.26–2.98(m,4H),2.44–2.21(m,2H).

[0844] Example 21 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazo-2-yl)acetamide (compound T-21) and its isomers T-21-1 and T-21-2

[0845] The synthesis is performed using the following route:

[0846] Step 1: Synthesis of compound 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0847] 2-(2,6-dioxadiazin-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 10.0 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (2.71 g, 12.0 mmol) were added to a reaction flask and dissolved in 20 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was added, and the mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. The reaction was completed by TLC. The solvent was removed by concentration, and the solid was purified by silica gel column chromatography to obtain 2.02 g of yellow solid, with a yield of 42%. LC-MS (APCI): m / z = 483.2 (M+1) + .

[0848] Step 2: Synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonane-2-yl)isoindoline-1,3-dione hydrochloride

[0849] Compound 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (72 mg, 0.15 mmol) and 4N hydrogen chloride solution of 1,4-dioxane (3 mL, 12.0 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1-2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. No purification was required before proceeding to the next reaction step. LC-MS (APCI): m / z = 383.6 (M+1) + .

[0850] Step 3: Synthesis of compound T-21

[0851] The compound 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonane-2-yl)isoindoline-1,3-dione hydrochloride, compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-((4-formylphenyl)ethynyl)-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (121 mg, 0.23 mmol) and 0.5 ml of acetic acid were added to the reaction flask. The mixture was dissolved in 5 ml of methanol, heated to 50 °C, and sodium cyanoborohydride (14.5 mg, 0.23 mmol) was added in portions. The mixture was stirred overnight, and the reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 43 mg of off-white solid, with a yield of 32%. LC-MS (APCI): m / z = 892.5(M+1) + . 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.68(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.21(m,4H),7.17(d,J=8.9Hz,2H ),6.90(d,J=8.9Hz,2H),5.82(s,1H),4.85(m,1H),4.23(s,2H),4.17(m,2H) ,4.02–3.44(m,8H),3.26–2.98(m,4H),2.63–2.21(m,6H),1.58–1.25(m,5H).

[0852] Preparation of compounds T-21-1 and T-21-2 in step 4

[0853] Compound T-21 was separated by reversed-phase preparative chromatography to obtain target products T-21-1 (retention time: 12.07 min, relative content: 22.2%) and T-21-2 (retention time: 10.12 min, relative content: 77.8%).

[0854] Chromatographic separation conditions:

[0855] Pillar: Waters, Prep C18 OBD TM 150×19mm, 5μm

[0856] Column temperature: 30℃

[0857] Flow rate: 1.0 mL / min

[0858] UV detection wavelength: 220nm

[0859] Mobile phase: 0.1% TFA water: acetonitrile = 30:70

[0860] Example 22 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-(((8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-1-oxa-8-azaspiro[4.5]decane-3-yl)amino)methyl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-22)

[0861] The synthesis is performed using the following route:

[0862] Step 1: Synthesis of tert-butyl carbamate (8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-1-oxa-8-azaspiro[4.5]decane-3-yl)

[0863] 2-(2,6-dioxadiazin-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 10.0 mmol) and tert-butyl 1-oxa-8-azaspiro[4.5]decane-3-ylcarbamate (3.07 g, 12.0 mmol) were added to a reaction flask and dissolved in 20 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was added, and the mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. The reaction was completed by TLC. The solvent was removed by concentration, and the solid was purified by silica gel column chromatography to obtain 2.61 g of yellow solid, with a yield of 51%. LC-MS (APCI): m / z = 513.5 (M+1) + .

[0864] Step 2: Synthesis of compound 5-(3-amino-1-oxa-8-azaspiro[4.5]decane-8-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride

[0865] Compound (77 mg, 0.15 mmol) of tert-butyl carbamate (8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-1-oxa-8-azaspiro[4.5]decane-3-yl) and a 4N solution of 1,4-dioxane hydrogen chloride (3 mL, 12.0 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1-2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. The mixture was then directly added to the next reaction step without purification. LC-MS (APCI): m / z = 413.2 (M+1) + .

[0866] Step 3: Synthesis of compound T-22

[0867] The compound 5-(3-amino-1-oxa-8-azaspiro[4.5]decane-8-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride, compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-((4-formylphenyl)ethynyl)-1-oxoisoindoline-2-yl)-N-(thiazo-2-yl)acetamide (121 mg, 0.23 mmol) and acetic acid (0.5 mL) were added to the reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (14.5 mg, 0.23 mmol) was added in portions. The mixture was stirred overnight. The reaction was monitored by TLC until it was complete. After cooling to room temperature, the mixture was concentrated to remove the solvent. The solid was purified by silica gel column chromatography to obtain 46 mg of off-white solid, with a yield of 33%. LC-MS (APCI): m / z = 922.1 (M+1) + . 1 HNMR(400MHz,DMSO-d6)δ11.04(s,1H),10.65(s,1H),8.30(s,1H),8.05(d,J =8.2Hz,1H),7.89(s,1H),7.57(s,1H),7.50–7.20(m,4H),7.16(d,J=8.3Hz,2 H),6.89(d,J=8.3Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H) ,4.02–3.44(m,8H),3.26–2.98(m,4H),2.67–2.20(m,6H),1.47–1.22(m,6H).

[0868] Example 23 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-((4-(1-(4-(4-(4-methoxyphenyl)-4-oxobut-2-enoyl)azacyclobutane-3-yl)phenyl)ethynyl)-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-23)

[0869] The synthesis is performed using the following route:

[0870] Compounds 2-(6-((4-(azacyclobutan-3-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazolyl-2-yl)acetamide hydrochloride (82.3 mg, 0.14 mmol), 3-(4-methoxybenzoyl)acrylic acid (43 mg, 0.21 mmol), HATU (80 mg, 0.21 mmol), DIEA (45 mg, 0.35 mmol), and 3 mL of anhydrous DMF were added to a reaction flask. The mixture was stirred at room temperature under nitrogen protection for 4–6 hours. After the reaction was complete as detected by TLC, the mixture was concentrated and purified by silica gel column chromatography to give 69 mg of a pale yellow solid, with a yield of 67%. LC-MS (APCI): m / z = 741.1 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),8.26(s,1H),8.01(d,J=8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.33–7.20 (m,4H),7.11(d,J=6.6Hz,2H),6.89(d,J=6.6Hz,2H),5.82(s,1H),3.58(s,3H),3.26–2.91(m,4H),2.33(m,1H).

[0871] Example 24 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-((4-((4-(4-(4-(4-(4-methoxyphenyl)-4-oxobut-2-enoyl)piperazin-1-yl)methyl)phenyl)ethynyl)-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-24) and its isomers T-24-1, T-24-2 and T-24-3

[0872] The synthesis is performed using the following route:

[0873] Compounds 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(piperazin-1-ylmethyl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide hydrochloride (88.3 mg, 0.14 mmol), 3-(4-methoxybenzoyl)acrylic acid (43 mg, 0.21 mmol), HATU (80 mg, 0.21 mmol), DIEA (45 mg, 0.35 mmol), and 3 mL of anhydrous DMF were added to a reaction flask. The mixture was stirred at room temperature under nitrogen protection for 4–6 hours. After the reaction was complete, the solution was concentrated and purified by silica gel column chromatography to give 59 mg of a pale yellow solid, with a yield of 54%. LC-MS (APCI): m / z = 784.2 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),8.26(s,1H),8.01(d,J=8.4Hz,1H),7.88(s,1H),7.60(s,1H),7.33 –7.20(m,4H),7.13(d,J=6.6Hz,2H),6.90(d,J=6.6Hz,2H),5.82(s,1H),3.59(s,3H),3.26–2.75(m,8H).

[0874] Compound T-24 was separated by reversed-phase preparative chromatography to obtain the target products T-24-1 (retention time: 9.03 min, relative content: 24.7%), T-24-2 (retention time: 10.88 min, relative content: 15.7%), and T-24-3 (retention time: 8.09 min, relative content: 59.6%).

[0875] Chromatographic separation conditions:

[0876] Pillar: Waters, Prep C18 OBD TM 150×19mm, 5μm

[0877] Column temperature: 30℃

[0878] Flow rate: 1.0 mL / min

[0879] UV detection wavelength: 220nm

[0880] Mobile phase: 0.1% TFA water: acetonitrile = 30:70

[0881] Example 25 Preparation of 5-(4-((3-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)phenyl)azacyclobutane-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxoperidin-3-yl)pyridinecarboxamide (compound T-25)

[0882] The synthesis is performed using the following route:

[0883] Compound 2-(6-((4-(azacyclobutan-3-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazo-2-yl)acetamide hydrochloride (88.2 mg, 0.15 mmol), compound N-(2,6-dioxopiperidin-3-yl)-5-(4-formylpiperidin-1-yl)pyridinecarboxamide (79.1 mg, 0.23 mmol), and 0.5 mL of acetic acid were added to a reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (14.5 mg, 0.23 mmol) was added in portions. The mixture was stirred and reacted overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to give 75 mg of an off-white solid, with a yield of 57%. LC-MS (APCI): m / z = 881.3(M+1) + . 1 HNMR(400MHz,DMSO-d6)δ11.08(s,1H),10.67(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.21(m,4H),7.16(d,J=8.9Hz,2H ),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H), 4.02–3.44(m,12H),3.26–2.98(m,4H),2.67–2.20(m,6H),1.58–1.25(m,5H).

[0884] Example 26 Preparation of 4-(4-((3-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)phenyl)azacyclobutane-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxoperidin-3-yl)-2-fluorobenzamide (compound T-26)

[0885] The synthesis is performed using the following route:

[0886] Step 1: Synthesis of compound methyl 2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzoate

[0887] 1.72 g (10.0 mmol) of methyl 2,4-difluorobenzoate and 1.38 g (12.0 mmol) were added to a reaction flask and dissolved in 15 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was then added. The mixture was heated to 80 °C and stirred for 10 hours under nitrogen protection. The reaction was complete by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 2.24 g of a pale yellow solid, with a yield of 84%. LC-MS (APCI): m / z = 268.2 (M+1) + .

[0888] Step 2: Synthesis of compound 2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid

[0889] Methyl 2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (2.24 g, 8.4 mmol), lithium hydroxide monohydrate (1.9 g, 45.4 mmol), 10 mL tetrahydrofuran, and 10 mL water were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. The reaction was monitored by TLC until complete. The pH was adjusted to weakly acidic with 1 N dilute hydrochloric acid. The mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 2.0 g of a pale yellow solid, 94% yield. LC-MS (APCI): m / z = 254.5 (M+1) + .

[0890] Step 3: Synthesis of compound N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzamide

[0891] Compounds 2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid (2.0 g, 7.9 mmol), 3-amino-2,6-piperidinedione (1.5 g, 11.4 mmol), HATU (5.8 g, 15.2 mmol), and DIEA (2.9 g, 22.8 mmol) were added to a reaction flask and dissolved in 20 mL of anhydrous DMF under nitrogen protection. The mixture was stirred overnight at room temperature. After the reaction was complete, excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 2.12 g of a yellow solid, 74% yield. LC-MS (APCI): m / z = 364.7 (M+1) + .

[0892] Step 4: Synthesis of compound N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-1-yl)benzamide

[0893] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzamide (2.12 g, 5.85 mmol) was added to a reaction flask and dissolved in 25 mL of dichloromethane. Dess-Martin oxidant (4.94 g, 11.7 mmol) was added in portions, and the mixture was stirred at room temperature for 2–4 hours. The reaction was complete by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.16 g of a pale yellow solid, in 55% yield. LC-MS (APCI): m / z = 362.3 (M+1) + .

[0894] Step 5: Synthesis of compound T-26

[0895] Compound 2-(6-((4-(azacyclobutan-3-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazo-2-yl)acetamide hydrochloride (82.3 mg, 0.14 mmol), compound N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-1-yl)benzamide (75.8 mg, 0.21 mmol), and 0.5 mL of acetic acid were added to a reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added in portions. The mixture was stirred and reacted overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to give 60 mg of a pale yellow solid, with a yield of 48%. LC-MS (APCI): m / z = 898.6 (M+1) + . 1HNMR(400MHz,DMSO-d6)δ11.06(s,1H),10.67(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.56(s,1H),7.48–7.22(m,4H),7.16(d,J=8.9Hz,2H ),6.89(d,J=8.9Hz,2H),5.80(s,1H),4.87(m,1H),4.23(s,2H),4.12(m,2H), 4.01–3.47(m,12H),3.26–2.98(m,4H),2.69–2.22(m,6H),1.60–1.27(m,5H).

[0896] Example 27 Preparation of 5-(3-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)phenyl)azacyclobutane-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridinecarboxamide (compound T-27)

[0897] The synthesis is performed using the following route:

[0898] Step 1: Synthesis of compound 3-(4-ethynylphenyl)azacyclobutane hydrochloride

[0899] Add 2.57 g (10.0 mmol) of 3-(4-ethynylphenyl)azacyclobutane-1-carboxylic acid tert-butyl ester and 20 mL (80.0 mmol) of 4N 1,4-dioxane hydrogen chloride solution to the reaction flask. Stir the mixture at room temperature for 1–2 hours. After the reaction is complete as monitored by TLC, concentrate the solution to remove the solvent. No purification is required; the solution is directly added to the next reaction step. LC-MS (APCI): m / z = 158.2 (M+1) + .

[0900] Step 2: Synthesis of compound methyl 5-(3-(4-ethynylphenyl)azacyclobutan-1-yl)pyridinecarboxylate

[0901] 1.55 g (10.0 mmol) of methyl 5-fluoropyridinecarboxylate and 1.93 g (10.0 mmol) of compound 3-(4-ethynylphenyl)azacyclobutane hydrochloride were added to a reaction flask and dissolved in 15 mL of DMF. Triethylamine (2.02 g (20.0 mmol) was added, and the mixture was heated to 80 °C and stirred for 10 hours under nitrogen protection. The reaction was complete by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.81 g of a pale yellow solid, with a yield of 62%. LC-MS (APCI): m / z = 293.2 (M+1) + .

[0902] Step 3: Synthesis of compound 5-(3-(4-ethynylphenyl)azacyclobutan-1-yl)pyridinecarboxylic acid

[0903] To a reaction flask, methyl 5-(3-(4-ethynylphenyl)azacyclobutan-1-yl)pyridinecarboxylate (1.81 g, 6.2 mmol), lithium hydroxide monohydrate (1.9 g, 45.4 mmol), 10 mL tetrahydrofuran, and 10 mL water were added. The mixture was stirred at room temperature for 1–2 hours. The reaction was monitored by TLC until complete. The pH was adjusted to weakly acidic with 1 N dilute hydrochloric acid. The mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.52 g of a pale yellow solid, in 88% yield. LC-MS (APCI): m / z = 279.5 (M+1) + .

[0904] Synthesis of compound N-(2,6-dioxopiperidin-3-yl)-5-(3-(4-ethynylphenyl)azacyclobutane-1-yl)pyridinecarboxamide in step 4

[0905] Compounds 5-(3-(4-ethynylphenyl)azacyclobutan-1-yl)pyridinecarboxylic acid (1.52 g, 5.5 mmol), 3-amino-2,6-piperidinidone (1.5 g, 11.4 mmol), HATU (5.8 g, 15.2 mmol), and DIEA (2.9 g, 22.8 mmol) were added to a reaction flask and dissolved in 20 mL of anhydrous DMF under nitrogen protection. The mixture was stirred overnight at room temperature. After the reaction was complete, excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.47 g of a yellow solid, in 69% yield. LC-MS (APCI): m / z = 389.5 (M+1) + .

[0906] Step 5: Synthesis of compound T-27

[0907] The following compounds were added to a reaction flask: N-(2,6-dioxopiperidin-3-yl)-5-(3-(4-ethynylphenyl)azacyclobutane-1-yl)pyridinecarboxamide (78 mg, 0.2 mmol), 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)-N-(thiazo-2-yl)acetamide (105 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to obtain 110 mg of an off-white solid, with a yield of 70%. LC-MS (APCI): m / z = 784.6 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.67(s,1H),8.30(s,1H),8.01(d,J=8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.21(m,4H),7.21(d,J= 8.9Hz,2H),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.88(m,1H),4.26(s,2H ),4.16(m,2H),4.05–3.44(m,8H),3.26–2.98(m,2H),2.34–2.25(m,4H).

[0908] Example 28 Preparation of 4-(3-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)phenyl)azacyclobutane-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (compound T-28) and its isomers T-28-1 and T-28-2

[0909] The synthesis is performed using the following route:

[0910] Step 1: Synthesis of compound methyl 4-(3-(4-ethynylphenyl)azacyclobutane-1-yl)-2-fluorobenzoate

[0911] 1.72 g (10.0 mmol) of methyl 2,4-difluorobenzoate and 1.93 g (10.0 mmol) of compound 3-(4-ethynylphenyl)azacyclobutane hydrochloride were added to a reaction flask and dissolved in 15 mL of DMF. Triethylamine (2.02 g (20.0 mmol) was added, and the mixture was heated to 80 °C and stirred for 10 hours under nitrogen protection. The reaction was complete by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.48 g of a pale yellow solid, with a yield of 48%. LC-MS (APCI): m / z = 310.6 (M+1) + .

[0912] Step 2: Synthesis of compound 4-(3-(4-ethynylphenyl)azacyclobutane-1-yl)-2-fluorobenzoic acid

[0913] Methyl 4-(3-(4-ethynylphenyl)azacyclobutan-1-yl)-2-fluorobenzoate (1.48 g, 4.8 mmol), lithium hydroxide monohydrate (1.0 g, 24.0 mmol), 10 mL tetrahydrofuran, and 10 mL water were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. The reaction was monitored by TLC until complete. The pH was adjusted to weakly acidic with 1 N dilute hydrochloric acid. The mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.15 g of a pale yellow solid, in 81% yield. LC-MS (APCI): m / z = 296.5 (M+1) + .

[0914] Synthesis of compound N-(2,6-dioxopiperidin-3-yl)-4-(3-(4-ethynylphenyl)azacyclobutane-1-yl)-2-fluorobenzamide in step 3

[0915] Compounds 4-(3-(4-ethynylphenyl)azacyclobutan-1-yl)-2-fluorobenzoic acid (1.15 g, 3.9 mmol), 3-amino-2,6-piperidinedione (1.5 g, 11.4 mmol), HATU (5.8 g, 15.2 mmol), and DIEA (2.9 g, 22.8 mmol) were added to a reaction flask and dissolved in 20 mL of anhydrous DMF under nitrogen protection. The mixture was stirred overnight at room temperature. After the reaction was complete, excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 0.88 g of a yellow solid, in 56% yield. LC-MS (APCI): m / z = 406.2 (M+1) + .

[0916] Step 4: Synthesis of compound T-28

[0917] The following compounds were added to a reaction flask: N-(2,6-dioxopiperidin-3-yl)-4-(3-(4-ethynylphenyl)azacyclobutane-1-yl)-2-fluorobenzamide (81 mg, 0.2 mmol), 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)-N-(thiazo-2-yl)acetamide (105 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to obtain 75 mg of an off-white solid, with a yield of 47%. LC-MS (APCI): m / z = 801.1(M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.71(s,1H),8.30(s,1H),8.01(d,J=8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.20(m,4H),7.21(d,J= 8.9Hz,2H),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.89(m,1H),4.26(s,2H ),4.16(m,2H),4.05–3.44(m,6H),3.26–2.96(m,2H),2.34–2.29(m,4H).

[0918] Step 5: Preparation of compounds T-28-1 and T-28-2

[0919] Compound T-28 was separated by reversed-phase preparative chromatography to obtain target products T-28-1 (retention time: 8.34 min, relative content: 9.7%) and T-28-2 (retention time: 7.58 min, relative content: 90.3%).

[0920] Chromatographic separation conditions:

[0921] Pillar: Waters, Prep C18 OBD TM 150×19mm, 5μm

[0922] Column temperature: 30℃

[0923] Flow rate: 1.0 mL / min

[0924] UV detection wavelength: 220nm

[0925] Mobile phase: 0.1% TFA water: acetonitrile = 40:60

[0926] Example 29 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-((4-(1-(3-(2,6-dioxopiperidin-3-yl)phenyl)azacyclobutane-3-yl)piperazin-1-yl)methyl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-29) and its isomers T-29-1 and T-29-2

[0927] The synthesis is performed using the following route:

[0928] Step 1: Synthesis of compound 1-(3-bromophenyl)azacyclobutane-3-ol

[0929] 3-Bromoiodobenzene (973 mg, 3.45 mmol), aziridine-3-ol hydrochloride (168 mg, 2.3 mmol), cuprous iodide (7.6 mg, 0.04 mmol), L-proline (264 mg, 2.3 mmol), cesium carbonate (960 mg, 4.5 mmol), and 15 mL of anhydrous DMF were added to a reaction flask. The mixture was microwaved to 120 °C and reacted for 2 hours. The reaction was monitored by TLC until complete. After concentration, the reaction solution was purified by silica gel column chromatography to obtain 402 mg of product, with a yield of 77%. LC-MS (APCI): m / z = 228.1 (M+1) + .

[0930] Step 2: Synthesis of compound 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)azacyclobutane-3-ol

[0931] The following compounds were added to a reaction flask: 1-(3-bromophenyl)azacyclobutane-3-ol (402 mg, 1.77 mmol), pinacol diborate (900 mg, 3.54 mmol), Pd(dppf)Cl2 (64.7 mg, 0.09 mmol), potassium acetate (442 mg, 4.5 mmol), and 15 mL of 1,4-dioxane. The mixture was heated to 100 °C and reacted for 4–6 hours. The reaction was monitored by TLC until complete. After concentration, the reaction solution was purified by silica gel column chromatography to obtain 277 mg of product, yield 57%. LC-MS (APCI): m / z = 276.3 (M+1) + .

[0932] Step 3: Synthesis of compound 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)azacyclobutane-3-ol

[0933] Compound 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)azacyclobutane-3-ol (277 mg, 1.01 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (561 mg, 1.51 mmol), Pd(dppf)Cl2 (64.7 mg, 0.09 mmol), sodium carbonate (318 mg, 3.0 mmol), and 10 mL of anhydrous DMF were added to a reaction flask and dissolved. Nitrogen was bubbled for 5 minutes, and the mixture was heated to 90 °C and stirred for 5–6 hours. The reaction mixture was monitored by TLC until the reactants were fully reacted. The reaction solution was poured into 100 mL of ice water and extracted 2–3 times with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain 292 mg of a pale yellow solid, yield 66%. LC-MS (APCI): m / z = 439.3 (M+1). + .

[0934] Step 4: Synthesis of compound 3-(3-(3-hydroxyazacyclobutane-1-yl)phenyl)piperidine-2,6-dione

[0935] Compound 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)azacyclobutane-3-ol (292 mg, 0.67 mmol) was added to a reaction flask, dissolved in 10 mL of methanol, and a catalytic amount of palladium on carbon was added. The mixture was purged with hydrogen gas three times, and stirred overnight at room temperature. The reaction was monitored by TLC until completion. The catalyst was removed by filtration, and the filtrate was concentrated and purified by silica gel column chromatography to give 164 mg of an off-white solid, with a yield of 94%. LC-MS (APCI): m / z = 261.6 (M+1) + .

[0936] Step 5: Synthesis of compound 3-(3-(3-oxoazacyclobutane-1-yl)phenyl)piperidine-2,6-dione

[0937] Compound 3-(3-(3-hydroxyazacyclobutan-1-yl)phenyl)piperidin-2,6-dione (164 mg, 0.63 mmol) and 10 mL of anhydrous dichloromethane were added to a reaction flask. Dess-Martin oxidant (441 mg, 1.04 mmol) was added in portions at room temperature. The mixture was stirred under nitrogen protection for 4–6 hours after addition. The reaction was monitored by TLC until completion. The reaction was quenched with saturated sodium bicarbonate solution. The organic phase was separated and washed twice, successively with saturated sodium bicarbonate solution and saturated brine. After concentration, the solution was purified by silica gel column chromatography to obtain 86 mg of a pale yellow solid, with a yield of 53%. LC-MS (APCI): m / z = 259.1 (M+1) + .

[0938] Step 6: Synthesis of compound T-29

[0939] Compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(piperazin-1-ylmethyl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide hydrochloride (88.3 mg, 0.14 mmol), compound 3-(3-(3-oxozyracyclobutane-1-yl)phenyl)piperidine-2,6-dione (54.2 mg, 0.21 mmol), and 0.5 mL of acetic acid were added to a reaction flask. The solution was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added in portions. The mixture was stirred overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the solution was concentrated to remove the solvent. The solution was purified by silica gel column chromatography to give 43 mg of a pale yellow solid, with a yield of 37%. LC-MS (APCI): m / z = 838.6 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.65(s,1H),8.26(s,1H),8.01(d,J=8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.22(m,4H),7.19(d, J=8.4Hz,2H),6.70(d,J=8.4Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s ,2H),4.14(m,2H),4.02–3.47(m,12H),3.26–2.93(m,2H),2.68(m,1H).

[0940] Step 7: Preparation of compounds T-29-1 and T-29-2

[0941] Compound T-29 was separated by reversed-phase preparative chromatography to obtain target products T-29-1 (retention time: 9.08 min, relative content: 10.3%) and T-29-2 (retention time: 8.34 min, relative content: 89.7%).

[0942] Chromatographic separation conditions:

[0943] Pillar: Waters, Prep C18 OBD TM 150×19mm, 5μm

[0944] Column temperature: 30℃

[0945] Flow rate: 1.0 mL / min

[0946] UV detection wavelength: 220nm

[0947] Mobile phase: 0.1% TFA water: acetonitrile = 40:60

[0948] Example 30 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-((4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azacyclobutane-3-yl)piperazin-1-yl)methyl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-30) and its isomers T-30-1, T-30-2 and T-30-3

[0949] The synthesis is performed using the following route:

[0950] Following the synthetic method of compound T-29, 3-bromoiodobenzene (973 mg, 3.45 mmol) was replaced with 4-bromoiodobenzene (973 mg, 3.45 mmol). After 6 steps, compound T-30 was obtained as a white solid (37 mg), with an overall yield of 6.4%. LC-MS (APCI): m / z = 838.3 (M+1). + . 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),10.62(s,1H),8.26(s,1H),7.96(d,J=8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.22(m,4H),7.14(d, J=8.6Hz,2H),6.70(d,J=8.6Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s ,2H),4.13(m,2H),4.02–3.47(m,12H),3.26–2.91(m,2H),2.68(m,1H).

[0951] Compound T-30 was separated by reversed-phase preparative chromatography to obtain target products T-30-1 (retention time: 9.38 min, relative content: 13.8%), T-30-2 (retention time: 10.37 min, relative content: 5.7%), and T-30-3 (retention time: 8.66 min, relative content: 80.5%).

[0952] Chromatographic separation conditions:

[0953] Pillar: Waters, Prep C18 OBD TM 150×19mm, 5μm

[0954] Column temperature: 30℃

[0955] Flow rate: 1.0 mL / min

[0956] UV detection wavelength: 220nm

[0957] Mobile phase: 0.1% TFA water: acetonitrile = 30:70

[0958] Example 31 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidin-4-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-31)

[0959] The synthesis is performed using the following route:

[0960] Compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(piperidin-4-yl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide hydrochloride (86.2 mg, 0.14 mmol), compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-carboxaldehyde (74.6 mg, 0.21 mmol), and 0.5 mL of acetic acid were added to a reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added in portions. The mixture was stirred overnight, and the reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to give 54 mg of a pale yellow solid, with a yield of 42%. LC-MS (APCI): m / z = 920.5(M+1) + . 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.65(s,1H),8.26(s,1H),8.01(d,J =8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.22(m,4H),7.16(d,J=8.9Hz ,2H),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.27(s,2H),4.14(m ,2H),4.03–3.45(m,8H),3.26(m,1H),2.68–2.21(m,3H),1.62–1.27(m,7H).

[0961] Example 32 Preparation of 5-(3-((4-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)phenyl)piperidin-1-yl)methyl)azacyclobutane-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridinecarboxamide (compound T-32)

[0962] The synthesis is performed using the following route:

[0963] Step 1: Synthesis of compound methyl 5-(3-(hydroxymethyl)azacyclobutane-1-yl)pyridinecarboxylate

[0964] 1.55 g (10.0 mmol) of methyl 5-fluoropyridinecarboxylate and 1.48 g (12.0 mmol) of 3-hydroxymethylazine hydrochloride were added to a reaction flask and dissolved in 15 mL of DMF. Triethylamine (2.02 g (20.0 mmol) was then added. The mixture was heated to 80 °C and stirred for 10 hours under nitrogen protection. The reaction was complete by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.6 g of a pale yellow solid, with a yield of 72%. LC-MS (APCI): m / z = 223.5 (M+1) + .

[0965] Step 2: Synthesis of compound 5-(3-(hydroxymethyl)azacyclobutan-1-yl)pyridinecarboxylic acid

[0966] To a reaction flask, methyl 5-(3-(hydroxymethyl)azacyclobutan-1-yl)pyridinecarboxylate (1.6 g, 7.2 mmol), lithium hydroxide monohydrate (1.9 g, 45.4 mmol), 10 mL tetrahydrofuran, and 10 mL water were added. The mixture was stirred at room temperature for 1–2 hours. The reaction was monitored by TLC until complete. The pH was adjusted to weakly acidic with 1 N dilute hydrochloric acid. The mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.33 g of a pale yellow solid, in 89% yield. LC-MS (APCI): m / z = 209.1 (M+1) + .

[0967] Step 3: Synthesis of compound N-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azacyclobutane-1-yl)pyridinecarboxamide

[0968] Compounds 5-(3-(hydroxymethyl)azacyclobutan-1-yl)pyridinecarboxylic acid (1.33 g, 6.4 mmol), 3-amino-2,6-piperidinidone (1.5 g, 11.4 mmol), HATU (5.8 g, 15.2 mmol), and DIEA (2.9 g, 22.8 mmol) were added to a reaction flask and dissolved in 20 mL of anhydrous DMF under nitrogen protection. The mixture was stirred overnight at room temperature. After the reaction was complete, excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.36 g of a yellow solid, in 67% yield. LC-MS (APCI): m / z = 319.4 (M+1) + .

[0969] Synthesis of compound N-(2,6-dioxopiperidin-3-yl)-5-(3-formylazetane-1-yl)pyridinecarboxamide in step 4

[0970] N-(2,6-dioxoperidin-3-yl)-5-(3-(hydroxymethyl)azacyclobutane-1-yl)pyridinecarboxamide (1.36 g, 4.3 mmol) was added to a reaction flask and dissolved in 20 mL of dichloromethane. Dess-Martin oxidant (4.27 g, 10.1 mmol) was added in portions, and the mixture was stirred at room temperature for 1–2 hours. The reaction was complete by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 0.87 g of a pale yellow solid, in 64% yield. LC-MS (APCI): m / z = 317.5 (M+1) + .

[0971] Step 5: Synthesis of compound T-32

[0972] Compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(piperidin-4-yl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide hydrochloride (86.2 mg, 0.14 mmol), compound N-(2,6-dioxopiperidin-3-yl)-5-(3-formylazacyclobutane-1-yl)pyridinecarboxamide (66.4 mg, 0.21 mmol), and 0.5 mL of acetic acid were added to a reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added in portions. The mixture was stirred and reacted overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to give 70 mg of an off-white solid, with a yield of 57%. LC-MS (APCI): m / z = 881.4(M+1) + . 1H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.67(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.51–7.21(m,4H),7.16(d,J=8.9Hz,2H ),6.89(d,J=8.9Hz,2H),5.80(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H), 4.02–3.44(m,12H),3.26–2.98(m,4H),2.67–2.21(m,6H),1.59–1.25(m,5H).

[0973] Example 33 Preparation of 4-(3-((4-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)phenyl)piperidin-1-yl)methyl)azacyclobutane-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (compound T-33)

[0974] Following the preparation method of Example 32, methyl 5-fluoropyridinecarboxylate (1.55 g, 10.0 mmol) was replaced with methyl 2,4-difluorobenzoate (1.72 g, 10.0 mmol) to prepare compound T-33, a 75 mg off-white solid, in 60% yield. LC-MS (APCI): m / z = 898.4 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.66(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.51–7.22(m,4H),7.16(d,J=8.9Hz,2H ),6.89(d,J=8.9Hz,2H),5.81(s,1H),4.88(m,1H),4.26(s,2H),4.17(m,2H), 4.02–3.44(m,12H),3.26–2.94(m,4H),2.64–2.26(m,6H),1.58–1.30(m,5H).

[0975] Example 34 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)piperidin-1-yl)methyl)phenyl)ethynyl)-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-34)

[0976] The synthesis is performed using the following route:

[0977] Step 1: Synthesis of compound 5-iodo-2-methyl-3-trifluoromethylbenzoic acid

[0978] 2-Methyl-3-trifluoromethylbenzoic acid (4.08 g, 20 mmol) was added to a reaction flask and dissolved in 30 mL of concentrated sulfuric acid. The mixture was cooled to 0 °C in an ice bath. 1,3-Diiodo-5,5-dimethylhydantoin (9.12 g, 24 mmol) was added in portions. After the addition was complete, the mixture was brought to room temperature and stirred for 3–5 hours. The reaction was monitored by TLC until complete. The reaction solution was slowly added dropwise to ice water, precipitating a yellow solid. The solid was filtered, and the filter cake was dried under vacuum to obtain 3.9 g of yellow solid, with a yield of 59%. LC-MS (APCI): m / z = 330.9 (M+1) + .

[0979] Step 2: Synthesis of compound methyl 5-iodo-2-methyl-3-trifluoromethylbenzoate

[0980] 3.9 g (11.8 mmol) of 5-iodo-2-methyl-3-trifluoromethylbenzoic acid was added to a reaction flask and dissolved in 20 mL of DMF. Potassium carbonate (3.65 g, 26.4 mmol) and methyl iodoform (2.8 g, 19.8 mmol) were added sequentially. After addition, the mixture was stirred at room temperature for 4–6 hours. The reaction was monitored by TLC until complete. Excess water was added for dilution, and the mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 3.57 g of a yellow solid, in 88% yield. LC-MS (APCI): m / z = 344.8 (M+1) + .

[0981] Step 3: Synthesis of compound methyl 5-iodo-2-(bromomethyl)-3-trifluoromethylbenzoate

[0982] 3.57 g (10.4 mmol) of methyl 5-iodo-2-methyl-3-trifluoromethylbenzoate was added to a reaction flask and dissolved in 60 mL of anhydrous trifluorotoluene. Under nitrogen protection, NBS (2.35 g, 13.2 mmol) and AIBN (0.98 g, 6.0 mmol) were added, and the mixture was heated to 100 °C and stirred for 48 hours. The reaction was monitored by LC-MS until completion. The dissolved solids were removed by concentration, and the residue was purified by silica gel column chromatography to give 2.72 g of a pale yellow solid, with a yield of 62%. LC-MS (APCI): m / z = 422.7 (M+1) + .

[0983] Step 4: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-iodo-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)ethyl acetate

[0984] To a reaction flask, 1.06 g (4.32 mmol) of ethyl acetate 2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) hydrochloride and methyl 5-iodo-2-(bromomethyl)-3-trifluoromethylbenzoate (1.82 g (4.32 mmol) were added and dissolved in 15 mL of anhydrous DMF. Triethylamine (1.32 g (13 mmol)) was added, and the mixture was heated to 60 °C under nitrogen protection with stirring for 4–6 hours. The reaction was monitored by TLC until complete. After dilution with excess water, the mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.77 g of an off-white solid, 79% yield. LC-MS (APCI): m / z = 520.2 (M+1) + .

[0985] Step 5: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-iodo-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)acetic acid

[0986] Add ethyl acetate (1.77 g, 3.4 mmol), 10 mL tetrahydrofuran, 10 mL purified water, and lithium hydroxide (86 mg, 3.58 mmol) of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-iodo-1-oxo-4-(trifluoromethyl)isoindoline-2-yl) to the reaction flask. Stir the mixture at room temperature for 1–3 hours. After the reaction is complete as monitored by TLC, concentrate the solution to remove the solvent. No further purification is required; the solution can be directly added to the next reaction step. LC-MS (APCI): m / z = 492.3 (M+1) + .

[0987] Step 6: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-iodo-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)-N-(thiazolyl)acetamide

[0988] The compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-iodo-1-oxo-4-(trifluoromethyl)isoindololin-2-yl)acetic acid, 2-aminothiazole (537 mmol, 5.37 mmol), HATU (2.04 g, 5.37 mmol), DIEA (925 mg, 7.16 mmol), and 15 mL of anhydrous DMF were added to the reaction flask. The mixture was stirred overnight under nitrogen protection. After the reaction was complete, excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.25 g of an off-white solid. The yields of steps 5 and 6 were 64%. LC-MS (APCI): m / z = 574.1 (M+1) + .

[0989] Step 7: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-formylphenyl)ethynyl)-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)-N-(thiazol-2-yl)acetamide

[0990] Compounds 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-iodo-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide (115 mg, 0.2 mmol), 4-ynylbenzaldehyde (26 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF were added to a reaction flask. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to give 68 mg of an off-white solid, with a yield of 59%. LC-MS (APCI): m / z = 576.6 (M+1) + .

[0991] Step 8: Synthesis of compound T-34

[0992] Compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-formylphenyl)ethynyl)-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide (68 mg, 0.12 mmol), compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-yl)piperazin-1-yl)isoindoline-1,3-dione hydrochloride (92 mg, 0.2 mmol), and 0.5 mL of acetic acid were added to a reaction flask. The solution was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added in portions. The mixture was stirred overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the solution was concentrated to remove the solvent. The solution was purified by silica gel column chromatography to give 74 mg of an off-white solid, with a yield of 63%. LC-MS (APCI): m / z = 985.4 (M+1) + . 1 HNMR(400MHz,DMSO-d6)δ11.08(s,1H),10.67(s,1H),8.26(s,1H),8.01(d,J =8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.51–7.22(m,4H),7.16(d,J=8.9Hz,2 H),6.89(d,J=8.9Hz,2H),5.81(s,1H),4.85(m,1H),4.29(s,2H),4.16(m,2H) ,4.05–3.46(m,8H),3.26–2.98(m,4H),2.67–2.21(m,4H),1.50–1.29(m,4H).

[0993] Example 35 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)piperidin-1-yl)methyl)phenyl)ethynyl)-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide (compound T-35)

[0994] The synthesis is performed using the following route:

[0995] Add compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-iodo-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide (115 mg, 0.2 mmol) and compound 2-(2,6-dioxopiperidin-3-yl)-5-(3-(1-(4-ethynylbenzyl)piperidin-4-yl)azacyclobutane-1-yl)isoindoline to the reaction flask. 1,3-Diketone (102 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF were added. The mixture was heated to 70 °C and stirred for 5–7 hours under nitrogen protection. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to give 51 mg of an off-white solid, yield 27%. LC-MS (APCI): m / z = 944.3 (M+1) + . 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.67(s,1H),8.26(s,1H),8.01(d,J =8.2Hz,1H),7.89(s,1H),7.59(s,1H),7.50–7.21(m,4H),7.16(d,J=8.9Hz ,2H),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m ,2H),4.02–3.44(m,8H),2.98(m,2H),2.44–2.27(m,3H),1.59–1.27(m,5H).

[0996] Example 36 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)azacyclobutane-3-yl)phenyl)ethynyl)-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide (compound T-36)

[0997] The synthesis is performed using the following route:

[0998] Step 1: Synthesis of compound 3-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-3-oxo-7-(trifluoromethyl)isoindoline-5-yl)ethynyl)phenyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0999] Compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-iodo-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide (115 mg, 0.2 mmol), compound 3-(4-ethynylphenyl)azacyclobutane-1-carboxylic acid tert-butyl ester (51.4 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF were added to a reaction flask. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to obtain 98 mg of an off-white solid, with a yield of 70%. LC-MS (APCI): m / z = 703.3(M+1) + .

[1000] Step 2: Synthesis of compound 2-(6-((4-(azacyclobutane-3-yl)phenyl)ethynyl)-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazolyl-2-yl)acetamide hydrochloride

[1001] Compound 3-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-3-oxo-7-(trifluoromethyl)isoindoline-5-yl)ethynyl)phenyl)azacyclobutane-1-carboxylic acid tert-butyl ester (98 mg, 0.14 mmol) and 4N 1,4-dioxane hydrochloride solution (3 mL, 12.0 mmol) were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. No purification was required before proceeding to the next reaction step. LC-MS (APCI): m / z = 603.1 (M+1) + .

[1002] Step 3: Synthesis of compound T-36

[1003] The compound 2-(6-((4-(azacyclobutan-3-yl)phenyl)ethynyl)-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazo-2-yl)acetamide hydrochloride, compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (92 mg, 0.2 mmol) and 0.5 mL of acetic acid were added to the reaction flask. The mixture was dissolved in 5 mL of methanol, heated to 50 °C, and sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added in portions. The mixture was stirred and reacted overnight. The reaction was monitored by TLC until it was complete. After cooling to room temperature, the mixture was concentrated to remove the solvent, and purified by silica gel column chromatography to give 68 mg of an off-white solid, with a yield of 51%. LC-MS (APCI): m / z = 956.4 (M+1) + . 1 HNMR(400MHz,DMSO-d6)δ11.08(s,1H),10.68(s,1H),8.26(s,1H),8.01(d,J= 8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.22(m,4H),7.19(d,J=8.6Hz,2H ),6.89(d,J=8.6Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H),4.14(m,2H), 4.02–3.44(m,12H),3.26–2.98(m,2H),2.67–2.21(m,4H),1.58–1.25(m,5H).

[1004] Example 37 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)azacyclobutane-3-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-37)

[1005] The synthesis is performed using the following route:

[1006] Step 1: Synthesis of compound 4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[1007] 2.32 g (20.0 mmol) of tert-butyl acetate was added to the reaction flask and dissolved in 25 mL of anhydrous THF. The mixture was cooled to -78 °C under nitrogen protection, and 11.0 mL (22.0 mmol) of tetrahydrofuran solution of LDA was slowly added dropwise. After the addition was complete, the mixture was stirred at low temperature for 0.5–1 hour. Then, 1.99 g (10.0 mmol) of N-tert-butyloxycarbonyl-4-piperidinone was slowly added dropwise. After the addition was complete, the mixture was gradually heated to room temperature and reacted for 5–7 hours. The reaction was monitored by TLC until completion. The reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain 2.05 g of a colorless oily liquid, with a yield of 65%. LC-MS (APCI): m / z = 316.3 (M+1) + .

[1008] Step 2: Synthesis of compound 2-(4-hydroxypiperidin-4-yl)tert-butyl acetate hydrochloride

[1009] Add 2.05 g (6.5 mmol) of compound 4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester and 18 mL (72.0 mmol) of 4N 1,4-dioxane hydrogen chloride solution to the reaction flask. Stir the mixture at room temperature for 1–2 hours. After the reaction is complete, monitor the reaction by TLC. Concentrate the mixture to remove the solvent. No purification is required; the mixture can be directly added to the next reaction step. LC-MS (APCI): m / z = 216.1 (M+1) + .

[1010] Step 3: Synthesis of compound 2-(1-(2-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate

[1011] The compound 2-(4-hydroxypiperidin-4-yl)tert-butyl acetate hydrochloride, obtained in the previous step, 3,4-difluoronitrobenzene (1.03 g, 6.5 mmol), and DIEA (1.64 g, 16.25 mmol) were added to the reaction flask and dissolved in 15 mL of DMF. The mixture was heated to 100 °C and stirred for 4–6 hours. The reaction was monitored by TLC until completion. After cooling to room temperature, excess water was added to quench the reaction. The mixture was extracted 3–4 times with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated, and purified by silica gel column chromatography to give 1.89 g of a pale yellow solid, with a yield of 82%. LC-MS (APCI): m / z = 355.2 (M+1) + .

[1012] Step 4: Synthesis of compound 2-(1-(2-fluoro-4-aminophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate

[1013] 1.89 g (5.33 mmol) of 2-(1-(2-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate was added to a reaction flask and dissolved in 20 mL of tetrahydrofuran. A catalytic amount of palladium on carbon was added, and the mixture was purged with hydrogen gas three times. The reaction was carried out at room temperature for 2-4 hours using a hydrogen balloon. After the reaction was complete as monitored by TLC, the catalyst was removed by filtration. The filtrate was concentrated and used directly in the next reaction without further purification. LC-MS (APCI): m / z = 325.4 (M+1) + .

[1014] Step 5: Synthesis of compound 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate

[1015] The compound obtained in the previous step, 2-(1-(2-fluoro-4-aminophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate, 3-bromopiperidin-2,6-dione (2.05 g, 10.7 mmol), sodium bicarbonate (1.34 g, 16.0 mmol), and 20 mL of DMF were added to the reaction flask. The mixture was heated to 70 °C and stirred overnight under nitrogen protection. The reaction was monitored by TLC until completion. After cooling to room temperature, excess water was added to quench the reaction. The mixture was extracted 3-4 times with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated, and purified by silica gel column chromatography to give 1.71 g of a pale blue solid, with a yield of 74%. LC-MS (APCI): m / z = 436.3 (M+1) + .

[1016] Step 6: Synthesis of compound 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid

[1017] 1.71 g (3.94 mmol) of 2-(1-(4-((2,6-dioxopiridine-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate and 10 mL (40.0 mmol) of 4N 1,4-dioxane hydrochloride solution were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the residue was lyophilized to give 1.4 g of a pale blue solid. Yield: 94%. LC-MS (APCI): m / z = 380.5 (M+1) + .

[1018] Step 7: Synthesis of compound T-37

[1019] Compound 2-(6-((4-(azacyclobutan-3-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazo-2-yl)acetamide hydrochloride (82.3 mg, 0.14 mmol), compound 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid (79.6 mg, 0.21 mmol), HATU (80 mg, 0.21 mmol), DIEA (45 mg, 0.35 mmol), and 3 mL of anhydrous DMF were added to a reaction flask. The mixture was stirred at room temperature under nitrogen protection for 4–6 hours. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography to give 63 mg of an off-white solid, with a yield of 49%. LC-MS (APCI): m / z = 914.2(M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),10.67(s,1H),8.29(s,1H),8.01(d,J=8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.22(m,4H),7.18(d,J= 8.9Hz,2H),6.89(d,J=8.9Hz,2H),5.86(s,1H),4.89(m,1H),4.31(s,2H ),4.14(m,2H),4.02–3.44(m,8H),3.06–2.77(m,6H),2.20–1.59(m,4H).

[1020] Example 38 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)pyrrolidine-3-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-38) and its isomers T-38-1 and T-38-2

[1021] The synthesis is performed using the following route:

[1022] Step 1: Synthesis of compound 3-(4-((trimethylsilyl)ethynyl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[1023] 1.63 g (5.0 mmol) of 3-(4-bromophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester, 737 mg (7.5 mmol) of trimethylsilylacetylene, 175 mg (0.25 mmol) of Pd(PPh3)2Cl2, 95 mg (0.5 mmol) of cuprous iodide, 1.27 g (12.5 mmol) of triethylamine, and 5 mL of anhydrous THF were added to a reaction flask. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to obtain 1.39 g of a pale yellow solid, with a yield of 81%. LC-MS (APCI): m / z = 344.3 (M+1) + .

[1024] Step 2: Synthesis of compound 3-(4-(ethynyl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[1025] 1.39 g (4.05 mmol) of tert-butyl 3-(4-(trimethylsilyl)ethynyl)phenyl)pyrrolidine-1-carboxylic acid was added to a reaction flask and dissolved in 15 mL of tetrahydrofuran. A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (4.5 mL, 4.5 mmol) was added at room temperature. The mixture was stirred under nitrogen protection for 1–2 hours. After TLC monitoring, the reaction was completed. Excess water was added for dilution, and the mixture was extracted 3–4 times with ethyl acetate. The combined organic phases were washed 2–3 times with saturated brine. The concentrated organic phase was purified by silica gel column chromatography to give 0.65 g of a pale yellow solid, with a yield of 59%. LC-MS (APCI): m / z = 272.2 (M+1) + .

[1026] Step 3: Synthesis of compound 3-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[1027] Compound 3-(4-(ethynyl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (54 mg, 0.2 mmol), compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)-N-(thiazol-2-yl)acetamide (105 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF were added to a reaction flask. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to give 84 mg of an off-white solid, with a yield of 63%. LC-MS (APCI): m / z = 667.1 (M+1) + .

[1028] Step 4: Synthesis of compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(pyrrolidine-3-yl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide hydrochloride

[1029] Compound 3-(4-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (84 mg, 0.13 mmol) and 4N 1,4-dioxane hydrochloride solution (3 mL, 12.0 mmol) were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. No purification was required before proceeding to the next step of the reaction. LC-MS (APCI): m / z = 567.6 (M+1) + .

[1030] Step 5: Synthesis of compound T-38

[1031] The compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(pyrrolidine-3-yl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide hydrochloride, compound 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid (79.6 mg, 0.21 mmol), HATU (80 mg, 0.21 mmol), DIEA (45 mg, 0.35 mmol), and 3 ml of anhydrous DMF were added to the reaction flask. The mixture was stirred at room temperature under nitrogen protection for 4-6 hours. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography to give 63 mg of off-white solid, with a yield of 52%. LC-MS (APCI): m / z = 928.5 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.69(s,1H),8.27(s,1H),8.01(d,J=8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.21(m,4H),7.16(d,J= 6.8Hz,2H),6.90(d,J=6.8Hz,2H),5.82(s,1H),4.87(m,1H),4.29(s,2H ),4.14(m,2H),4.02–3.44(m,8H),3.06–2.71(m,6H),2.21–1.55(m,6H).

[1032] Step 6: Preparation of compounds T-38-1 and T-38-2

[1033] Compound T-38 was separated by reversed-phase preparative chromatography to obtain target products T-38-1 (retention time: 10.20 min, relative content: 15.5%) and T-38-2 (retention time: 9.08 min, relative content: 84.5%).

[1034] Chromatographic separation conditions:

[1035] Pillar: Waters, Prep C18 OBD TM 150×19mm, 5μm

[1036] Column temperature: 30℃

[1037] Flow rate: 1.0 mL / min

[1038] UV detection wavelength: 220nm

[1039] Mobile phase: 0.1% TFA water:acetonitrile = 35:65

[1040] Example 39 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((4-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperidin-4-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-39)

[1041] The synthesis is performed using the following route:

[1042] Compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-((4-(piperidin-4-yl)phenyl)ethynyl)isoindoline-2-yl)-N-(thiazo-2-yl)acetamide hydrochloride (74 mg, 0.12 mmol), compound 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid (79.6 mg, 0.21 mmol), HATU (80 mg, 0.21 mmol), DIEA (45 mg, 0.35 mmol), and 3 mL of anhydrous DMF were added to a reaction flask. The mixture was stirred at room temperature under nitrogen protection for 4–6 hours. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography to give 70 mg of an off-white solid, with a yield of 62%. LC-MS (APCI): m / z = 942.3 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.69(s,1H),8.26(s,1H),8.01(d,J=8.2Hz,1H),7.88(s,1H),7.57(s,1H),7.50–7.22(m,4H),7.18(d,J= 8.9Hz,2H),6.89(d,J=8.9Hz,2H),5.82(s,1H),4.87(m,1H),4.26(s,2H ),4.14(m,2H),4.02–3.44(m,8H),3.08–2.76(m,6H),2.17–1.48(m,8H).

[1043] Example 40 Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-((2-(2-(1-(4-(((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)ethynyl)-4-fluoro-1-oxoisoindoline-2-yl)-N-(thiazolyl-2-yl)acetamide (compound T-40)

[1044] The synthesis is performed using the following route:

[1045] Step 1: Synthesis of compound 6-((trimethylsilyl)ethynyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester

[1046] 1.56 g (5.0 mmol) of 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester, 737 mg (7.5 mmol) of trimethylsilylacetylene, 175 mg (0.25 mmol) of Pd(PPh3)2Cl2, 95 mg (0.5 mmol) of cuprous iodide, 1.27 g (12.5 mmol) of triethylamine, and 5 mL of anhydrous THF were added to a reaction flask. The mixture was heated to 70 °C under nitrogen protection and stirred for 5–7 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.23 g of a pale yellow solid, with a yield of 75%. LC-MS (APCI): m / z = 330.6 (M+1) + .

[1047] Step 2: Synthesis of compound 6-(ethynyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester

[1048] 1.23 g (3.74 mmol) of 6-((trimethylsilyl)ethynyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester was added to a reaction flask and dissolved in 15 mL of tetrahydrofuran. A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (4.5 mL, 4.5 mmol) was added at room temperature. The mixture was stirred under nitrogen protection for 1–2 hours. After TLC monitoring, the reaction was completed. Excess water was added for dilution, and the mixture was extracted 3–4 times with ethyl acetate. The combined organic phases were washed 2–3 times with saturated brine. The concentrated organic phase was purified by silica gel column chromatography to give 0.65 g of a pale yellow solid, with a yield of 68%. LC-MS (APCI): m / z = 258.2 (M+1) + .

[1049] Step 3: Synthesis of compound 6-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindoline-5-yl)ethynyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester

[1050] Compound 6-(ethynyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (51.4 mg, 0.2 mmol), compound 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindolin-2-yl)-N-(thiazolyl-2-yl)acetamide (105 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (9.2 mg, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of anhydrous THF were added to a reaction flask. The mixtu...

Claims

1. A compound of Formula (I): ###0001### (I) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof. wherein represents a single or double bond; X is C(O) or N; Ring A is C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R; Ring B is C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R; R1is H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3- 6 cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R; R2and R3are each independently H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R; R4is H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R; R5and R6are each independently H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl, or R5and R6together with the C atom to which they are attached form a C 3-6 cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R; L is -SO- (L1) i -S1- (L2) j -S2- (L3) k -S3-; wherein i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is other than 0; S0 is a bond, -O-, -S-, -NR a -, a (CR b R c ) p -, b R c ) p NR a -, a (CR b R c ) p -, b R c ) p C(O)NR a -, b R c ) p -, b R c ) p C(O)-, -NR a C(O)(CR b R c ) p -, b R c ) p NR a C(O)-, -(CR b R c ) p - or -(CR b R c CR b R c O) q -; S1, S2and S3are each independently a bond, -O-, -S-, -NR a -, -NR a (CR b R c ) p -, -(CR b R c ) p NR a -, -C(O)-, -C(O)NR a -, -NR a C(O)-, -C(O)NR a (CR b R c ) p -, -(CR b R c ) p C(O)NR a -, -C(O)(CR b R c ) p -, -(CR b R c ) p C(O)-, -NR a C(O)(CR b R c ) p -, -(CR b R c ) p NR a C(O)-, -S(O)2-, -S(O)2NR a -, -NR a S(O)2-, -S(O)2NR a (CR b R c ) p -, -(CR b R c ) p S(O)2NR a -, -S(O)2(CR b R c ) p -, -(CR b R c ) p S(O)2-, -NR a S(O)2(CR b R c ) p -, -(CR b R c ) p NR a S(O)2-, -(CR b R c ) p - or -(CR b R c CR b R c O) q -; each L1, L2, and L3 is independently a divalent group selected from a 3-6 membered monocyclic carbocyclic ring, a 4-7 membered monocyclic heterocyclic ring, a 6-10 membered fused carbocyclic ring, a 6-10 membered fused heterocyclic ring, a 6-10 membered bridged carbocyclic ring, a 6-10 membered bridged heterocyclic ring, a 6-9 membered spiro carbocyclic ring, or a 6-9 membered spiro heterocyclic ring; wherein the above groups are optionally substituted with one or more R'; or, when S0 is a chemical bond and i is 1, ring A shares two contiguous ring atoms and a chemical bond with L1; Each R a Each independently is H or C 1-6 alkyl; each R b and R c each independently H, D, -OH, -CN, halogen, C 1-6 alkyl or C 1-6 haloalkyl; p is 1, 2, 3, or 4; q is 1, 2, or 3; each R and R' is independently D, -CN, -OH, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl; U is selected from the group consisting of formula (U A ), formula (U B ), formula (U C ), formula (U D ), formula (U E ), formula (U F ), formula (U G ), formula (U H ), formula (U J ), formula (U K ), formula (U L ), formula (U M ), formula (U N ), formula (U O ), formula (U P ): wherein represents a single or double bond; each V is independently a bond, C(O), NH, O, S, C(O)NH, C(O)NH, or CH2; each W is independently a bond, C(O), NH, O, S, C(O)NH, C(O)NH, or CH2; each Q1 is independently C(O) or C(R9)2; each Q2 is independently N or CH; each Q3 and Q4 is independently N or CR9; each K1, K2, and K3 is independently N or CR9; K4 and K5 are each independently N or C; H1 is N, C, or CR9; H2 and H3 are each independently C(O), N, O, S, NR9, CR9, or C(R9)2; H4 is N or CR9; H5, H6, and H7 are each independently C(O), O, S, NR9, or C(R9)2; each R7is independently H or C 1-6 alkyl; each R8is independently D, halo, C 1-6 alkyl or C 1-6 haloalkyl; or two R8together with the atoms to which they are attached form a C 3-7 cycloalkane or 4-7 membered heterocycle; each R9is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R9together with the atoms to which they are attached form a C 3-7 cycloalkane, 4- to 7-membered heterocycle, C 6-10 arene or 5- to 10-membered heteroarene; each o is independently 0, 1, or 2; each h is independently 0, 1, 2, 3, or 4; each z is independently 0, 1, or 2; each r, s, t, and u is independently 0, 1, 2, 3, or 4.

2. The compound of claim 1, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of Formula (I): wherein represents a single or double bond; X is C(O) or N; Ring A is C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R; Ring B is C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R; R1is H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3- 6 cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R; R2and R3are each independently H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R; R4is H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R; R5and R6are each independently H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl, or R5and R6together with the C atom to which they are attached form a C 3-6 cycloalkyl or 4-7 membered heterocyclyl; wherein the above groups are optionally substituted with one or more R; L is -SO- (L1) i -S1- (L2) j -S2- (L3) k -S3-; wherein i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is other than 0; S0 is a bond, -O-, -S-, -NR a -, a (CR b R c ) p -, b R c ) p NR a -, a (CR b R c ) p -, b R c ) p C(O)NR a -, b R c ) p -, b R c ) p C(O)-, -NR a C(O)(CR b R c ) p -, b R c ) p NR a C(O)-, -(CR b R c ) p - or -(CR b R c CR b R c O) q -; S1, S2and S3are each independently a bond, -O-, -S-, -NR a -, -NR a (CR b R c ) p -, -(CR b R c ) p NR a -, -C(O)-, -C(O)NR a -, -NR a C(O)-, -C(O)NR a (CR b R c ) p -, -(CR b R c ) p C(O)NR a -, -C(O)(CR b R c ) p -, -(CR b R c ) p C(O)-, -NR a C(O)(CR b R c ) p -, -(CR b R c ) p NR a C(O)-, -S(O)2-, -S(O)2NR a -, -NR a S(O)2-, -S(O)2NR a (CR b R c ) p -, -(CR b R c ) p S(O)2NR a -, -S(O)2(CR b R c ) p -, -(CR b R c ) p S(O)2-, -NR a S(O)2(CR b R c ) p -, -(CR b R c ) p NR a S(O)2-, -(CR b R c ) p - or -(CR b R c CR b R c O) q -; each L1, L2, and L3 is independently a divalent group selected from a 3-6 membered monocyclic carbocyclic ring, a 4-7 membered monocyclic heterocyclic ring, a 6-10 membered fused carbocyclic ring, a 6-10 membered fused heterocyclic ring, a 6-10 membered bridged carbocyclic ring, a 6-10 membered bridged heterocyclic ring, a 6-9 membered spiro carbocyclic ring, or a 6-9 membered spiro heterocyclic ring; wherein the above groups are optionally substituted with one or more R'; or, when S0 is a chemical bond and i is 1, ring A shares two contiguous ring atoms and a chemical bond with L1; Each R a Each independently is H or C 1-6 alkyl; each R b and R c each independently H, D, -OH, -CN, halogen, C 1-6 alkyl or C 1-6 haloalkyl; p is 1, 2, 3, or 4; q is 1, 2, or 3; each R and R' is independently D, -CN, -OH, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl; U is selected from the following formula (U A ), formula (U B ), formula (U C ), formula (U D ), formula (U E ), formula (U F ), formula (U G ), formula (U H ) or formula (U J ): wherein represents a single or double bond; each V is independently a bond, C(O), NH, O, S, C(O)NH, C(O)NH, or CH2; each W is independently a bond, C(O), NH, O, S, C(O)NH, C(O)NH, or CH2; each Q1 is independently C(O) or C(R9)2; each Q2 is independently N or CH; each Q3 and Q4 is independently N or CR9; each K1, K2, and K3 is independently N or CR9; K4 and K5 are each independently N or C; H1 is N, C, or CR9; H2 and H3 are each independently C(O), N, O, S, NR9, CR9, or C(R9)2; each R7is independently H or C 1-6 alkyl; each R8is independently D, halo, C 1-6 alkyl or C 1-6 haloalkyl; or two R8together with the atoms to which they are attached form a C 3-7 cycloalkane or 4-7 membered heterocycle; each R9is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R9together with the atoms to which they are attached form a C 3-7 cycloalkane, 4- to 7-membered heterocycle, C 6-10 arene or 5- to 10-membered heteroarene; each o is independently 0, 1, or 2; each h is independently 0, 1, 2, 3, or 4.

3. The compound of claim 1 or 2, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Ring A is phenyl or 5-6 membered heteroaryl.

4. The compound of any one of claims 1-3, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Ring A is phenyl or 6 membered heteroaryl.

5. The compound of claim 4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Ring A is phenyl.

6. The compound of claim 4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Ring A is pyridyl.

7. The compound of any one of claims 1-6, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Ring B is 5-6 membered heteroaryl.

8. The compound of claim 7, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Ring B is thiazolyl.

9. The compound of claim 7, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Ring B is pyridyl.

10. The compound of claim 1 or 2, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of Formula (II) or Formula (III): wherein Y is CH or N, R1, R2, R3, R4, R5, R6, L, and U are as described in claim 1.

11. The compound of claim 10, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII): wherein Y is CH or N, R4, R5, R6, L, and U are as described in claim 1.

12. The compound of any one of claims 1-11, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R4 is H.

13. The compound of any one of claims 1-11, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R4 is F.

14. The compound of any one of claims 1-13, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R5 and R6 are H.

15. The compound of any one of claims 1-13, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R5 and R6 are methyl.

16. The compound according to any one of claims 1-13, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R5 and R6 together with the C atom to which they are attached form cyclopropane.

17. The compound of any one of claims 1-16, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is -SO- (L1) i -S1- (L2) j -S2- (L3) k -S3-; wherein i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0; S0 is a bond, -(CR b R c ) p - or -(CR a R b ) c ) p - or -(CR b R c ) p NR a -; S1, S2and S3are each independently a bond, -NR a (CR b R c ) p -, -(CR b R c ) p NR a -, -C(O)-, -C(O)NR a -, -NR a C(O)-, -C(O)NR a (CR b R c ) p -, -(CR b R c ) p C(O)NR a -, -C(O)(CR b R c ) p -, -(CR b R c ) p C(O)-, -NR a C(O)(CR b R c ) p -, -(CR b R c ) p NR a C(O)-, -S(O)2-, -S(O)2NR a -, -NR a S(O)2-, -S(O)2NR a (CR b R c ) p -, -(CR b R c ) p S(O)2NR a -, -S(O)2(CR b R c ) p -, -(CR b R c ) p S(O)2-, -NR a S(O)2(CR b R c ) p -, -(CR b R c ) p NR a S(O)2- or -(CR b R c ) p -； each L1, L2, and L3 is independently a bivalent radical selected from 3-6 membered monocyclic carbocyclic ring, 4-7 membered monocyclic heterocyclic ring, 6-10 membered fused carbocyclic ring, 6-10 membered fused heterocyclic ring, 6-10 membered bridged carbocyclic ring, 6-10 membered bridged heterocyclic ring, 6-9 membered spiro carbocyclic ring, or 6-9 membered spiro heterocyclic ring; wherein the aforementioned rings are optionally substituted with one or more R’; or, when S0 is a bond and i is 1, ring A shares two adjacent ring atoms and one bond with L1; each R is independently H or C1-4alkyl; a independently H or C1-4alkyl; 1-6 alkyl; each R b and R c each independently H, D, -OH, -CN, halogen, C 1-6 alkyl or C 1-6 haloalkyl; p is 1, 2, 3, or 4; each R' is independently D, -CN, -OH, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl.

18. The compound of claim 17, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is -SO- (L1) i -S1- (L2) j -S2- (L3) k -S3-; wherein i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0; S0 is a bond, -CH2-, -NHCH2-, or -CH2NH-; S1, S2, and S3 are each independently a bond, -NHCH2-, -CH2NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)NHCH2-, -CH2C(O)NH-, -C(O)CH2-, -CH2C(O)-, -NHC(O)CH2-, -CH2NHC(O)-, -S(O)2-, -S(O)2NH-, -NHS(O)2-, -S(O)2NHCH2-, -CH2S(O)2NH-, -S(O)2CH2-, -CH2S(O)2-, -NHS(O)2CH2-, -CH2NHS(O)2-, or -CH2-; each L1, L2, and L3is independently a bivalent radical selected from 3-6 membered monocyclic carbocyclic ring, 4-7 membered monocyclic heterocyclic ring, 6-10 membered fused carbocyclic ring, 6-10 membered fused heterocyclic ring, 6-10 membered bridged carbocyclic ring, 6-10 membered bridged heterocyclic ring, 6-9 membered spiro carbocyclic ring, or 6-9 membered spiro heterocyclic ring; wherein the above radicals are optionally substituted with one or more R'; or, when S0is a bond and i is 1, ring A shares two contiguous ring atoms and a bond with L1; each R' is independently D, -CN, -OH, halo, C 1-3 alkyl or C 1-3 haloalkyl.

19. The compound of claim 17, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is -SO- (L1) i -S1- (L2) j -S2- (L3) k -S3-; wherein i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0; S0is a bond, -CH2-, -NHCH2-, or -CH2NH-; S1, S2, and S3are independently a bond, -C(O)-, -C(O)CH2-, -CH2C(O)-, -S(O)2-, -S(O)2CH2-, -CH2S(O)2-, or -CH2-; each L1, L2, and L3is independently a bivalent radical selected from 4-7 membered monocyclic heterocyclic ring, 6-10 membered fused heterocyclic ring, 6-10 membered bridged heterocyclic ring, or 6-9 membered spiro heterocyclic ring; wherein the above radicals are optionally substituted with one or more R'; or, when S0is a bond and i is 1, ring A shares two contiguous ring atoms and a bond with L1; each R' is independently D, -CN, -OH, halo, C 1-3 alkyl or C 1-3 haloalkyl.

20. The compound of claim 17, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is -SO- (L1) i -S1- (L2) j -S2- (L3) k -S3-; wherein i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0; S0is a bond or -CH2-; S1, S2, and S3are independently a bond, -C(O)-, -C(O)CH2-, -CH2C(O)-, -S(O)2-, -S(O)2CH2-, -CH2S(O)2-, or -CH2-; each L1, L2, and L3is independently a bivalent radical selected from 4-7 membered monocyclic heterocyclic ring, 6-10 membered fused heterocyclic ring, 6-10 membered bridged heterocyclic ring, or 6-9 membered spiro heterocyclic ring; wherein the above radicals are optionally substituted with one or more R'; or, when S0is a bond and i is 1, ring A shares two contiguous ring atoms and a bond with L1; each R' is independently D, -CN, -OH, halo, C 1-3 alkyl or C 1-3 haloalkyl.

21. The compound of any one of claims 1-20, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, i is 1.

22. The compound of claim 17, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is -SO-L1-S1-(L2) j -; wherein j is 0 or 1; S0is a bond, -CH2-, -NHCH2-, or -CH2NH-; S1is a bond, -C(O)-, -C(O)CH2-, -CH2C(O)-, -S(O)2-, -S(O)2CH2-, -CH2S(O)2-, or -CH2-; L1and L2are independently a bivalent radical selected from 4-7 membered monocyclic heterocycle, 6-10 membered fused heterocycle, 6-10 membered bridged heterocycle, or 6-9 membered spirocyclic heterocycle; wherein the above radicals are optionally substituted with one or more R'; or, when S0is a bond, ring A shares two adjacent ring atoms and a bond with L1; each R' is independently D, -CN, -OH, halo, C 1-3 alkyl or C 1-3 haloalkyl.

23. The compound of claim 17, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is: wherein the above radicals are optionally substituted with one or more R', each R' is independently D, -CN, -OH, F, Cl, Br, C 1-3 alkyl or C 1-3 haloalkyl.

24. The compound of claim 17, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is -S0-L1-C(O)-CH2-L2-; wherein S0is a bond or -CH2-; L1and L2are independently a bivalent radical selected from 4-7 membered monocyclic heterocycle, 6-10 membered fused heterocycle, 6-10 membered bridged heterocycle, or 6-9 membered spirocyclic heterocycle; wherein the above radicals are optionally substituted with one or more R'; each R' is independently D, -CN, -OH, halo, C 1-3 alkyl or C 1-3 haloalkyl.

25. The compound of claim 24, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L1is: wherein the above groups are optionally substituted with one or more R'; each R' is independently D, -CN, -OH, F, Cl, Br, C 1-3 alkyl or C 1-3 haloalkyl; represents the connection to S0, * represents the connection to -C(O)-.

26. The compound of claim 24 or 25, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L2 is: wherein the above radicals are optionally substituted with one or more R'; each R' is independently D, -CN, -OH, F, Cl, Br, C 1-3 alkyl or C 1-3 haloalkyl; represents the connection to CH2, * represents the connection to U.

27. The compound of claim 26, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L2 is wherein, represents the connection to CH2, * represents the connection to U.

28. The compound of claim 17, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is -S0-L1-C(O)-CH2-L2-; wherein S0is a bond; L1 is which is optionally substituted by one or more R'; wherein, represents the connection to S0, * represents the connection to -C(O)-. L2is a bivalent radical selected from 4-7 membered monocyclic heterocycle, 6-10 membered fused heterocycle, 6-10 membered bridged heterocycle, or 6-9 membered spirocyclic heterocycle; wherein the above radicals are optionally substituted with one or more R'; each R' is independently D, -CN, -OH, halo, C 1-3 alkyl or C 1-3 haloalkyl.

29. The compound of claim 28, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L2 is: wherein the above radicals are optionally substituted with one or more R'; each R' is independently D, -CN, -OH, F, Cl, Br, C 1-3 alkyl or C 1-3 haloalkyl; represents the connection to CH2, * represents the connection to U.

30. The compound of claim 29, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L2 is wherein represents the connection to CH2, * represents the connection to U.

31. The compound of any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is selected from the following formula (U A1 ), formula (U B1 ), formula (U C1 ), formula (U D1 ), formula (U E1 ), formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U F1 ), formula (U G1 ), formula (U H1 ): wherein, represents a single or double bond; V is a bond; each W is independently a bond, C(O), NH, O, S, C(O)NH, C(O)NH, or CH2; each Q1is independently C(O) or C(R9)2; each Q2is independently N or CH; each Q3and Q4is independently N or CR9; each R7is independently H or C 1-6 alkyl; each R8is independently D, halo, C 1-6 alkyl or C 1-6 haloalkyl; or two R8together with the atoms to which they are attached form a C 3-7 cycloalkyl or 4-7 membered heterocyclyl; each R9is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R9together with the atoms to which they are attached form a C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; each h is independently 0, 1, 2, 3, or 4; each k’ is independently 0, 1, 2, 3, or 4.

32. The compound of claim 31, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, Q3is N or CR9; each R9is independently H, D, or halogen; each k’ is independently 0 or 1.

33. The compound of any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is selected from the following formula (U E8 ) or formula (U E9 ) : wherein, V is a bond; each Q2is independently N or CH; each R8is independently D, halo, C 1-6 alkyl or C 1-6 haloalkyl; or two R8together with the atoms to which they are attached form a C 3-7 cycloalkyl or 4-7 membered heterocyclyl; each R9is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R9together with the atoms to which they are attached form a C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; each h is independently 0, 1, 2, 3, or 4; each k’ is independently 0, 1, 2, 3, or 4.

34. The compound of claim 33, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, each R9is independently H, D, or halogen; each k’ is independently 0 or 1.

35. The compound of any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is selected from the following formula (U K1 ), formula (U K2 ), formula (U L1 ), formula (U L2 ), formula (U M1 ), formula (U N1 ), formula (U O1 ), formula (U P1 ): wherein, each V is independently a bond; each W is independently a bond, C(O), NH, O, S, C(O)NH, C(O)NH or CH2; each Q1is independently C(O) or C(R9)2; each Q2is independently N or CH; each R8is independently D, halo, C 1-6 alkyl or C 1-6 haloalkyl; or two R8together with the atoms to which they are attached form a C 3-7 cycloalkane or 4-7 membered heterocycle; each R9is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R9together with the atoms to which they are attached form a C 3-7 cycloalkane, 4- to 7-membered heterocycle, C 6-10 arene or 5- to 10-membered heteroarene; each z is independently 0, 1 or 2; each h is independently 0, 1, 2, 3 or 4; each k’ is independently 0, 1, 2, 3 or 4; each r, s, t and u is independently 0, 1, 2, 3 or 4.

36. The compound of claim 35, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, each R9is independently H, D or halogen; each k’ is independently 0 or 1.

37. The compound of any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, each R9is independently H, D or halogen; each k’ is independently 0 or 1.

38. The compound according to any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, each R9is independently H, D or halogen; each k’ is independently 0 or 1.

39. The compound of any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, R9is H, D or halogen; k’ is 0 or 1.

40. The compound of any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, R9is H, D or halogen; k’ is 0 or 1.

41. The compound according to any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, Q3is N or CR9; each R9is independently H, D or halogen; k’ is independently 0 or 1.

42. The compound according to any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, R9is H, D or halogen; k’ is 0 or 1.

43. The compound of any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, R9is H, D or halogen; k’ is 0 or 1.

44. The compound according to any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, each R9is independently H, D or halogen; each k’ is independently 0 or 1.

45. The compound according to any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, R9is H, D or halogen; k’ is 0 or 1.

46. The compound according to any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, each R9is independently H, D or halogen; each k’ is independently 0 or 1.

47. The compound according to any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, R9is H, D or halogen; k’ is 0 or 1.

48. The compound according to any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, each R9is independently H, D or halogen; each k’ is independently 0 or 1.

49. A compound, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, isotopic variant, hydrate, or solvate thereof, wherein, The compounds are: wherein, R9is H, D or halogen; k’ is 0 or 1. wherein, each R9is independently H, D or halogen; each k’ is independently 0 or 1. wherein, each R9is independently H, D or halogen; each k’ is independently 0 or 1.

50. A pharmaceutical composition comprising a compound of any one of claims 1-49, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable excipient.

51. The pharmaceutical composition of claim 50, further comprising another therapeutic agent.

52. The pharmaceutical composition of claim 51, wherein the other therapeutic agent is another EGFR inhibitor, an EGFR antibody, a c-MET inhibitor, an immune checkpoint inhibitor, a RAF inhibitor, an ALK inhibitor or a MEK inhibitor; preferably, the other EGFR inhibitor is gefitinib, erlotinib, icotinib, afatinib, dacomitinib, neratinib, osimertinib, lazertinib, amatinib or futmerib; preferably, the EGFR antibody is cetuximab, panitumumab or necitumumab; preferably, the c-MET inhibitor is galvotineb, tepotinib, capmatinib or savolitinib; preferably, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, atezolizumab, durvalumab, ipilimumab or tremelimumab; preferably, the EGFR antibody is cetuximab or panitumumab; preferably, the RAF inhibitor is sorafenib, vemurafenib, dabrafenib or encorafenib; preferably, the ALK inhibitor is ceritinib, alectinib, brigatinib, entrectinib, lorlatinib, or irrexistim; preferably, the MEK inhibitor is trametinib, selumetinib, or refametinib.

53. Use of a compound of any one of claims 1-49, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of any one of claims 50-52, in the manufacture of a medicament for treating a mutant EGFR-mediated disease; preferably, wherein the mutant EGFR is E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L858R, or L861Q, or any combination thereof; preferably, wherein the mutant EGFR is Del19, L858R, T790M, C797S, L718Q, L792H, or L861Q, or any combination thereof; preferably, wherein the mutant EGFR is G119A, R531Q, V948R, or I941R; preferably, wherein the mutant EGFR is L858R; preferably, wherein the mutant EGFR is T790M; preferably, wherein the mutant EGFR is C797S; preferably, wherein the mutant EGFR is L718Q; preferably, wherein the mutant EGFR is L792H; preferably, wherein the mutant EGFR is L861Q; preferably, wherein the mutant EGFR is L858R / T790M double mutation; preferably, wherein the mutant EGFR is L858R / C797S double mutation; preferably, wherein the mutant EGFR is L858R / T790M / C797S triple mutation.

54. A method of treating a mutant EGFR-mediated disease in a subject, the method comprising administering to the subject a compound of any one of claims 1-49, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a pharmaceutical composition of any one of claims 50-52; preferably, wherein the mutant EGFR is E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L858R, or L861Q, or any combination thereof; preferably wherein the mutant EGFR is Del19, L858R, T790M, C797S, L718Q, L792H, or L861Q, or any combination thereof; preferably wherein the mutant EGFR is G119A, R531Q, V948R, or I941R; preferably wherein the mutant EGFR is L858R; preferably wherein the mutant EGFR is T790M; preferably wherein the mutant EGFR is C797S; preferably wherein the mutant EGFR is L718Q; preferably wherein the mutant EGFR is L792H; preferably wherein the mutant EGFR is L861Q; preferably wherein the mutant EGFR is L858R / T790M double mutation; preferably wherein the mutant EGFR is L858R / C797S double mutation; preferably wherein the mutant EGFR is L858R / T790M / C797S triple mutation.

55. The compound of any one of claims 1-49, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition of any one of claims 50-52, for use in the treatment of a mutant EGFR-mediated disease; preferably wherein the mutant EGFR is E709A / G / K / V, L718Q / V, G719C / S / A / D, G724S, Del19, L747S / P, D761Y, M766Q, S768I, T790M, L792F / H / V, G796R / S / C / D, C797S / G / N, ex20ins, G834L, V843I, L844V, T854A, L858R, or L861Q, or any combination thereof; preferably wherein the mutant EGFR is Del19, L858R, T790M, C797S, L718Q, L792H, or L861Q, or any combination thereof; preferably wherein the mutant EGFR is G119A, R531Q, V948R, or I941R; preferably wherein the mutant EGFR is L858R; preferably wherein the mutant EGFR is T790M; preferably wherein the mutant EGFR is C797S; preferably wherein the mutant EGFR is L718Q; preferably wherein the mutant EGFR is L792H; preferably wherein the mutant EGFR is L861Q; preferably wherein the mutant EGFR is L858R / T790M double mutation; preferably wherein the mutant EGFR is L858R / C797S double mutation; preferably wherein the mutant EGFR is L858R / T790M / C797S triple mutation.

56. The use of claim 53 or the method of claim 54 or the use of a compound or composition of claim 55, wherein the mutant EGFR-mediated disease is lung cancer, brain cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, colon cancer, rectal cancer, breast cancer, head and neck cancer, glioblastoma, pancreatic cancer, thyroid cancer, astrocytoma, esophageal cancer, uterine cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urothelial cancer, kidney cancer, stomach cancer, sarcoma, melanoma, endometrial cancer, testicular cancer, pancreatic cancer, prostate cancer, mesothelioma, and metastases thereof (especially brain metastases or CNS metastases); Preferably, wherein the disease is lung cancer and metastases thereof (especially brain metastases or CNS metastases); Preferably, wherein the disease is non-small cell lung cancer and metastases thereof (especially brain metastases or CNS metastases).

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