Cyclin modulators

Abstract

The invention provides a cyclin regulator. Specifically, the invention provides a compound shown as a formula (I) or pharmaceutically acceptable salt thereof. # imgabs0 #

Description

Cell cycle regulators Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and in particular relates to a cell cycle protein regulator. Background Art

[0002] Unlike most traditional drugs that directly inhibit the action of molecular targets, molecular glue degraders kill cancer cells by destroying target proteins through the ubiquitin-proteasome system. For example, the multiple myeloma drug lenalidomide is a molecular glue degrader that recruits E3 ubiquitin ligase to mark the target protein in the cell and then degrade it. Unlike traditional small molecule inhibitors, molecular glues drive target ubiquitination and induce degradation in a catalytic manner, which is a new strategy that can inactivate targets that are difficult to treat with traditional pharmacological methods. Molecular glues also cleverly circumvent the limitations of traditional inhibitors, turning some targets from "non-drugable" to "drugable."

[0003] The cell cycle is a fundamental process in cellular life, controlling the transition of cells from a quiescent phase to a proliferative phase. Cyclin-dependent kinases (CDKs) and cyclins are core molecules in the entire cell cycle regulatory mechanism. In normal cells, the activity of cyclins is strictly controlled by their cell cycle-specific transcription and protein degradation, as well as the influence of certain CDK inhibitory proteins. In addition to promoting cell division, cyclins are also responsible for regulating various cellular functions. This mechanism is jointly operated by cyclins and their catalytic partners, cyclin-dependent kinases (CDKs). However, these influencing factors often become uncontrolled in human cancers, leading to abnormal activation of cyclins. Abnormal activity of the cell cycle mechanism is present in virtually all types of tumors and is a driving force in tumorigenesis. Targeting specific cyclins may become an effective anti-cancer strategy.

[0004] To date, only a few CDK inhibitors have been marketed, all of which are CDK4 / 6 inhibitors. Inhibitors that selectively target other CDK families struggle to achieve the required specificity and are almost all multi-target inhibitors, exhibiting unacceptable toxicity in clinical practice, thus hindering their clinical application. Furthermore, while kinase inhibitors can lead to the removal of kinase subunits, they simultaneously maintain the integrity of cell cycle proteins, potentially triggering compensatory mechanisms. Kinase degradation can lead to effects that outlast the inhibitory effect.

[0005] While molecular glue degraders are highly desirable, clinically effective, and highly sought-after, few have been discovered to date, and most have been discovered by chance. CR8, a newly discovered cyclin K (Cyclin K) degrader, is primarily a multikinase inhibitor that inhibits the activity of multiple cyclins in the CDK family, resulting in toxicity that limits its clinical application. In addition to its poor selectivity, its activity in degrading Cyclin K is also modest, limiting its use in catalytic amounts.

[0006] In summary, there is an urgent need in the art to develop a class of cell cycle protein regulators such as cell cycle protein degraders with higher activity and / or lower toxicity.

[0007] Summary of the Invention

[0008] The purpose of the present invention is to provide a cell cycle protein degrader with higher activity, or a novel cell cycle protein regulator.

[0009] In the first aspect of the present invention, there is provided a compound as represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0010] in,

[0011] R 1 Each independently is H or C 1-4 alkyl;

[0012] Subscript n1 is 1, 2, or 3;

[0013] Cyclic Ar 1 Select from the following group: C 6-10 Aromatic ring, 5- to 10-membered heteroaromatic ring, 5- to 10-membered bridged ring;

[0014] Cyclic Cr 1 Selected from the following group: H, C 3-10 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0015] R a and R b Each independently selected from the group consisting of: H, R e or R; or R a and R b With cyclic Ar 1 and cyclic Cr 1 Together in,

[0016] X 7 Each independently selected from the group consisting of: -O-, -S-, -N(R c )-、-C(R c)2-、-C(R c )2-C(R c )2-;

[0017] Subscripts n5 and n6 are each independently 0, 1, 2 or 3;

[0018] R e Each independently selected from the group consisting of: hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Alkylene-R f ;

[0019] Among them, R f Selected from the group consisting of: -CN, -OH, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2;

[0020] Subscripts n3 and n4 are each independently 0, 1, 2, 3 or 4;

[0021] R 2 Selected from the group consisting of H, CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl;

[0022] X 1 、X 2 and X 6 Each independently is N or C(R c );

[0023] X 3 、X 4 and X 5 are each independently N or C;

[0024] M 1 Select from the following groups: None, X 8 、(M 4 ) s ;in,

[0025] X 8 N(R c ) or C(R c )2;

[0026] M 4 Each independently selected from the group consisting of O, S, C(O)O, C(O), N(R c ) and C 1-4 alkylene;

[0027] s is 1, 2, or 3;

[0028] M 2 Is none or a ring as shown in formula A;

[0029] In formula A, X 9 It is with M 1 The location of the connection, X 10 It is with M 3 Connection location; X 9 N or C(R m ), X 10 Selected from the group consisting of O, S, N, or C(R m );X 11 and X 12 Each independently selected from the group consisting of: -C(R m )2-、-N(R m )-; subscripts m1 and m2 are each independently 0, 1, 2 or 3, and m1+m2≥2;

[0030] Among them, R m Each independently is R c or R m1 ;in,

[0031] R m1 Each independently selected from the group consisting of: hydroxy, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Hydroxyalkyl, optionally substituted C 1-6 haloalkyl; or, two R m1 Together form a single bond, optionally substituted C 1-4 alkylene or optionally substituted 1- to 4-membered heteroalkylene;

[0032] M 3 Select from the following group: None, R 3 、-NH-R 3 ;in,

[0033] R 3 Selected from the group consisting of: H, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6- Hydroxyalkyl, optionally substituted C 1-6- alkyl halide;

[0034] R c Each independently is H or C 1-4 alkyl;

[0035] Unless otherwise defined, the optional substitution refers to unsubstituted or one or more (such as 1, 2, 3 or 4) hydrogen in the group is replaced by a substituent R, and R is selected from the following groups: D, halogen, C 1-6Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -OR', -NO2, -NR'R", -SR', -OC(O)R', -C(O)R', -CO2R', -CONR', -OC(O)NR'R", -NR"C(O)R', -NR"-C(O)NR'R", -NR"C(O)2R', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR"S(O)2R', C(O)2R', optionally substituted with one or more R' 3-10 Cycloalkyl, 4 to 10 membered heterocycloalkyl optionally substituted by one or more R'", C 6-10 aryl, 5- to 10-membered heteroaryl optionally substituted by one or more R'", -C 1-4 Alkylene-C 3-10 Cycloalkyl, -C 1-4 Alkylene-4 to 10 membered heterocycloalkyl, optionally substituted with one or more R'"-C 1-4 Alkylene-C 6-10 Aryl, optionally substituted with one or more R'" -C 1-4 Alkylene-5 to 10 membered heteroaryl;

[0036] Each R' is independently H, D, or a group selected from the group consisting of: C 1-6 Alkyl, C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, -C 1-4 Alkylene-4 to 10 membered heterocycloalkyl, -C 1-4 Alkylene-C 6-10 Aryl-C 1-4 Alkylene-5 to 10 membered heteroaryl;

[0037] Each R" is selected from the group consisting of H, D, C 1-4 Alkyl, C 1-4 Haloalkyl, and C 3-4 Cycloalkyl;

[0038] Each R"' is independently selected from the group consisting of D, halogen, hydroxy, nitro, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

[0039] In another preferred embodiment, the compound is not CR8 as shown below:

[0040] In another preferred embodiment, R 1 is H. In another preferred embodiment, n1=1. In another preferred embodiment, R 1 is H, and n1=1.

[0041] In another preferred embodiment, ring Ar 1 Select from the following group: C 6-10 aromatic ring, 5- to 10-membered heteroaromatic ring.

[0042] In another preferred embodiment, ring Ar 1 Selected from the group consisting of a benzene ring and a 5- to 10-membered heteroaromatic ring.

[0043] In another preferred embodiment, ring Ar 1 Select from the following groups:

[0044] Among them, * represents the ring Cr 1 Connection location; X a 、X b 、X c and X d are independently CH and N; X g Selected from the group consisting of NH, O, S; X h 、X i and X j Each is independently -CH2- or -CH2-CH2-.

[0045] In another preferred embodiment, for

[0046] In another preferred embodiment, ring Ar 1 middle, for

[0047] In another preferred embodiment, ring Ar 1 Select from the following groups:

[0048] Among them, * represents the ring Cr 1 Connection location; X a 、X b 、X c and X d are independently CH and N; X g Selected from the group consisting of NH, O, S.

[0049] In another preferred embodiment, ring Ar 1 for

[0050] Among them, * represents the ring Cr 1 The location of the connection.

[0051] In another preferred embodiment, for * represents the ring Cr 1 Connection location

[0052] In another preferred embodiment, the ring Cr 1 In the embodiment, the carbocyclic ring is a saturated or unsaturated carbocyclic ring containing 1 or 2 double bonds.

[0053] In another preferred embodiment, the ring Cr 1 In the C 3-10 Carbon ring is C 4-10 Carbocyclic ring; preferably, C 4-6 Carbon ring.

[0054] In another preferred embodiment, the ring Cr 1 In the embodiment, the 3- to 10-membered heterocyclic group is a saturated 3- to 10-membered heterocyclic group.

[0055] In another preferred embodiment, the ring Cr 1 In the embodiment, the 3- to 10-membered heterocyclic group is a 4- to 10-membered heterocyclic group; preferably, it is a 4- to 6-membered heterocyclic group.

[0056] In another preferred embodiment, the ring Cr 1 Select from the following groups:

[0057] Among them, X d and X e are each independently N or CH; X f NH, S, O; X g is N or CH.

[0058] In another preferred embodiment, for

[0059] In another preferred embodiment, the ring Cr 1 Ring Ar 2 ; and cyclic Ar 2 Select from the following group: C 6-10 aryl, and 5- to 10-membered heteroaryl.

[0060] In another preferred embodiment, ring Ar 2 Select from the following groups:

[0061] Among them, X d and X e are each independently -N- or -CH-; Xf is -NH-, -S-, -O-; X g is N or CH.

[0062] In another preferred embodiment, ring Ar 2 for In another preferred embodiment, ring Ar 2 It is phenyl.

[0063] In another preferred embodiment, when M 2 When it is nothing, the ring Ar 2 It is not a nitrogen-containing heteroaryl group (wherein the nitrogen-containing heteroaryl group is a heteroaryl group having 1 or 2 nitrogen heteroatoms in the ring and no other heteroatoms, such as pyridyl, pyrazolyl, imidazolyl and pyrazinyl).

[0064] In another preferred embodiment, when M2 is absent, the ring Ar 2 Not for

[0065] In another preferred embodiment, n3 is 0 (ie, ring Ar 1 is unsubstituted); or, n3 is 1, 2, 3 or 4 (i.e., ring Ar 1 1, 2, 3 or 4 R a substituted), and R a Each independently selected from the group consisting of: D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

[0066] In another preferred embodiment, n3 is 0. In another preferred embodiment, n3 is 1, and R a R e .

[0067] In another preferred embodiment, n4 is 0 (ie, ring Cr 1 is unsubstituted); or, n4 is 1, 2, 3 or 4 (i.e., ring Cr 1 1, 2, 3 or 4 R b substituted), and R b Each independently selected from the group consisting of: D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

[0068] In another preferred embodiment, n4 is 0. In another preferred embodiment, n4 is 1, and R b R e .

[0069] In another preferred embodiment, n3 is 0 (ie, ring Ar 1 is unsubstituted); or, n3 is 1, 2, 3 or 4 (i.e., ring Ar 1 1, 2, 3 or 4 R asubstituted), and R a Each independently selected from the group consisting of: D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

[0070] In another preferred embodiment, when M2 is zero, Not for

[0071] In another preferred embodiment, for

[0072] In another preferred embodiment, X 1 N, X 2 CR c , X 3 C, X 4 C, X 5 N and X 6 CR c In another preferred embodiment, X 1 CR c , X 2 CR c , X 3 CR c , X 4 N, X 5 is C and X 6 CR c In another preferred embodiment, X 1 N, X 2 CR c , X 3 CR c , X 4 N, X 5 is C and X 6 CR c In another preferred embodiment, X 1 CR c , X 2 CR c , X 3 CR c , X 4 N, X 5 N and X 6 CR c In another preferred embodiment, X 1 CR c , X 2 CR c , X 3 N, X 4 CR c , X 5 is C and X 6CR c In another preferred embodiment, X 1 CR c , X 2 N, X 3 N, X 4 CR c , X 5 is C and X 6 CR c In another preferred embodiment, X 1 N, X 2 CR c , X 3 N, X 4 CR c , X 5 is C and X 6 CR c .

[0073] In another preferred embodiment, R c Both are H.

[0074] In another preferred embodiment, X 1 N, X 2 CH, X 3 C, X 4 C, X 5 N and X 6 In another preferred embodiment, X 1 CH, X 2 CH, X 3 CH, X 4 N, X 5 is C and X 6 In another preferred embodiment, X 1 N, X 2 CH, X 3 CH, X 4 N, X 5 is C and X 6 In another preferred embodiment, X 1 CH, X 2 CH, X 3 CH, X 4 N, X 5 N and X 6 In another preferred embodiment, X 1 CH, X 2 CH, X 3 N, X 4 CH, X 5 is C and X 6 In another preferred embodiment, X 1 CH, X2 N, X 3 N, X 4 CH, X 5 is C and X 6 In another preferred embodiment, X 1 N, X 2 CH, X 3 N, X 4 CH, X 5 is C and X 6 For CH.

[0075] In another preferred embodiment,

[0076] Select from the following groups:

[0077] In another preferred embodiment,

[0078] for

[0079] In another preferred embodiment, R 2 is optionally substituted C 1-6 In another preferred embodiment, R 2 C 1-6 In another preferred embodiment, R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0080] In another preferred embodiment, in formula A, when two R m1 When located on the same carbon atom, the two R m1 Together they form an optionally substituted C 2-4 alkylene or optionally substituted 2- to 4-membered heteroalkylene (ie, the ring shown in formula A is a spiro ring).

[0081] In another preferred embodiment, in formula A, when two R m1 When located on two adjacent ring atoms, the two R m1 Together they form an optionally substituted C 1-4 alkylene or an optionally substituted 1- to 4-membered heteroalkylene (ie, the ring shown in formula A is fused).

[0082] In another preferred embodiment, in formula A, when two R m1 When located on two ring atoms separated by at least one ring atom, the two R m1 Together form a single bond, optionally substituted C 1-3 alkylene or an optionally substituted 1- to 3-membered heteroalkylene (ie, the ring shown in formula A is fused).

[0083] In another preferred embodiment, the two R m1 Together they form C 1-4 Alkylene.

[0084] In another preferred embodiment, 2≤m1+m2≤4 (ie, the ring shown in formula A is a 4- to 6-membered ring).

[0085] In another preferred embodiment, X 10 When it is O or S, M 3 For nothing; X 10 N or C(R m ) when M 3 R 3-- or -NH-R 3 .

[0086] In another preferred embodiment, M 1 None or X 8 .

[0087] In another preferred embodiment, M 1 M 3 -NH-R 3 , and M 2 For nothing.

[0088] In another preferred embodiment, R 3 Optionally substituted C 1-6- Hydroxyalkyl.

[0089] In another preferred embodiment, for

[0090] In another preferred embodiment, M 1 M 3 None or R 3 , and M 2 is a ring as shown in formula A.

[0091] In another preferred embodiment, m1 and m2 are each independently 1 or 2. In another preferred embodiment, m1 and m2 are both 2.

[0092] In another preferred embodiment, X 9 is N.

[0093] In another preferred embodiment, R 3 For H.

[0094] In another preferred embodiment, X 10 N, M 3 R 3 , and R 3 H or C 1-6 In another preferred embodiment, X 10 N, M 3 R3 , and R 3 For H.

[0095] In another preferred embodiment, X 11 and X 12 Each is independently -C(R m )2-.

[0096] In another preferred embodiment, X 11 and X 12 There are at most two R m R m1 , the rest R m R c (Preferably, the remaining R m for H).

[0097] In another preferred embodiment, M 1 M 3 None or R 3 , and M 2 is a ring of formula A; and, in formula A, X 9 N or C(R m ), X 10 Selected from the group consisting of O, S, N, or C(R m );X 11 and X 12 Each is independently -C(R m )2-; subscripts m1 and m2 are each independently 1 or 2 (preferably, subscripts m1 and m2 are both 2).

[0098] In another preferred embodiment, M 1 M 3 R 3 , and M 2 is a ring of formula A; and, in formula A, X 9 N or C(R m ), X 10 N; X 11 and X 12 Each independently is C(R m )2-; subscripts m1 and m2 are each independently 1 or 2 (preferably, subscripts m1 and m2 are both 2).

[0099] In another preferred embodiment, M 1 M 3 R 3 , and R 3 is H, and M 2 is a ring of formula A; and, in formula A, X 9 N, X 10 N; X 11 and X 12 Each is independently -C(Rm )2-; subscripts m1 and m2 are each independently 1 or 2 (preferably, subscripts m1 and m2 are both 2).

[0100] In another preferred embodiment, for

[0101] In another preferred embodiment, for Where m3 is 0, 1 or 2.

[0102] In another preferred embodiment, Select from the following groups:

[0103] In another preferred embodiment, the compound is as shown in formula I-1

[0104] Wherein, each group is as defined above.

[0105] In another preferred embodiment, M 1 For X 8 or (M 4 ) s , M 3 None or R 3 , and M 2 is a ring as shown in formula A; wherein, M 4 Each independently selected from the group consisting of O and C 1-4 Alkylene; s is 1, 2 or 3; and at most one M 4 It is O.

[0106] In another preferred embodiment, M 1 For X 8 , M 3 None or R 3 , and M 2 is a ring as shown in formula A.

[0107] In another preferred embodiment, X 8 N(R c ).

[0108] In another preferred embodiment, R 3 For H.

[0109] In another preferred embodiment, m1 and m2 are each independently 1, 2 or 3. In another preferred embodiment, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4.

[0110] In another preferred embodiment, X 10 N or C(R c ), M 3 R 3 , and R3 H or C 1-6 In another preferred embodiment, X 10 N or CH, M 3 R 3 , and R 3 For H.

[0111] In another preferred embodiment, X 10 N, M 3 R 3 , and R 3 H or C 1-6 In another preferred embodiment, X 10 N, M 3 R 3 , and R 3 For H.

[0112] In another preferred embodiment, X 11 and X 12 There is only one R in m R m1 , the rest R m R c (Preferably, the remaining R m for H).

[0113] In another preferred embodiment, M 1 For X 8 , M 3 R 3 , and M 2 is a ring as shown in formula A; and, in formula A, X 9 N or C(R m ), X 10 N or C(R m );X 11 and X 12 Each independently selected from the group consisting of: -C(R m )2-、-N(R m )-; subscripts m1 and m2 are each independently 1, 2 or 3 (preferably, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4).

[0114] In another preferred embodiment, M 1 For X 8 , M 3 R 3 , and M 2 is a ring as shown in formula A; and, in formula A, X 9 N or C(R m ), X 10 N; X 11 and X 12 Each is independently -C(Rm )2-; subscripts m1 and m2 are each independently 1, 2 or 3 (preferably, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4).

[0115] In another preferred embodiment, M 1 For X 8 , X 8 N(R c );M 3 R 3 , and R 3 is H, and M 2 Is a ring of formula A; in formula A, X 9 C(R m ), X 10 N; X 11 and X 12 Each is independently -C(R m )2-; subscripts m1 and m2 are each independently 1, 2 or 3 (preferably, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4).

[0116] In another preferred embodiment, for

[0117] In another preferred embodiment, for wherein the subscripts m1 and m2 are each independently 1, 2 or 3 (preferably, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4).

[0118] In another preferred embodiment, Select from the following groups:

[0119] In another preferred embodiment, the compound is as shown in formula I-2

[0120] Wherein, each group is as defined above.

[0121] In another preferred embodiment, M 1 M 3 -NH-R 3 , and M 2 is a ring as shown in formula A.

[0122] In another preferred embodiment, m1 and m2 are each independently 1, 2 or 3. In another preferred embodiment, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4.

[0123] In another preferred embodiment, R 3 For H.

[0124] In another preferred embodiment, X 9 is N.

[0125] In another preferred embodiment, X 10 C(R m ). In another preferred embodiment, X 10 C(R c ). In another preferred embodiment, X 10 For CH.

[0126] In another preferred embodiment, X 11 and X 12 Each is independently -C(R m In another preferred embodiment, X 11 and X 12 Each is independently -C(R c In another preferred embodiment, X 11 and X 12 Each is independently -CH2-.

[0127] In another preferred embodiment, M 1 M 3 -NH-R 3 , and M 2 is a ring as shown in formula A; and, in formula A, X 9 N or C(R m ), X 10 C(R m );X 11 and X 12 Each is independently -C(R m )2-; subscripts m1 and m2 are each independently 1, 2 or 3 (preferably, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4).

[0128] In another preferred embodiment, M 1 M 3 -NH-R 3 , and M 2 is a ring as shown in formula A; and, in formula A, X 9 N, X 10 C(R m );X 11 and X 12 Each is independently -C(R m )2-; subscripts m1 and m2 are each independently 1, 2 or 3 (preferably, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4).

[0129] In another preferred embodiment, M 1 M 3-NH-R 3 , and M 2 is a ring as shown in formula A; and, in formula A, X 9 N, X 10 C(R c );X 11 and X 12 Each is independently -C(R c )2-; subscripts m1 and m2 are each independently 1, 2 or 3 (preferably, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4).

[0130] In another preferred embodiment, for

[0131] In another preferred embodiment, for wherein the subscripts m1 and m2 are each independently 1, 2 or 3 (preferably, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4).

[0132] In another preferred embodiment, Select from the following groups:

[0133] In another preferred embodiment, the compound is as shown in formula I-3

[0134] Wherein, each group is as defined above.

[0135] In another preferred embodiment, M 1 For X 8 , M 3 -NH-R 3 , and M 2 is a ring as shown in formula A.

[0136] In another preferred embodiment, X 8 N(R c ).

[0137] In another preferred embodiment, R 3 For H.

[0138] In another preferred embodiment, m1 and m2 are each independently 1, 2 or 3. In another preferred embodiment, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4.

[0139] In another preferred embodiment, X 9 C(R m ); preferably, X 9 C(R c ); preferably, X 9 For CH.

[0140] In another preferred embodiment, X 10 C(R m ); preferably, X 10 C(R c ); preferably, X 10 For CH.

[0141] In another preferred embodiment, X 11 and X 12 Each is independently -C(R m In another preferred embodiment, X 11 and X 12 Each is independently -C(R c In another preferred embodiment, X 11 and X 12 Each is independently -CH2-.

[0142] In another preferred embodiment, M 1 For X 8 , M 3 -NH-R 3 , and M 2 is a ring as shown in formula A; and, X 8 N(R c ) or C(R c )2; In formula A, X 9 C(R c ), X 10 C(R c );X 11 and X 12 Each is independently -C(R c )2-; subscripts m1 and m2 are each independently 1, 2 or 3 (preferably, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4).

[0143] In another preferred embodiment, M 1 For X 8 , M 3 -NH-R 3 , and M 2 is a ring as shown in formula A; and, X 8 N(R c ); In formula A, X 9 C(R c ), X 10 C(R c );X 11 and X 12 Each is independently -C(R c)2-; subscripts m1 and m2 are each independently 1, 2 or 3 (preferably, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4).

[0144] In another preferred embodiment, M 1 For X 8 , M 3 -NH-R 3 , and M 2 is a ring as shown in formula A; and, X 8 is NH; in formula A, X 9 CH, X 10 CH; X 11 and X 12 Each is independently -CH2-; subscripts m1 and m2 are each independently 1, 2 or 3 (preferably, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4).

[0145] In another preferred embodiment, for

[0146] In another preferred embodiment, for wherein the subscripts m1 and m2 are each independently 1, 2 or 3 (preferably, m1 and m2 are each independently 1, 2 or 3 and m1+m2≤4).

[0147] In another preferred embodiment, Select from the following groups:

[0148] In another preferred embodiment, the compound is as shown in formula I-4

[0149] Wherein, each group is as defined above.

[0150] In another preferred embodiment, the compound is a compound of formula I-1, wherein for m3 is 0, 1 or 2.

[0151] In another preferred embodiment, R 1 、R 2 、R 3 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X11 、X 12 、M 1 、M 2 、M 3 、M 4 , subscript n1, subscript n3, subscript n4, subscript n5, subscript n6, subscript m1, subscript m2, subscript m3, subscript s, Ar 1 、Ar 2 Cr 1 、R a 、R b 、R c 、R e 、R f 、R m 、R m1 , R, R', R" and R'" are each independently the corresponding groups in the Example compounds or the specific compounds in Tables A1, A2, A3 and A4.

[0152] In another preferred embodiment, the compound is a compound selected from Table A1, A2, A3 and Table A4.

[0153] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0154] (i) the compound according to the first aspect or a pharmaceutically acceptable salt thereof; and

[0155] (ii) a pharmaceutically acceptable carrier.

[0156] In the third aspect of the present invention, there is provided a use of the compound of formula (I) or a pharmaceutically acceptable salt thereof as described in the first aspect in the preparation of a medicament for treating cancer.

[0157] In a fourth aspect of the present invention, a method for treating cancer is provided, comprising the steps of administering a safe and effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof as described in the first aspect to a subject in need.

[0158] In a fifth aspect of the present invention, a method for degrading cyclin K is provided, comprising the steps of treating a subject with the compound represented by formula (I) as described in the first aspect, thereby degrading cyclin K.

[0159] In another preferred embodiment, the object is a cell.

[0160] In another preferred embodiment, the object is HepG2 cells.

[0161] In another preferred embodiment, the method is non-therapeutic in vitro.

[0162] In the sixth aspect of the present invention, a conjugate or a pharmaceutically acceptable salt thereof is provided, wherein the conjugate is a conjugate formed by the compound represented by formula (I) as described in the first aspect and a polypeptide element or a targeting ligand.

[0163] In another preferred embodiment, the conjugate is as shown in formula II D -M L -M P (II)

[0164] in,

[0165] M D is a moiety derived from the compound represented by formula (I) as described in the first aspect;

[0166] M L None or used to connect M D and M P The connecting part;

[0167] M P A moiety derived from a polypeptide element or a targeting ligand.

[0168] In another preferred embodiment, the targeting ligand refers to a small molecule that can bind to an extracellular receptor.

[0169] In another preferred embodiment, the polypeptide element includes (but is not limited to): polypeptide, antibody, antibody fragment, fusion protein, or a combination thereof.

[0170] In another preferred embodiment, M P Selected from the group consisting of a polypeptide, an antibody, an antibody fragment, a fusion protein, or a small molecule ligand portion capable of binding to an extracellular receptor.

[0171] In another preferred embodiment, the antibody includes (but is not limited to): nanobody, minibody, antibody fragment (such as scFv, Fab), dibody, monoclonal antibody (mAb), or a combination thereof.

[0172] In another preferred embodiment, the target of the polypeptide (such as a targeting polypeptide) includes but is not limited to: EGFR, FGFR, SSTR1-14, GnRH, TRPV1-6, RGD, iRGD, EphA2, or a combination thereof.

[0173] In another preferred embodiment, the targets that the small molecule ligand can bind to include (but are not limited to): FR, HSP90, PSMA, ASGPR, and combinations thereof.

[0174] In another preferred embodiment, the antibody can bind to an antigen or receptor selected from the group consisting of: DLL3, EDAR, CLL1, BMPR1B, E16, STEAP1, 0772P, MPF, 5T4, NaPi2b, Sema 5b, PSCAhlg, ETBR, MSG783, STEAP2, TrpM4, CRIPTO, CD21, CD22, CD79b, CD19, CD37, CD38, CD138, FcRH2, B7-H4, HER2, NCA, MDP, IL20Rα, Brevican, EphB2R, ASLG659, PSCA, GEDA, BAFF-R, CD79a, CXCR5, HLA-DOB, P2X5, CD72, LY64, FcRH1, IRTA2, TENB2, PMEL17, TMEFF1, GDNF-Ra1, Ly6E, TMEM46, Ly6G6D, LGR5, RET, LY6K, GPR19, GPR54, ASPHD1, Tyrosinase ), TMEM118, GPR172A, MUC1, CD70, CD71, MUC16, methenamine, FOLR1, TroP1-2, gpNMB, EGFR, ENPP3, PSMA, CA6, GPC-3, PTK7, CD44, CD56, TIM-1, Cadherin-6, ASG-15ME, ASG-22ME, CanAg, AXL, CEACAM5, EphA4, cMet, FGFR2, FGFR3, CD123, Her3, LAMP1, LRRC15, TDGF1, CD66, CD25, BCMA, GCC, Noch3, cMet, EGFR and CD33, or receptors such as CD70, Trop2, PD-L1, CD47, CLDN-18.2.

[0175] In another preferred embodiment, the targeting ligand can also bind to receptors that can be targeted by specific small molecules, such as folic acid, HSP90, glucose transporter 1 (GLUT1), aminopeptidase N (APN), low-density lipoprotein receptor-related protein 1 (LRP1), prostate-specific membrane antigen (PSMA), integrin αvβ3, bombesin receptor, somatostatin receptor (SSTR), tumor hypoxic microenvironment, and carbonic anhydrase IX (CAIX) and other receptors.

[0176] In a seventh aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0177] (i) the conjugate according to the sixth aspect or a pharmaceutically acceptable salt thereof; and

[0178] (ii) a pharmaceutically acceptable carrier.

[0179] In the eighth aspect of the present invention, there is provided a use of the conjugate according to the sixth aspect or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.

[0180] In the ninth aspect of the present invention, a method for treating cancer is provided, comprising the step of administering a safe and effective amount of the conjugate or a pharmaceutically acceptable salt thereof as described in the sixth aspect to a subject in need thereof.

[0181] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0182] FIG1 shows the immunohistochemical staining (IHC) results of compounds CR-8, UB-018, UB-022, and UB-027.

[0183] FIG2 shows the degradation effects of CR-8 and the compounds of the present invention on cyclin K in HEK293 cells. DETAILED DESCRIPTION

[0184] After extensive and in-depth research, the inventors unexpectedly discovered a class of compounds with novel structures (such as the compounds represented by formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4) herein), especially when Cr 1 When there is no N atom on the ring, by modifying the functional groups at other positions of the mother nucleus, it also has an excellent effect of inducing the degradation of cyclin K. Based on this, the inventors completed the present invention.

[0185] the term

[0186] Unless otherwise indicated, the bonds represented by dashed lines in each structural formula represent the points of attachment to other moieties.

[0187] As used herein, unless otherwise defined, the term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon radical (i.e., C 1-6 Preferably, the alkyl group has 1 to 4 carbon atoms, i.e., C 1-4 Alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Preferably, alkenyl groups have 2 to 4 carbon atoms, i.e., C 2-4 Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. Preferably, the alkynyl group has 2 to 4 carbon atoms, i.e., C 2-4 Examples of such unsaturated alkyl groups include, but are not limited to, ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers.

[0188] Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with other terms refers to a stable straight or branched chain group in which one or more (e.g., 1 or 2) carbon atoms of an alkyl group as defined above are replaced by a heteroatom, such as one selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatoms O, N, and S may be located at any interior position of the heteroalkyl group. The heteroatom Si may be located at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule.

[0189] The term "alkylene" by itself or as part of another substituent refers to a divalent group derived from an alkane, for example -CH2-. Preferably, in this application, a alkylene group having 1, 2, 3 or 4 carbon atoms (i.e., C 1-4 alkylene).

[0190] The term "heteroalkylene" by itself or as part of another substituent refers to a divalent radical derived from heteroalkyl.

[0191] As used herein, the term "carbocyclyl" or "carbocycle" refers to a carbocyclic ring having the specified number of ring atoms (e.g., C 3-10 Carbocyclic ring, C 4-10 Carbocyclic ring, C 4-6 The term "heterocyclyl" or "heterocycle" refers to a hydrocarbon ring (radical) that is fully saturated or has one or two double bonds between the ring vertices. The term also includes bicyclic and polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The term "heterocyclyl" or "heterocycle" refers to a carbocyclic ring (radical) containing 1 to 5 heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heterocyclic ring (radical) can be a monocyclic, bicyclic or polycyclic ring system, preferably a monocyclic ring. Non-limiting examples of heterocyclic rings include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc. The heterocyclic ring can be attached to the rest of the molecule through a ring carbon or a heteroatom.

[0192] The term "cycloalkyl" refers to a group having the specified number of ring atoms (e.g., C 3-6 The cycloalkyl group may be monovalent or divalent.

[0193] The term "alkoxy" is used in its conventional sense to refer to those alkyl groups that are attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.

[0194] Unless otherwise indicated, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom. In addition, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-4 "Haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0195] Unless otherwise stated, the term "aryl" represents a polyunsaturated (usually aromatic) hydrocarbon radical, which can be a monocyclic or polycyclic (maximum three rings) fused together or covalently attached. The term "heteroaryl" refers to an aryl (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized. Heteroaryl can be attached to the remainder of the molecule through heteroatoms. The non-limiting example of aryl includes phenyl, naphthyl, and biphenyl, and the non-limiting example of heteroaryl includes pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isobenzofuranyl, benzothiazolyl ...

[00145] In some embodiments, the aryl and heteroaryl rings may be radicals of the following types: aryl, benzothiazolyl, benzofuranyl, benzothiophenyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, and the like. Substituents for each of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0196] In some embodiments, the above terms (such as "alkyl," "aryl," and "heteroaryl") will include both substituted and unsubstituted forms of the designated groups. Preferred substituents for each type of group are provided below. For brevity, the terms aryl and heteroaryl will refer to substituted or unsubstituted forms as provided below, while the term "alkyl" and related aliphatic groups refer to the unsubstituted form unless substituted is indicated.

[0197] Substituents for alkyl groups (including those groups commonly referred to as alkylene, alkenyl, alkynyl and cycloalkyl) may be various groups selected from the group consisting of -halogen, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR" C(O)2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -CN and -NO2, in a number from zero to (2M'+1), where M' is the total number of carbon atoms in such a group. R', R" and R"' each independently represent hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C1-8 Alkyl, C 1-8 Alkoxy or C 1-8 Thioalkoxy, or unsubstituted aryl-C 1-4 Alkyl. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl. The term "acyl" used alone or as part of another group refers to a group in which both substituents on the carbon closest to the point of attachment of the group are replaced with a substituent =0 (e.g., -C(O)CH3, -C(O)CH2CH2OR', etc.).

[0198] Similarly, the substituents for aryl and heteroaryl groups are varied and are typically selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R"', -NH- C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -N3, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, in a number from zero to the total number of open valences on the aromatic ring system; wherein R', R" and R"' are independently selected from hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4 Alkyl and unsubstituted aryloxy-C 1-4 Other suitable substituents include each of the above aryl substituents attached to a ring atom via an alkylene chain of 1 to 4 carbon atoms.

[0199] As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0200] For the compounds provided herein, a bond from a substituent (typically an R group) to the center of an aromatic ring (e.g., benzene, pyridine, etc.) will be understood to mean a bond providing attachment at any available vertex of the aromatic ring. In some embodiments, this description also includes attachment to a ring fused to an aromatic ring. For example, a bond drawn to the center of an indole benzene moiety will represent a bond attached to any available vertex of a six-membered or five-membered ring moiety of indole.

[0201] As used herein, "a portion derived from..." refers to the portion or fragment of an active substance (e.g., a polypeptide element such as an antibody or a targeting ligand) that remains after the active substance is linked to another portion by certain means (e.g., reacting an active group thereon, or introducing an active group therein for reaction), and the portion or fragment retains the function of the active substance (e.g., the ability to target a desired receptor). Specific linking groups formed by "derivation" include, but are not limited to, -NH-, -CONH-, -CO-, -SS-, and the like.

[0202] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents on the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrazine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and the like; and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galactunoric acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, which can allow the compounds to be converted into either base or acid addition salts.

[0203] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (e.g., solubility in polar solvents), but other than that, for the purposes of the present invention, those salts are equivalent to the parent form of the compound.

[0204] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir containing an appropriate enzyme or chemical reagent, a prodrug can be slowly converted to a compound of the present invention.

[0205] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Solvated forms are generally equivalent to unsolvated forms and are intended to be encompassed within the scope of this invention. Certain compounds of the present invention may exist in polymorphic or amorphous forms. Generally, for the applications contemplated by the present invention, all physical forms are equivalent and are intended to be encompassed within the scope of this invention.

[0206] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., isolated enantiomers) are intended to be encompassed within the scope of the present invention. When compounds provided herein have defined stereochemistry (denoted as R or S, or indicated by dashed or wedge-shaped bonds), those skilled in the art will understand that those compounds are substantially free of other isomers (e.g., at least 80%, 90%, 95%, 98%, 99%, and up to 100% free of other isomers).

[0207] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the isotopic atoms that make up such compounds. An unnatural proportion of an isotope can be defined as the amount of the atom in question found in nature to 100% of that atom. For example, a compound may incorporate a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes such as deuterium ( 2 H) or carbon-13 ( 13C) In addition to those uses described herein, such isotopic variants may provide additional uses. For example, isotopic variants of the compounds of the present invention may have additional uses, including but not limited to, as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic properties, thereby contributing to increased safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present invention, whether or not radioactive, are intended to be encompassed by the present invention.

[0208] Molecular glue degrader

[0209] Current studies have found that the cyclin-dependent kinase (CDK) inhibitor CR8 is also a molecular glue degrader. CR8 can more effectively kill cancer cells by inducing CDK12 / cyclin K to directly form a complex with CUL4 / DDB1, causing cyclin K to be ubiquitinated and degraded through the proteasome system.

[0210] Further structural analysis of the protein-small molecule-protein complex CUL4-RBX1-DDB1-CR8-CDK12-cyclin revealed that CDK12 plays a role similar to that of a CRBN substrate receptor. The presence and correct orientation of the 2-pyridine moiety on the CDK12 surface and CR8 increase the gain of function of CR8, leading to the degradation of cyclin K. Specifically, CR8-phenylpyridine imparts molecular glue activity, inducing cyclin K degradation and increasing the toxicity of CR8.

[0211] By modifying the CR8 structure, the authors discovered that the activity of the CR8 molecular glue is largely dependent on a 2-pyridine moiety exposed on the kinase surface. They concluded that this chemical group enables CR8 to function as a molecular glue degrader. Therefore, chemically modifying the surface-exposed portion of inhibitors can transform them into molecular glue degraders for specific protein targets.

[0212] However, the inventors have found in their research that compounds having the structures represented by the present invention, formula (I), formula (I-1), formula (I-2), formula (I-3), and formula (I-4), especially the structure represented by formula (I-1), still have excellent effects of inducing the degradation of cell cycle proteins such as cyclin K, regardless of the presence or absence of a pyridine substituent (or other nitrogen-containing heteroaromatic ring substituent) or whether it is a pyridine substituent (or other nitrogen-containing heteroaromatic ring substituent). Based on this, the inventors provide a series of novel cell cycle protein regulators (more specifically, molecular glue degraders).

[0213] In one embodiment, a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0214] Wherein, each group is as defined in the first aspect.

[0215] In a preferred embodiment, a compound represented by formula (I-1), formula (I-2), formula (I-3) or formula (I-4) or a pharmaceutically acceptable salt thereof is provided;

[0216] Wherein, each group is as defined above.

[0217] In one aspect of the present invention, a molecular glue degradation agent is provided as shown below:

[0218] Wherein, n2 is 2-4 (i.e., the ring where n2 is located is a 4- to 6-membered ring), and ring Ar 1 Optionally, n3 R a Substituent substitution (not shown) and ring Cr 1 Also optionally n4 R b Substituents (not shown); R 1 、R 2 、R 3 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 8 、X 9 、Subscript n1、n3、n4、Ar 1 Cr 1 、R a and R b As defined elsewhere herein.

[0219] In another aspect of the present invention, a molecular glue degradation agent is provided as shown below:

[0220] Wherein, n2 is 2-4 (i.e., the ring where n2 is located is a 4- to 6-membered ring); Ring Ar 1 Optionally, n3 R a Substituents (not shown) and ring Ar 2 Also optionally n4 R b Substituents (not shown); R 1 、R 2 、R 3 、X 1 、X 2 、X3 、X 4 、X 5 、X 6 、X 8 、X 9 、Subscript n1、n3、n4、Ar 1 Cr 1 、R a and R b As defined elsewhere herein.

[0221] Active ingredient

[0222] As used herein, the term "compound of the present invention" refers to a compound represented by formula (I), and also includes various crystalline forms or pharmaceutically acceptable salts of the compound of formula (I).

[0223] Herein, the active ingredient may also be a conjugate formed by the compound represented by formula (I) and an antibody or a polypeptide.

[0224] Pharmaceutical compositions and methods of administration

[0225] Because the compounds of the present invention have excellent activity in inducing cyclin K degradation, the compounds of the present invention and their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates, or solvates, as well as pharmaceutical compositions containing the compounds of the present invention as the primary active ingredient, or conjugates formed from the compounds of the present invention and antibodies or polypeptides, can be used to treat or prevent diseases related to or involving cyclin K. According to prior art, the compounds of the present invention can be used to treat the following diseases: cancer, etc.

[0226] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects.

[0227] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0228] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0229] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0230] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0231] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures thereof.

[0232] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0233] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0234] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0235] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0236] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0237] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0238] polypeptide element

[0239] As used herein, the term "polypeptide element" includes peptide segments (e.g., short peptides of 3-20 aa) or proteins. In addition, the term also includes intact proteins or fragments thereof. Preferred polypeptide elements include antibodies (e.g., intact antibodies, single-chain antibodies, nanobodies, antibody fragments), especially antibodies against tumor cell markers (e.g., tumor markers located on the surface of tumor cells, such as cell surface receptors) or against inflammatory factors (e.g., inflammatory factors associated with autoimmune diseases).

[0240] As used herein, the terms "antibody" or "immunoglobulin" are heterotetrameric glycoproteins of approximately 150,000 daltons with identical structural features, consisting of two identical light chains (L) and two identical heavy chains (H). Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide bonds varies between heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bonds. Each heavy chain has a variable region (VH) at one end, followed by multiple constant regions. Each light chain has a variable region (VL) at one end and a constant region at the other end; the constant region of the light chain is opposite the first constant region of the heavy chain, and the variable region of the light chain is opposite the variable region of the heavy chain. Specific amino acid residues form an interface between the variable regions of the light and heavy chains.

[0241] As used herein, the terms "single-domain antibody" and "nanobody" have synonymous meanings and refer to the construction of a single-domain antibody consisting solely of a single heavy chain variable region by cloning the variable region of an antibody heavy chain. This is the smallest fully functional antigen-binding fragment. Typically, antibodies naturally lacking the light chain and heavy chain constant region 1 (CH1) are first obtained, and then the variable region of the antibody heavy chain is cloned to construct a single-domain antibody consisting solely of a single heavy chain variable region.

[0242] As used herein, the term "variable" refers to certain portions of the variable region of an antibody that differ in sequence, which contribute to the binding and specificity of each particular antibody for its specific antigen. However, variability is not evenly distributed throughout the variable region of an antibody. It is concentrated in three segments called complementarity determining regions (CDRs) or hypervariable regions in the variable regions of the light and heavy chains. The more conserved portions of the variable region are called framework regions (FRs). The variable regions of native heavy and light chains each contain four FR regions, which are generally in a β-pleated configuration and are connected by three CDRs that form a connecting loop, which in some cases can form a partially folded structure. The CDRs in each chain are closely together through the FR regions and, together with the CDRs of the other chain, form the antigen-binding site of the antibody. The constant regions are not directly involved in the binding of the antibody to the antigen, but they exhibit different effector functions, such as involvement in the antibody's antibody-dependent cellular toxicity.

[0243] The "light chains" of vertebrate antibodies (immunoglobulins) can be assigned to one of two distinct classes, called kappa and lambda, based on the amino acid sequence of their constant regions. Immunoglobulins can be divided into different classes based on the amino acid sequence of their heavy chain constant regions. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which are further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. The heavy chain constant regions corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known in the art.

[0244] Generally, an antibody's antigen-binding properties are described by three specific regions located in the variable regions of the heavy and light chains, known as the variable regions (CDRs). These regions are divided into four framework regions (FRs). The amino acid sequences of the four FRs are relatively conserved and do not directly participate in the binding reaction. These CDRs form a ring structure, spatially close to each other through the β-sheet formed by the FRs between them. The CDRs on the heavy chain and the corresponding CDRs on the light chain constitute the antibody's antigen-binding site. The amino acid sequences of antibodies of the same type can be compared to determine which amino acids constitute the FR or CDR regions.

[0245] In the present invention, polypeptide elements may include not only intact antibodies, but also immunologically active antibody fragments (e.g., Fab or (Fab')2 fragments; antibody heavy chains; or antibody light chains) or fusion proteins formed by antibodies and other sequences. Therefore, the present invention also includes fragments, derivatives, and analogs of such antibodies.

[0246] Targeting ligands

[0247] A targeting ligand (or target protein moiety or target protein ligand or ligand) is a small molecule that is capable of binding to a target protein of interest.

[0248] In some embodiments of the present application, the targeting ligand may be (or be derived from) a target molecule.

[0249] Some embodiments of the present application relate to target molecules, representative target molecules include but are not limited to: folic acid, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting proteins containing human BET bromodomains, compounds targeting cytoplasmic signaling protein FKBP12, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, compounds targeting aryl hydrocarbon receptor (AHR) and compounds targeting tumor anaerobic microenvironment.

[0250] In certain embodiments, the targeting ligand is capable of binding to a kinase, a BET bromodomain-containing protein, a cytoplasmic signaling protein (e.g., FKBP12), a nuclear protein, a histone deacetylase, a lysine methyltransferase, a protein that regulates angiogenesis, a protein that regulates the immune response, the aryl hydrocarbon receptor (AHR), an estrogen receptor, an androgen receptor, a glucocorticoid receptor, or a transcription factor (e.g., SMARCA4, SMARCA2, TRIM24).

[0251] In certain embodiments, the kinases to which the targeting ligand can bind include, but are not limited to, tyrosine kinases (e.g., AATK, ABL, ABL2, ALK, AXL, BLK, BMX, BTK, CSF1R, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, ERBB2, ERBB3, ERBB4, FER, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1, FLT3, FLT4, FRK, FYN, GSG2, HCK, HRAS, HSP90, IGF1R, ILK, INSR, INSRR, IRAK4, ITK, JAK1, JAK2, JAK3, KDR, KIT, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD, KD RA S, KSP, KSR1, LCK, LMTK2, LMTK3, LTK, LYN, MATK, MERTK, MET, MLTK, MST1R, MUSK, NPR1, N RA S, NTRK1, NTRK2, NTRK3, PDGF RA , PDGF RB, PLK4, PTK2, PTK2B, PTK6, PTK7, RET, ROR1, ROR2, ROS1, RYK, SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TIE1, TNK1, TNK2, TNNI3K, TXK, TYK2, TYRO3, YES1, or ZAP70), serine / threonine kinases (e.g., casein kinase 2, protein kinase A, protein kinase B, protein kinase C, Raf kinase, CaM kinase, AKT1, AKT2, AKT3, ALK1, ALK2, ALK3, ALK4, AuroraA, AuroraB, AuroraC, CHK1, CHK2, CLK1, CLK2, CLK3, DAPK1, DAPK2, DAPK3, DMPK, ERK1, ERK2, ERK5, GCK, GSK3, HIPK, KHS1, LKB1, LOK, MAPKAPK2, MAP KAPK, MEK, MNK1, MSSK1, MST1, MST2, MST4, NDR, NEK2, NEK3, NEK6, NEK7, NEK9, NEK11, PAK1, PAK2, PAK3, PAK4, PAK5, PAK6, PIM1, PIM2, PLK1, RIP2, RIP5, RSK1, RSK2, SGK2, SGK3, SIK1, STK33, TAO1, TAO2, TGF-β, TLK2, TSSK1, TSSK2, MLK1 or MLK2), cyclin-dependent protein kinases (e.g., Cdk1-Cdk11), and leucine-rich repeat kinases (e.g., LRRK2).

[0252] The main advantages of the present invention include

[0253] (a) The compound of the present invention has an excellent effect of inducing the degradation of cyclin K.

[0254] (b) Further studies have revealed that the compounds of the present invention also have the function of inducing the degradation of other cell cycle proteins, thereby further increasing their cytotoxicity.

[0255] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0256] A. Preparation Examples

[0257] General synthetic method

[0258] The compounds of the present invention can be prepared, isolated or obtained by any method that is obvious to those skilled in the art. The compounds of the present invention can also be prepared according to the exemplary preparation schemes provided below (such as the method in the examples). The reaction conditions, steps and reactants not provided in the exemplary preparation schemes are obvious and known to those skilled in the art. As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether specific abbreviations are specifically defined, have meanings well known to those skilled in the art. Specifically, but not limited to, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mm (millimole); μM (micromolar); MHz (hertz); MHz (megahertz); mmol (millimole); hr or hrs (hours); min (minutes); MS (mass spectrometry); ESI (electrospray ionization); TLC (thin layer chromatography); HPLC (high performance liquid chromatography); THF (tetrahydrofuran); CDCl3 (deuterated chloroform); AcOH (acetic acid); DCM (dichloromethane); DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate); MeOH (methanol); ; and BOC (tert-butyloxycarbonyl), etc.

[0259] Unless otherwise stated, the starting materials used in the examples were commercially available or synthesized in a manner known to those skilled in the art or in a similar manner to those described in the examples.

[0260] Example 1: Synthesis of Compound UB-001

[0261] Step 1: UB-001c

[0262] UB-001a (2000 mg, 13.6 mol), UB-001b (2.32 g, 13.6 mmol), pdCl2dppf (300 mg), and Na2CO3 (2.8 g) were added to dioxane (32 mL) and water (8 mL). The reaction system was stirred at 80°C for 16 hours and then cooled to room temperature. The mixture was added to water, extracted with ethyl acetate, brine (30 mL), dried over sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol = 5%) to obtain UB-001c (1.8 g, 55.5% yield) as a yellow solid. LCMS [M+H] + =239.2

[0263] Step 2: UB-001d

[0264] LAH (4.2 ml, 1 M in THF) was added dropwise to a solution of UB-001c (500 mg, 2.1 mmol) in anhydrous THF (10 mL). The reaction system was stirred at 20°C for 16 hours. Upon completion, the reaction was quenched with Na2SO4*10H2O. The mixture was added to water, extracted with ethyl acetate, brine (30 mL), dried over sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol = 2-20%) to afford UB-001d (200 mg, 44.5% yield) as a yellow solid. LCMS [M+H] + =215.3

[0265] Step 3: UB-001f

[0266] A mixture of UB-001d (100 mg, 0.47 mmol) and UB-001e (0.1 g, 0.47 mmol) was dissolved in n-butanol (2 mL) and reacted at 120°C for 3 hours. The reaction solution was concentrated, and the crude product was separated by column chromatography (PE / EA = 30-70%) to afford UB-001f (120 mg, 65.1% yield) as a white solid. LCMS [M+H] + =394.2

[0267] Step 4: UB-001

[0268] A mixture of UB-001f (30 mg, 0.08 mmol), morpholine (33.12 mg, 0.38 mmol), and HCl (cat.) was dissolved in n-butanol (2 mL) and reacted at 180°C for 5 hours. The reaction mixture was concentrated, and the crude product was separated by column chromatography (DCM / MeOH = 0-10%) to afford UB-001 (10 mg, 29.1% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ8.06(s,1H),8.03–7.95(m,2H),7.89–7.73(m,3H),7.45(d,J=8.1Hz,2H),7.40(d,J=7.6Hz,1H),5.4 3(t,J=5.9Hz,1H),4.65(s,1H),4.61(d,J=5.8Hz,2H),4.02(q,J=7.2Hz,2H),3.61(s,8H),1.35(t,J=7.2Hz,3H).LCMS[M+H] + =446.6

[0269] Example 2: Synthesis of Compound UB-002

[0270] Step 1: UB-002

[0271] A mixture of UB-001f (30 mg, 0.08 mmol), 1-Boc-piperazine (14 mg, 0.08 mmol), and HCl (cat.) was dissolved in n-butanol (2 mL) and reacted at 180°C for 3 hours. The reaction mixture was concentrated, and the crude product was separated by column chromatography (DCM / MeOH = 0-10%) to afford a yellow solid (5 mg, 14.8% yield). 1 H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.99(d,J=8.0Hz,2H),7.88–7.81(m,2 H),7.76(d,J=7.8Hz,1H),7.46(d,J=8.0Hz,2H),7.41(d,J=7.6Hz,1H),5.45 (s,1H),4.67–4.58(m,3H),4.03(q,J=7.2Hz,2H),3.80(t,J=5.2Hz,4H),2. 96(t,J=5.1Hz,4H),1.36(t,J=7.2Hz,3H),1.24(d,J=3.5Hz,1H).LCMS[M+H] + =445.6

[0272] Example 3: Synthesis of Compound UB-003

[0273] Step 1: UB-003

[0274] A mixture of UB-001f (30 mg, 0.08 mmol), 1-methylpiperazine (76 mg, 0.8 mmol), and HCl (cat.) was dissolved in n-butanol (2 mL) and reacted at 180°C for 3 hours. The reaction mixture was concentrated, and the crude product was separated on a preparative plate (DCM / MeOH = 10%) to afford UB-003 (5.9 mg, 16.9% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.05(s,1H),8.01–7.96(m,2H),7.87–7.79(m,2H),7.75(d,J=7.8Hz,1H),7.45(d,J=8.1Hz,2H),7.40(d,J=7.5Hz,1H),5 .45(t,J=5.9Hz,1H),4.62(t,J=8.0Hz,3H),4.02(q,J=7.2Hz,2H),3.70( s,4H),2.49–2.39(m,4H),2.24(s,3H),1.35(t,J=7.2Hz,3H).LCMS[M+H] + =459.3.

[0275] Example 4: Synthesis of Compound UB-004

[0276] Step 1: UB-004c

[0277] A mixture of UB-004a (100 mg, 0.47 mmol), UB-004b (101 mg, 0.47 mmol), and DIPEA (95 mg) was dissolved in n-butanol (2 mL) and reacted at 120°C for 3 hours. The reaction solution was concentrated, and the crude product was separated by column chromatography (PE / EA = 30-70%) to afford UB-004c (120 mg, 60.4% yield) as a white solid. LCMS [M+H] + =364.2

[0278] Step 2: UB-004

[0279] A mixture of UB-004e (30 mg, 0.08 mmol), tert-butyl piperazine-1-carboxylate (70.8 mg, 0.38 mmol), and HCl (cat.) was dissolved in n-butanol (2 mL) and reacted at 180°C for 5 hours. The reaction mixture was concentrated, and the crude product was separated by column chromatography (DCM / MeOH = 0-10%) to afford UB-004 (10 mg, 27.0% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ7.78(s,1H),7.65–7.54(m,4H),7.48–7.40(m,4H),7.37–7.30(m,1H),4.63( s,2H),4.01(q,J=7.2Hz,2H),3.68–3.54(m,4H),2.75–2.63(m,4H),1.35(t,J=7.2Hz,3H).LCMS[M+H] + =414.4

[0280] Example 5: Synthesis of Compound UB-005

[0281] Step 1: UB-005a

[0282] LAH (4.2 ml, 1 M in THF) was added dropwise to a solution of UB-005a (500 mg, 2.1 mmol) in anhydrous THF (10 mL). The reaction was stirred at 20°C for 16 hours and quenched with Na2SO4*10H2O. The mixture was added to water, extracted with ethyl acetate, brine (30 mL), dried over sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol = 2-20%) to afford UB-005b (200 mg, 44.5% yield) as a yellow solid. LCMS [M+H] + =214.2

[0283] Step 2: UB-005d

[0284] A mixture of UB-005b (100 mg, 0.47 mmol), UB-005c (101 mg, 0.47 mmol), and DIPEA (95 mg) was dissolved in n-butanol (2 mL) and reacted at 120°C for 3 hours. The reaction solution was concentrated, and the crude product was separated by column chromatography (PE / EA = 30-70%) to afford UB-005d (120 mg, 65.1% yield) as a white solid. LCMS [M+H] + =394.3

[0285] Step 3: UB-005

[0286] A mixture of UB-005e (30 mg, 0.08 mmol), tert-butyl piperazine-1-carboxylate (70.8 mg, 0.38 mmol), and HCl (cat.) was dissolved in n-butanol (2 mL) and reacted at 180°C for 5 hours. The reaction mixture was concentrated, and the crude product was separated by column chromatography (DCM / MeOH = 0-10%) to afford UB-005 (10 mg, 29.5% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ7.99(d,J=8.3Hz,3H),7.87–7.73(m,3H),7.45(d,J=8.1Hz,2H),7.40(d,J=7.6Hz,1H),5.41(s,1H), 4.61(d,J=4.2Hz,4H),4.01(q,J=7.2Hz,2H),3.63(t,J=5.1Hz,4H),2.74(d,J=10.2Hz,4H),1.35(t,J=7.2Hz,3H).LCMS[M+H] + =444.6

[0287] Example 6: Synthesis of Compound UB-006

[0288] Step 1: UB-006

[0289] A mixture of UB-006a (50 mg, 0.14 mmol) and UB-006b (59.7 mg, 0.69 mmol) was dissolved in n-butanol (2 mL) and reacted at 180°C for 16 hours. The reaction mixture was concentrated, and the crude product was separated by column chromatography (DCM / MeOH = 0-10%) to afford UB-006 (16 mg, 26.3% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ8.67–8.60(m,1H),8.04–7.97(m,2H),7.93–7.82(m, 2H),7.72(s,1H),7.45(d,J=8.0Hz,2H),7.35–7.28(m,1H),6.08(d,J=7.6Hz ,1H),4.65(s,2H),4.48(d,J=4.5Hz,1H),3.97(q,J=7.2Hz,2H),3.61(s,1H) ,1.79(d,J=11.3Hz,4H),1.33(t,J=7.2Hz,3H),1.28–1.14(m,5H).LCMS[M+H] + =444.9

[0290] Example 7: Synthesis of Compound UB-007

[0291] Step 1: UB-007b

[0292] Compound UB-007a (35.8 g, 0.2 mol) was added to a three-necked reaction flask and dissolved in tetrahydrofuran (360 mL). Under argon, lithium aluminum tetrahydride (17.6 g, 0.44 mol) was added in five batches. The reaction mixture was allowed to react at 16°C for 2 hours. The reaction mixture was quenched with saturated sodium sulfate solution (20 g), the solid was filtered, and the filter cake was washed with tetrahydrofuran (100 mL). The filtrate was dried to give the product (UB-007b, 37 g, 100% yield) as a yellow solid. LCMS [M+1] + =184.3

[0293] Step 2: UB-007d

[0294] Compound UB-007b (18.4 g, 0.1 mol), UB-007c (18.9 g, 0.1 mol), and triethylamine (40.4 g, 0.4 mol) were dissolved in tert-butanol (200 mL) and reacted at 110°C for 14 hours. The reaction mixture was cooled to 20°C, whereupon a large amount of solid precipitated. This solid was filtered, washed with ethanol / water (100 mL / 10 mL), and dried under vacuum to yield the target compound (UB-007d, 20.7 g, 80% yield) as a yellow solid. LCMS [M+1] + =336.8

[0295] Step 3: UB-007f

[0296] Compound UB-007d (27 g, 0.08 mol) and K2CO3 (55.2 g, 0.4 mol) were dissolved in dimethyl sulfoxide (270 mL) and stirred at room temperature for 5 minutes. Compound UB-007e (59.3 g, 0.48 mol) was added dropwise to the reaction mixture. The reaction mixture was allowed to react at 30°C for 14 hours. The reaction mixture was quenched with water (1000 mL) and extracted with ethyl acetate (200 mL x 3). The resulting layer was washed with brine, dried over anhydrous sodium sulfate, and then purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound UB-007f (27 g, 90% yield) as a light yellow solid. LCMS [M+1] + =378.9.1H NMR (400MHz, CDCl3) δ7.72 (s, 1H), 7.62 (dd, J = 8.0, 2.0Hz, 4H), 7.48 (t, J = 8.1Hz, 4H),7.39(t,J=7.3Hz,1H),6.58(s,1H),5.04–4.80(m,3H),1.60(d,J=6.8Hz,6H).

[0297] Step 4: UB-007

[0298] Compound UB-007f (110 mg, 0.29 mmol) and compound UB-007g (446 mg, 1.45 mmol) were dissolved in 2 mL of dimethyl sulfoxide and reacted at 145°C for 14 hours. The reaction mixture was cooled to 20°C and extracted three times with ethyl acetate (20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and dried by spin chromatography. Purification by column chromatography (petroleum ether / ethyl acetate = 1 / 2) afforded compound UB-007 (39 mg, 31.2% yield) as a light yellow solid. LCMS [M+1] + =431.6. 1 H NMR (400MHz, CDCl3) δ7.66–7.58(m,4H),7.57(s,1H),7.53–7.44(m,4H),7.38(t,J=7.3Hz,1H),6.77(s,1H),5.00(d,J=6.0Hz, 1H),4.83(s,2H),4.61(dt,J=13.5,6.8Hz,1H),4.01–3.91(m,1H),3.85(dd,J=10.7,2.3Hz,1H),3.67(dd,J=10.5,7.6Hz,1H), 1.73–1.57(m,2H),1.53(d,J=6.7Hz,6H),1.05(t,J=7.4Hz,3H).

[0299] Example 8: Synthesis of Compound UB-008

[0300] Step 1: UB-008 (LS22002-016)

[0301] Compound UB-007f (185.15 mg, 0.49 mmol) and piperidine (200 mg, 2.35 mmol) were dissolved in 2 mL of dimethyl sulfoxide and reacted at 145°C for 18 hours. The reaction mixture was cooled to 20°C, quenched with water (50 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and dried by spin-drying. Purification by column chromatography (petroleum ether / ethyl acetate = 1 / 2) afforded compound UB-007 (31 mg, 14.8% yield) as a pale yellow solid. LCMS [M+1] + =427.5

[0302] Example 9: Synthesis of Compound UB-009

[0303] Step 1: UB-009

[0304] Compound UB-007f (200 mg, 0.53 mmol) and morpholine (416 mg, 5.3 mmol) were dissolved in 3 mL of dimethyl sulfoxide and reacted at 145°C for 18 hours. The reaction mixture was cooled to 20°C, quenched with water (50 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and dried by spin-drying. Purification by column chromatography (petroleum ether / ethyl acetate = 1 / 2) afforded compound UB-009 (38.5 mg, 17% yield) as a pale yellow solid. LCMS [M+1] + =429.6. 1 H NMR(400MHz, CDCl3)δ7.68(s,1H),7.59(dd,J=15.8,7.8Hz,4H),7.51–7.43(m,4H),7.38(t,J=7.3 Hz,1H),6.64(s,1H),4.85(s,2H),4.75–4.60(m,1H),3.80(d,J=3.4Hz,8H),1.56(d,J=6.7Hz,6H).

[0305] Example 10: Synthesis of Compound UB-010

[0306] Step 1: UB-010

[0307] Compound UB-007f (200 mg, 0.53 mmol) and piperazine (461 mg, 5.3 mmol) were dissolved in 3 mL of dimethyl sulfoxide and reacted at 145°C for 18 hours. The reaction mixture was cooled to 20°C, quenched with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and dried by spin-drying. Purification by column chromatography (dichloromethane / methanol = 13 / 1) afforded compound UB-010 (85 mg, 37.5% yield) as a pale yellow solid. LCMS [M+1] + =428.6. 1 H NMR(400MHz, CDCl3) δ7.80(s,1H),7.57(dd,J=12.3,7.9Hz,4H),7.45(dd,J=12.5,7.7Hz,4H),7.36 (s,1H),4.79(s,2H),4.66(dt,J=12.9,6.3Hz,2H),4.11(s,4H),3.22(s,4H),1.55(d,J=6.7Hz,6H).

[0308] Example 11: Synthesis of Compound UB-011

[0309] Step 1: UB-011

[0310] Compound UB-007f (110 mg, 0.29 mmol) and N-methylpiperazine (290 mg, 2.9 mmol) were dissolved in 2 mL of dimethyl sulfoxide and reacted at 145°C for 18 hours. The reaction mixture was cooled to 20°C, quenched with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and dried by spin chromatography. Purification by column chromatography (dichloromethane / methanol = 13 / 1) afforded compound UB-011 (53.9 mg, 42% yield) as a pale yellow solid. LCMS [M+1] + =442.7. 1 H NMR(400MHz, CDCl3) δ7.59(dd,J=12.8,7.9Hz,5H),7.50–7.44(m,4H),7.37(t,J=7.3Hz,1H),6.43(s ,1H),4.85(s,2H),4.73–4.63(m,1H),4.00(s,4H),2.67(s,4H),2.49(s,3H),1.56(d,J=6.8Hz,6H).

[0311] Example 12: Synthesis of Compound UB-012

[0312] Step 1: UB-012b

[0313] Compound UB-007f (188.5 mg, 0.5 mmol) and compound UB-012a (500 mg, 2.5 mmol) were dissolved in 3 mL of dimethyl sulfoxide and reacted at 145°C for 18 hours. The reaction mixture was cooled to 20°C, quenched with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and spin-dried to obtain compound UB-012b (200 mg, 90.1% yield) as a light yellow solid. LCMS [M+1] + =542.6

[0314] Step 2: UB-012

[0315] Compound UB-012b (200 mg, 0.45 mmol) was dissolved in 3 mL of methanol. 1N hydrochloric acid in methanol (3 mL) was added with stirring and the mixture was allowed to react at 25°C for 18 hours. The reaction solution was dried by vortexing, the pH was adjusted to 9 with saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and dried by vortexing. Purification by column chromatography (dichloromethane / methanol = 13 / 1) afforded compound UB-012 (131 mg, 66% yield) as a pale yellow solid. LCMS [M+1] + =442.7. 1 H NMR (500MHz, DMSO-d6) δ8.17(s,2H),7.81(s,1H),7.61(dd,J=15.5,7.7Hz,4H),7.44(t,J=7.8Hz,4H),7.34(t,J=7.3Hz,1H),6.17(s,1H),4.6 3(s,2H),4.57–4.44(m,1H),3.61(d,J=7.2Hz,1H),2.91(t,J=11.1Hz,1H),1.95(t,J=15.9Hz,4H),1.45(t,J=12.4Hz,7H),1.32–1.07(m,2H).

[0316] Example 13: Synthesis of Compound UB-013

[0317] Step 1: UB-013b (LS22002-011-1)

[0318] Compound UB-007f (188.5 mg, 0.5 mmol) and compound UB-012a (500 mg, 2.5 mmol) were dissolved in 3 mL of dimethyl sulfoxide and reacted at 145°C for 18 hours. The reaction mixture was cooled to 20°C, quenched with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and spin-dried to obtain compound UB-013b (200 mg, 90.1% yield) as a light yellow solid. LCMS [M+1] + =542.6

[0319] Step 2: UB-013 (LS22002-011-2)

[0320] Compound UB-013b (200 mg, 0.45 mmol) was dissolved in 3 mL of methanol. 1N hydrochloric acid in methanol (3 mL) was added with stirring and the mixture was allowed to react at 25°C for 18 hours. The reaction solution was dried by vortexing, the pH was adjusted to 9 with saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and dried by vortexing. Purification by column chromatography (dichloromethane / methanol = 13 / 1) afforded compound UB-013 (77 mg, 38% yield) as a pale yellow solid. LCMS [M+1] + =442.7 1 H NMR (500MHz, DMSO-d6) δ8.09(s,1H),7.89(s,1H),7.61(dd,J=18.2,7.8Hz,4H),7.50(d,J=7. 7Hz,2H),7.44(t,J=7.7Hz,2H),7.34(t,J=7.3Hz,1H),4.75–4.56(m,3H),4.30(d,J=12.9Hz, 1H),3.54–3.21(m,2H),3.09(dd,J=13.9,6.2Hz,2H),3.00(t,J=10.9Hz,1H),2.51(s,1H),2. 01(d,J=10.0Hz,1H),1.73(dd,J=9.2,4.0Hz,1H),1.63–1.52(m,1H),1.47(t,J=10.0Hz,7H).

[0321] Example 14: Synthesis of Compound UB-014

[0322] Step 1: UB-014b

[0323] Compound UB-007f (188.5 mg, 0.5 mmol) and compound UB-014a (500 mg, 2.5 mmol) were dissolved in 3 mL of dimethyl sulfoxide and reacted at 145°C for 18 hours. The reaction mixture was cooled to 20°C, quenched with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and spin-dried to obtain compound UB-014b (200 mg, 90.1% yield) as a pale yellow solid. The crude product was used directly in the next step. LCMS [M+1] + =542.6

[0324] Step 2: UB-014

[0325] Compound UB-014b (200 mg, 0.45 mmol) was dissolved in 3 mL of methanol. 1N hydrochloric acid in methanol (3 mL) was added with stirring and allowed to react at 25°C for 18 hours. The reaction solution was dried by vortexing, the pH adjusted to 9 with saturated sodium carbonate solution, and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and dried by vortexing. Purification by column chromatography (dichloromethane / methanol = 13 / 1) afforded compound UB-014 (35 mg, 17.6% yield) as a pale yellow solid. LCMS [M+1] + =442.5. 1 H NMR (400MHz, DMSO-d6) δ8.05(s,1H),7.90(s,1H),7.63(dd,J=14.2,8.0Hz,4H),7.48(dd,J=16.7,8.5Hz,4H),7.37(t,J=7.3Hz,1 H),4.80–4.47(m,4H),4.31(d,J=12.9Hz,1H),3.03(d,J=7.5Hz,4H),2.02–1.92(m,1H),1.79–1.69(m,1H),1.51(d,J=6.8Hz,9H).

[0326] Example 15: Synthesis of Compound UB-015

[0327] Step 1: UB-015b

[0328] Compound UB-007f (188.5 mg, 0.5 mmol) and compound UB-015a (500 mg, 2.5 mmol) were dissolved in 3 mL of dimethyl sulfoxide and reacted at 145°C for 18 hours. The reaction mixture was cooled to 20°C, quenched with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and spin-dried to obtain compound UB-015b (200 mg, 90.1% yield) as a pale yellow solid. The crude product was used directly in the next step. LCMS [M+1] + =542.5

[0329] Step 2: UB-015

[0330] Compound UB-015b (200 mg, 0.45 mmol) was dissolved in 3 mL of methanol. 1N hydrochloric acid in methanol (3 mL) was added with stirring and the mixture was allowed to react at 25°C for 18 hours. The reaction solution was dried by vortexing, the pH was adjusted to 9 with a saturated potassium carbonate solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and dried by vortexing. Purification by column chromatography (dichloromethane / methanol = 13 / 1) afforded compound UB-015 (45 mg, 22.6% yield) as a pale yellow solid. LCMS [M+1] + =442.5

[0331] Example 16: Synthesis of Compound UB-016

[0332] Step 1: UB-016c

[0333] N 6 -([1,1'-biphenyl]-4-ylmethyl)-9-isopropyl-N 2 -(Piperidin-4-yl)-9H-purine-2,6-diamine

[0334] UB-016a (200 mg, 0.53 mmol), UB-016b (318.4 mg, 1.59 mmol), Pd2(dba)3 (49 mg, 0.054 mmol), Xphos (126 mg, 0.265 mmol) and Cs2CO3 (518 mg, 1.59 mmol), and 1,4-dioxane (10 mL) were added to the reaction flask. The reaction mixture was purged with argon three times and then heated to 100°C and stirred overnight. The reaction mixture was diluted with water (30 mL) and then extracted with ethyl acetate (30 mL*3). The organic phase was separated, washed with brine (50 mL), and dried over anhydrous sodium sulfate, then concentrated and purified by chromatography (dichloromethane: dichloromethane / methanol 10 / 1 = 40:60) to obtain the product as a yellow solid compound (UB-016c, 369.6 mg, crude). LCMS [M+1] + =542.3.

[0335] Step 2: UB-016

[0336] N 6 -([1,1'-biphenyl]-4-ylmethyl)-9-isopropyl-N 2 -(Piperidin-4-yl)-9H-purine-2,6-diamine

[0337] To a 100 mL bottom flask was added UB-016c (369.6 mg, 0.68 mmol), a solution of hydrochloric acid in 1,4-dioxane (4 mL) and dichloromethane (8.0 mL) at room temperature. The solution was then stirred at room temperature for 2 hours. The reaction mixture was filtered, the filter cake was washed with dichloromethane (5 mL), neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane (3*50 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then methanol and water were added and freeze-dried to give a yellow solid product (UB-016, 85.6 mg, yield: 28.4%) LCMS [M+1] + =442.2. 1H NMR(400MHz, DMSO-d6)δ7.80(s,1H),7.59(dd,J=17.4,7.8Hz,4H),7.47–7.40(m,4H ),7.33(t,J=7.3Hz,1H),6.17(d,J=7.2Hz,1H),4.64(s,2H),4.52(dt,J=13.2,6.5Hz ,1H),3.72(s,1H),2.95(d,J=11.3Hz,2H),2.56(d,J=11.2Hz,1H),1.86(s,2H),1.7 8(s,2H),1.46(d,J=6.7Hz,6H),1.32(dd,J=16.4,8.8Hz,2H),1.24(d,J=6.1Hz,1H).

[0338] Example 17: Synthesis of Compound UB-017

[0339] Step 1: UB-017

[0340] Compound UB-007f (188.5 mg, 0.5 mmol) and 4-aminopiperidine (250 mg, 2.5 mmol) were dissolved in 3 mL of dimethyl sulfoxide and reacted at 145°C for 18 hours. The reaction mixture was cooled to 20°C, quenched with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and dried by spin-drying. Purification by column chromatography (petroleum ether / ethyl acetate = 1 / 2) afforded compound UB-017 (147 mg, 66% yield) as a pale yellow solid. LCMS [M+1] + =442.7. 1 H NMR(500MHz,DMSO-d6)δ8.09(s,1H),7.87(s,1H),7.78(s,2H),7.65–7.60 (m,2H),7.58(d,J=8.2Hz,2H),7.48–7.42(m,4H),7.34(t,J=7.4Hz,1H),4. 68–4.54(m,4H),3.26–3.16(m,1H),2.86(t,J=11.7Hz,2H),2.54(s,1H),1. 88(d,J=10.5Hz,2H), 1.47(d,J=6.8Hz,6H), 1.37(dd,J=19.5,10.2Hz,2H).

[0341] Example 18: Synthesis of Compound UB-018

[0342] Step 1: UB-018

[0343] Compound UB-007f (188.5 mg, 0.5 mmol) and compound UB-018a (285.5 mg, 2.5 mmol) were dissolved in 3 mL of dimethyl sulfoxide and reacted at 145°C for 14 hours. The reaction mixture was cooled to 20°C, quenched with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and spin-dried. Purification by column chromatography (petroleum ether / ethyl acetate = 1 / 2) afforded compound UB-018 (85 mg, 37% yield) as a pale yellow solid. LCMS [M+1] + =456.3 1 H NMR(500MHz,DMSO-d6)δ8.08(s,1H),7.89(s,2H),7.62(d,J=7.3Hz,2H),7.59(d,J =8.2Hz,2H),7.48(d,J=7.9Hz,2H),7.44(t,J=7.7Hz,2H),7.34(t,J=7.3Hz,1H),4. 79–4.49(m,4H),4.27(d,J=13.1Hz,1H),3.15–2.97(m,3H),2.54(s,1H),2.05–1.9 4(m,1H),1.73(dd,J=8.9,4.4Hz,1H),1.54(d,J=8.7Hz,1H),1.48(d,J=6.8Hz,8H).

[0344] Example 19: Synthesis of Compound UB-019

[0345] Step 1: UB-019b

[0346] Compound UB-007f (188.5 mg, 0.5 mmol) and compound UB-019a (535.5 mg, 2.5 mmol) were dissolved in 3 mL of dimethyl sulfoxide and reacted at 145°C for 14 hours. The reaction mixture was cooled to 20°C, quenched with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and spin-dried to obtain compound UB-019b (200 mg, 85.1% yield) as a pale yellow solid. The crude product was used directly in the next step. LCMS [M+1] + =556.6

[0347] Step 2: UB-019

[0348] Compound UB-019b (200 mg, 0.45 mmol) was dissolved in 3 mL of methanol, and 1N hydrochloric acid in methanol (3 mL) was added with stirring. The mixture was allowed to react at 25°C for 14 hours. The reaction solution was dried by vortexing, the pH was adjusted to 9 with saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and dried by vortexing. Purification by column chromatography (dichloromethane / methanol = 13 / 1) afforded compound UB-019 (26 mg, 11.4% yield) as a pale yellow solid. LCMS [M+1] + =556.6

[0349] Example 20: Synthesis of Compound UB-020

[0350] Step 1: UB-020c

[0351] Tert-Butyl (R)-4-(6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)-3-methylpiperazine-1-carboxylate

[0352] To a solution of UB-007f (200 mg, 0.530 mmol) and UB-020b (424 mg, 0.120 mmol) in anhydrous dioxane (10 mL) was added Pd2(dba)3 (48 mg, 0.054 mmol), Cs2CO3 (518 mg, 1.59 mmol), and XPhos (126 mg, 0.265 mmol) under Ar. The mixture was stirred at 100°C for 3 hours. The reaction solution was concentrated and purified by flash chromatography using PE / EA = 0-50% as the eluent to give a white solid compound (UB-020c, 110 mg, 38.3% yield). LCMS [M+1] + =542.4

[0353] Step 2: UB-020

[0354] (R)-N-([1,1'-biphenyl]-4-ylmethyl)-9-isopropyl-2-(2-methylpiperazin-1-yl)-9H-purin-6-amine

[0355] UB-020c (110 mg, 0.203 mmol) and 8 mL of DCM solution were added to the reaction flask, followed by a solution of HCl in dioxane (3 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with NaHCO₃ (5 mL) and extracted with DCM (10 mL*3). The organic phase was separated, washed with brine (10 mL*3), and dried over Na₂SO₄, then concentrated and purified by flash chromatography using DCM: 10% MeOH / DCM = 0-100% as the eluent to give the compound (UB-020, 42.5 mg, 47.5% yield) as a white solid (LCMS [M+1]). + =442.3 1 H NMR (400MHz, DMSO-d6) δ7.99(s,1H),7.84(s,1H),7.64–7.59(m,2H),7.58(d,J=8.2Hz,2H),7.47–7.40(m,4H),7.33(t,J=7.3Hz,1H),4.70(dd,J=15 .0,11.6Hz,2H),4.56(dt,J=13.4,6.7Hz,2H),4.38–4.29(m,1H),3.00–2. 83(m,2H),2.79(s,2H),1.47(dd,J=6.7,1.0Hz,6H),1.08(d,J=6.5Hz,3H).

[0356] Example 21: Synthesis of Compound UB-021

[0357] Step 1: UB-021c

[0358] (S)-tert-Butyl 4-(6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)-3-methylpiperazine-1-carboxylate

[0359] Compound UB-021b (637 mg, 3.18 mmol), compound UB-007f (200 mg, 0.53 mmol), cesium carbonate (519 mg, 1.59 mmol), Pd2(dba)3 (73 mg, 0.08 mmol), and Xphos (142 mg, 0.30 mmol) were dissolved in 6 mL of ultra-dry dioxane and reacted at 100°C overnight. After completion, the reaction mixture was cooled to room temperature, concentrated, and purified on a silica gel column (EA / PE = 40%) to obtain compound UB-021c (280 mg, 97% yield) as a yellow solid. LCMS [M+1]+ = 542.3.

[0360] Step 2: UB-021

[0361] (S)-N-([1,1'-biphenyl]-4-ylmethyl)-9-isopropyl-2-(2-methylpiperazin-1-yl)-9H-purin-6-amine

[0362] Compound UB-021c (280 mg, 0.52 mmol) was dissolved in dichloromethane (6 mL) and 1,4-dioxane hydrochloride (6 mmol, 1.5 mL) was added. The reaction was stirred at 40°C for 4 hours. After completion of the reaction, a saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8-9, and the mixture was extracted with DCM (40 mL*3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The extract was concentrated and purified on a silica gel column (DCM / MeOH = 30%) and lyophilized to obtain the desired compound UB-021 (40 mg, 24% yield) as a white solid. LCMS [M+1] + =442.3. 1 H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.88(s,1H),7.60(dd,J=13.8,8.0Hz,4 H),7.47–7.42(m,4H),7.34(t,J=7.3Hz,1H),4.87(s,1H),4.56(ddd,J=33.3, 26.3,16.3Hz,4H),3.15(d,J=12.0Hz,1H),3.09–2.90(m,3H),2.74(t,J=22. 8Hz, 1H), 1.47 (d, J = 6.7Hz, 6H), 1.24 (d, J = 6.0Hz, 1H), 1.12 (d, J = 6.5Hz, 3H).

[0363] Example 22: Synthesis of Compound UB-022

[0364] Step 1: UB-022h

[0365] To a three-necked flask were added compound UB-007f (270 mg, 0.72 mmol), UB-022g (416 mg, 2.34 mmol), Cs2CO3 (624 mg, 2.15 mmol), Pd2(dba)3 (90 mg, 0.10 mmol), and XPhos (234 mg, 0.49 mmol). The mixture was replaced with argon three times, then anhydrous 1,4-dioxane (16 mL) was added and the mixture was stirred at 100°C for 19 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM: 10% MeOH in DCM = 0-78%) to obtain the product UB-022h (65 mg, yield: 16%). LCMS [M+1] + =558.3

[0366] Step 2: UB-022

[0367] To a mixture of compound UB-022h (65 mg, 0.12 mmol) in CH2Cl2 (3 mL) was added HCl / dioxane (4 N, 1.5 mL). The reaction mixture was stirred at 25°C for 17 hours. The reaction mixture was concentrated and adjusted to pH = 8-9 with saturated aqueous Na2CO3. After extraction with CH2Cl2 (20 mL*3), the combined organic layers were washed with brine and dried over anhydrous Na2SO4. The mixture was then concentrated under reduced pressure and purified by reverse phase column to give the product UB-022 (15.7 mg, yield: 29%) as a white solid. LCMS [M+1]+ = 458.3.1H NMR(400MHz, DMSO-d6)δ8.00(s,1H),7.84(s,1H),7.65–7.60(m,2H),7.58(d,J=8.2H z,2H),7.48–7.40(m,4H),7.33(t,J=7.3Hz,1H),4.67–4.51(m,4H),4.43(d,J=12.9Hz ,1H),3.79(t,J=9.3Hz,1H),3.42(dd,J=9.8,4.7Hz,2H),3.23(d,J=12.3Hz,2H),3.00 –2.87(m,2H),2.68(dd,J=12.3,4.0Hz,1H),2.64–2.54(m,1H),1.46(d,J=6.2Hz,6H).

[0368] Example 23: Synthesis of Compound UB-023

[0369] Step 1: UB-023c

[0370] Tert-Butyl (R)-4-(6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

[0371] To a reaction flask under Ar was added UB-007f (300 mg, 0.8 mmol), UB-023b (520 mg, 2.4 mmol), and anhydrous dioxane solution (18 mL). Pd2(dba)3 (80 mg, 0.08 mmol), Cs2CO3 (800 mg, 2.4 mmol), and XPhos (200 mg, 0.4 mmol) were also added. The mixture was stirred at 100°C for 3 hours. The reaction was concentrated and purified by flash chromatography using DCM / (DCM:MeOH=10:1)=0-40% as the eluent to give UB-023c as a yellow oil (200 mg, 44.8% yield). LCMS [M+1] + =558.3

[0372] Step 2: UB-023

[0373] (R)-(1-(6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)piperazin-2-yl)methanol

[0374] UB-023c (200 mg, 0.359 mmol), 8 mL of DCM solution, and a dioxane solution of HCl (2 mL) were added to the reaction flask. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with NaHCO3 (4 mL) and extracted with DCM (20 mL*3). The organic phase was separated, washed with brine (20 mL*3), and dried over Na2SO4, then concentrated and purified by flash chromatography using DCM / (DCM:MeOH=10:1)=0-100% as the eluent to obtain the compound (UB-023, 25.5 mg, 15.5% yield) as a light yellow solid. LCMS [M+1] + =458.3. 1H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.87(s,1H),7.65–7.60(m,2H),7.58(d,J=8.2Hz,2H),7 .48–7.41(m,4H),7.34(t,J=7.3Hz,1H),4.70(s,1H),4.67–4.58(m,2H),4.54(dd,J=13.3,5. 7Hz,2H),3.78(t,J=9.2Hz,1H),3.49(dd,J=10.1,4.8Hz,1H),3.37(s,1H),3.07(dd,J=24.9, 12.1Hz, 2H), 2.84 (dd, J=12.3, 3.7Hz, 1H), 2.71 (dd, J=23.4, 11.4Hz, 1H), 1.50–1.44 (m, 6H).

[0375] Example 24: Synthesis of Compound UB-024

[0376] Step 1: UB-024i

[0377] To a stirred suspension of K2CO3 (8.39 g, 60.17 mmol) in MeCN (100 mL) was added compound UB-024g (4.00 g, 20.24 mmol) at room temperature. The resulting mixture was stirred for 15 minutes, then benzyl bromide (2.6 mL, 21.89 mmol) was added. The reaction mixture was stirred at reflux temperature for 14 hours. The reaction mixture was concentrated and purified by silica gel chromatography (40 g, 45 mL / min; DCM: 10% MeOH in DCM = 0-6-30%) to give the product UB-024i (3.95 g, yield: 77%) as a white solid. LCMS [M+1] + =252.1

[0378] Step 2: UB-024k

[0379] To a stirred solution of compound UB-024i (3.95 g, 15.73 mmol) in DCM (80 mL) was added Et3N (3.3 mL, 23.74 mmol), followed by the slow addition of bromoacetyl bromide (3.81 g, 18.88 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (PE:EA=0-15-30%) to give the product UB-024k (4.62 g, yield: 79%) as a colorless liquid. LCMS [M+1]+=372.1 & 374.1

[0380] Step 3: UB-024l

[0381] Compound UB-024k (4.62 g, 12.43 mmol) was dissolved in CH3OH (20 mL), followed by the addition of a 7N solution of NH3 in CH3OH (1.5 mL). The mixture was stirred at room temperature for 17 h. The solvent was then removed under reduced pressure and purified by silica gel column chromatography (25 g, 45 mL / min; CH2Cl2 / 10% CH3OH in CH2Cl2 = 0-30%) to afford product UB-024l (2.18 g, 64% yield) as a white solid. LCMS [M+1] + =277.1

[0382] Step 4: UB-024m

[0383] To a stirred solution of UB-024l (2.18 g, 7.92 mmol) in anhydrous tetrahydrofuran (30 mL) cooled to 0°C in an ice bath was slowly added a solution of LiAlH4 in THF (48 mL, 48 mmol). The resulting suspension was kept at 0°C for 10 minutes and then refluxed for 1.5 hours. The reaction was then cooled down and water and sodium sulfate were added directly to the mixture until gas evolution was complete. The mixture was then filtered through celite, the filter cake was washed with MeOH, and the solvent was removed to give the product UB-024m (1.70 g, 75% yield) as a light orange oil. LCMS [M+1] + =221.2

[0384] Step 5: UB-024n

[0385] To a solution of compound UB-024m (1.74 g, 7.90 mmol) in (40 mL) was added a solution of sodium bicarbonate (1.99 g, 23.69 mmol) in water (20 mL) at room temperature. Di-tert-butyl dicarbonate (2.59 g, 11.87 mmol) was slowly added to the above mixture, and the mixture was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (25 g, 45 mL / min; DCM: 10% MeOH in DCM = 0-10%) to give the product UB-024n (1.78 g, yield: 71%) as a light yellow liquid. LCMS [M+1] + =321.2

[0386] Step 6: UB-024o

[0387] Pd / C was added to a solution of compound UB-024n (1.78 g, 5.56 mmol) in EtOH (40 mL) at room temperature. The mixture was degassed and refilled with H2 three times. The mixture was then stirred at room temperature for 24 hours. The mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was concentrated to give the product UB-024o (1.28 g, 100% yield). LCMS [M+1] + =231.2

[0388] Step 7: UB-024p

[0389] Compound UB-007f (170 mg, 0.45 mmol), UB-024o (225 mg, 0.98 mmol), Cs2CO3 (440 mg, 1.35 mmol), Pd2(dba)3 (43 mg, 0.05 mmol) and XPhos (112 mg, 0.23 mmol) were added to a three-necked round-bottom flask. The mixture was degassed and refilled with argon three times. Dry dioxane (14 mL) was added to the mixture via a syringe. The mixture was then stirred at 100°C for 4 hours. The reaction mixture was concentrated and purified by silica gel chromatography (DCM: 10% MeOH in DCM = 0-24%) to give the product UB-024p (158 mg, yield: 61%) as a yellow solid. LCMS [M+1] + =572.3

[0390] Step 8: UB-024

[0391] To a mixture of compound UB-024p (158 mg, 0.28 mmol) in CH2Cl2 (6 mL) was added HCl / dioxane (4N, 1.5 mL). The reaction mixture was stirred at 25°C for 17 hours. The reaction mixture was concentrated and adjusted to pH = 8-9 with aqueous Na2CO3. The mixture was then concentrated under reduced pressure and purified by silica gel chromatography (DCM: 10% MeOH in DCM = 0-33%) to give the product UB-024 (41 mg, yield: 32%) as a white solid. LCMS [M+1] + =472.3 1H NMR (400MHz, DMSO-d6) δ7.97(s,1H),7.83(s,1H),7.62(dd,J=5.2,3.3Hz,2H),7.58(d,J=8.3Hz,2H),7.44(dd,J=8.0,6.8H z,4H),7.37–7.29(m,1H),4.65(s,3H),4.53(m,1H),4.44(d,J=11.2Hz,1H),3.36(t,J=6.9Hz,2H),2.91–2.77(m,3H),2.69– 2.60(m,1H),1.84(d,J=6.6Hz,2H),1.46(dd,J=6.7,3.4Hz,6H).

[0392] Example 25: Synthesis of Compound UB-025

[0393] Step 1: UB-025c

[0394] Dimethylbenzyl-L-aspartic acid

[0395] K2CO3 (6.29 g, 45.54 mmol) and 20 mL of MeCN were added to the reaction flask at room temperature, and UB-025a (3.0 g, 15.18 mmol) was added to the stirred suspension. The reaction mixture was stirred for 15 minutes. UB-025b (2.726 g, 15.94 mmol) was added. The reaction mixture was stirred at reflux for 16 hours. The solvent was evaporated, and the residue was extracted with DCM (3 × 50 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography using DCM:(DCM:MeOH=10:1) = 0-10% to give UB-025c as a colorless oil (3.0 g, 78.7% yield). LCMS [M+1] + =252.1

[0396] Step 2: UB-025e

[0397] N-Benzyl-N-(2-bromoacetyl)-L-aspartic acid dimethyl ester

[0398] UB-025c (3.0 g, 12 mmol), anhydrous DCM (15 mL) solution, and Et3N (1.82 g, 18 mmol) were added to a reaction flask. The mixture was cooled to 0°C and a solution of UB-025d (1.89 g, 14.3 mmol) in 5 mL of anhydrous DCM was slowly added. The reaction was stirred at room temperature for 1 hour. The brown solution was washed twice with 1M HCl solution, twice with saturated NaHCO3 solution, and once with brine. The organic phase was dried over Na2SO4, then concentrated and purified by flash chromatography using PE / EA = 0-20% to obtain a light yellow oil (UB-025e, 3.1 g, 69.6% yield). LCMS [M+1] + =372.0;374.0

[0399] Step 3: UB-025f

[0400] S)-2-(1-benzyl-3,6-dioxopiperazin-2-yl)acetate

[0401] UB-025e (3.1 g, 8.36 mmol) and CH3OH (10 mL) were added to a reaction flask and stirred until uniform. Then, 6 mL of 7M NH3 / CH3OH solution was added and the mixture was stirred at room temperature for 7 hours. The solvent was then removed and the residue was purified by flash chromatography (DCM / MeOH = 0-30%) to obtain the compound (UB-025f, 1.6 g, 69.3% yield) as a white solid. LCMS [M+1] + =277.1

[0402] Step 4: UB-025g

[0403] (S)-2-(1-Benzylpiperazin-2-yl)ethan-1-ol

[0404] UB-025f (500 mg, 1.81 mmol) and 10 mL of anhydrous THF solution were added to the reaction flask under an ice bath, followed by the slow dropwise addition of a LiAlH4 / THF solution (10.9 mL, 1 mmol / mL). The resulting suspension was stirred at 0°C for 10 minutes and then refluxed for 90 minutes. The reaction mixture was quenched with Na2SO4 and H2O. The mixture was filtered through celite and concentrated to afford a yellow oil (UB-025g, 400 mg, 100% yield), which was used directly in the next reaction. LCMS [M+1] + =221.2

[0405] Step 5: UB-025h

[0406] (S)-tert-Butyl 4-benzyl-3-(2-hydroxyethyl)piperazine-1-carboxylate

[0407] NaHCO3 (1570 mg, 18.7 mmol) and water (10 mL) were added to a solution of UB-025g (380 mg, 1.7 mmol) in 1,4-dioxane (10 mL) at room temperature. (Boc)2O (524 mg, 2.4 mmol) was added and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (20 mL) and EA (20 mL) were added and the layers were separated. The aqueous layer was extracted again with EA (20 mL). The combined organics were washed with water (30 mL) and saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel, eluting with DCM / (DCM:MeOH=10:1)=10-30% to give a yellow oily compound (UB-025h, 500 mg, 91.9% yield). LCMS[M+1] + =321.3

[0408] Step 6: UB-025i

[0409] (S)-tert-Butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate

[0410] Pd / C (50 mg, 10% wt) was added to a container purged with nitrogen. EtOH (5 mL) was added, followed by a solution of UB-025h (500 mg) in EtOH (5 mL). The container was sealed, purged with nitrogen, purged with hydrogen, and reacted at room temperature under hydrogen pressure overnight. The reaction mixture was filtered and concentrated in vacuo to give a yellow oily compound (1246i, 200 mg, 58.2% yield). LCMS [M+1] + =231.2

[0411] Step 7: UB-025k

[0412] Tert-Butyl (S)-4-(6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylate

[0413] To a reaction flask under Ar was added UB-025i (156 mg, 0.413 mmol), UB-007f (190 mg, 0.825 mmol), Pd2(dba)3 (38 mg, 0.041 mmol), Cs2CO3 (404 mg, 1.24 mmol), XPhos (100 mg, 0.21 mmol) and anhydrous dioxane (10 mL) solution. The mixture was stirred at 100 ° C for 3 hours. The reaction was concentrated and purified by flash chromatography, eluting with DCM / (DCM:MeOH=10:1)=0-40% to give a yellow solid compound (UB-025k, 90 mg, 38% yield). LCMS [M+1] + =572.3

[0414] Step 8: UB-025047

[0415] (S)-2-(1-(6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)piperazin-2-yl)ethan-1-ol

[0416] UB-025k (90 mg, 0.16 mmol) and 6 mL of DCM solution were added to a reaction flask, stirred until uniform, and TFA (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with NaHCO₃ and extracted with DCM (10 mL*3). The organic phase was separated, washed with brine (10 mL*3), and dried over Na₂SO₄, then concentrated and purified by flash chromatography using DCM / (DCM:MeOH=10:1)=0-100% to obtain the compound (UB-025, 25 mg, 33.8% yield) as a white solid. LCMS [M+1] + =472.2. 1 H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.84(s,1H),7.64–7.60(m,2H),7.58(d,J=8.2Hz,2H),7.47 –7.41(m,4H),7.34(d,J=7.4Hz,1H),4.66(d,J=30.1Hz,3H),4.54(dd,J=13.5,6.8Hz,1H),4.50– 4.44(m,1H),3.37(t,J=6.7Hz,3H),2.91(t,J=10.9Hz,3H),2.75–2.64(m,1H),1.93–1.80(m,2H),1.46(dd,J=6.7,3.2Hz,6H).

[0417] Example 26: Synthesis of Compound UB-026

[0418] Step 1: UB-026h

[0419] Compounds UB-007f (80 mg, 0.11 mmol) and UB-026g (210 mg, 1.05 mmol) were dissolved in N-methylpyrrolidone (2 mL), and N,N-diisopropylamine (216 mg, 1.68 mmol) was added. The mixture was then reacted in a microwave oven at 180°C for 3 hours. The reaction mixture was cooled to room temperature and water (10 mL) was added to precipitate a solid. The precipitate was filtered and washed with water (20 mL). The solid was dissolved in dichloromethane and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the desired product (UB-026h, 84 mg, 74% yield) as a yellow liquid. LCMS [M+1] + =542.

[0420] Step 2: UB-026

[0421] Compound UB-026h (84 mg, 0.15 mmol) was dissolved in dichloromethane (4 mL) and hydrochloric acid / dioxane in dioxane (1 mL), then stirred at 40°C for 1 hour. The reaction mixture was concentrated and adjusted to pH 8-9 with saturated aqueous sodium bicarbonate. After extraction with dichloromethane (20 mL*3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residual aqueous solution was lyophilized to obtain the desired product (UB-026, 20.2 mg, 30% yield) as a white solid. LCMS [M+1] + =442. 1 H NMR(400MHz, CDCl3)δ7.99(s,1H),7.84(s,1H),7.65–7.54(m,4H),7.44(dt,J=7.8,3 .6Hz,4H),7.38–7.29(m,1H),4.57(td,J=13.5,13.0,6.2Hz,3H),4.44(dd,J=12.7,3 .0Hz,2H),2.86(d,J=11.1Hz,1H),2.68(td,J=12.0,2.7Hz,1H),2.57(td,J=11.4,4. 7Hz, 3H), 2.31 (dd, J=12.5, 10.3Hz, 1H), 1.46 (d, J=6.7Hz, 6H), 0.98 (d, J=6.2Hz, 3H).

[0422] Example 27: Synthesis of Compound UB-027

[0423] Step 1: UB-027c

[0424] (R)-tert-Butyl 4-(6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)-2-methylpiperazine-1-carboxylate

[0425] Compound UB-027b (2650 mg, 13.26 mmol) and compound UB-007f (1000 mg, 2.65 mmol) were dissolved in 7 mL of NMP and reacted at 180°C in a microwave oven for 3 hours. The reaction mixture was cooled to room temperature, and water was added until a solid precipitated. The solid was then filtered. The residue was dissolved and purified on a silica gel column (DCM / MeOH = 10%) to afford compound UB-027c (712 mg, 50% yield, and 470 mg of product (Boc)) as a yellow oil. LCMS [M+1]+ = 542.3.

[0426] Step 2: UB-027

[0427] (R)-N-([1,1'-biphenyl]-4-ylmethyl)-9-isopropyl-2-(3-methylpiperazin-1-yl)-9H-purin-6-amine

[0428] Compound UB-027c (712 mg, 1.32 mmol) was dissolved in dichloromethane (16 mL) and 1,4-dioxane hydrochloride (16 mmol, 4 mL) was added. The reaction was stirred at 40°C for 4 hours. After completion, a saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 8-9, and the mixture was extracted with DCM (40 mL x 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The extract was concentrated and lyophilized to yield the desired compound UB-027 (525.9 mg, 45% yield) as a white solid. LCMS [M+1] + =442.3 1 H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.84(s,1H),7.64–7.55(m,4H),7.47–7 .41(m,4H),7.33(t,J=7.3Hz,1H),4.56(dt,J=13.4,6.7Hz,3H),4.44(d,J=12 .3Hz,2H),2.85(d,J=11.3Hz,1H),2.67(t,J=12.0Hz,1H),2.61–2.53(m,2H) ,2.30(dd,J=12.3,10.4Hz,1H),1.46(d,J=6.7Hz,6H),0.97(d,J=6.2Hz,3H).

[0429] Example 28: Synthesis of Compound UB-028

[0430] Step 1: UB-028c

[0431] (R)-tert-Butyl 4-(6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate

[0432] Compound UB-028b (287 mg, 1.33 mmol) and compound UB-007f (100 mg, 0.27 mmol) were dissolved in 3 mL of NMP and reacted in a microwave oven at 180°C for 3 hours. The reaction mixture was cooled to room temperature, and water was added until a solid precipitated. The solid was then filtered. The residue was dissolved and purified on a silica gel column (DCM / MeOH = 30%) to yield compound UB-028c (42 mg, 59% yield) as a yellow oil. LCMS [M+1]+ = 558.3.

[0433] Step 2: UB-028

[0434] (R)-(4-(6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)piperazin-2-yl)methanol

[0435] Compound UB-028c (42 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL) and 1,4-dioxane hydrochloride (2 mmol, 0.5 mL) was added. The reaction was stirred at 40°C for 4 hours. After completion, a saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 8-9, and the mixture was extracted with DCM (40 mL x 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The extract was concentrated and lyophilized to obtain the desired compound UB-028 (17.5 mg, 54% yield) as a white solid. LCMS [M+1] + =458.2. 1 H NMR (400MHz, DMSO-d6) δ8.06(s,1H),7.87(s,1H),7.60(dd,J=16.3,7.7Hz,4H),7.48–7.41(m,4H),7.33(t,J=7.3Hz,1H),4.87(s,1H ),4.69–4.42(m,5H),3.42(d,J=3.4Hz,2H),3.01(d,J=11.4Hz,1H),2.85(t,J=11.2Hz,1H),2.79–2.54(m,3H),1.47(d,J=6.7Hz,6H).

[0436] Example 29: Synthesis of Compound UB-029

[0437] Step 1: UB-029b

[0438] (S)-Piperazin-2-ylmethanol

[0439] UB-029a (250 mg, 1.16 mmol) and 8 mL of DCM solution were added to the reaction flask, stirred until uniform, and TFA (2 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain a white solid compound (UB-029b, 400 mg, 100% yield), which was used directly in the next reaction. LCMS [M+1] + =117.1

[0440] Step 2: UB-029

[0441] (S)-(4-(6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)piperazin-2-yl)methanol

[0442] A solution of UB-029b (153 mg, 1.323 mmol), UB-007f (100 mg, 0.265 mmol), DIPEA (274 mg, 2.12 mmol), and NMP (4 mL) was added to a microwave tube. The mixture was stirred at 180°C for 3 hours under microwave conditions. The reaction mixture was poured into H2O. The resulting precipitate was collected by filtration, and the filtrate was extracted three times with EA. The combined organic phases were filtered and purified by silica gel column chromatography [eluent: DCM / (10% MeOH / DCM) = 0-100%] to obtain the compound (UB-029, 62 mg, 51% yield) as a white solid. LCMS [M+1] + =458.3. 1 H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.85(s,1H),7.64–7.60(m,2H),7.58(d,J=8.2Hz,2H) ,7.49–7.41(m,4H),7.33(t,J=7.3Hz,1H),4.68(t,J=5.1Hz,1H),4.61(d,J=6.3Hz,1H),4. 56(dd,J=13.4,6.8Hz,2H),4.45(d,J=12.6Hz,1H),3.38–3.34(m,2H),2.93(d,J=11.5Hz,1 H),2.76(t,J=12.0Hz,1H),2.60(t,J=9.8Hz,2H),2.48–2.39(m,1H),1.46(d,J=6.7Hz,6H).

[0443] Example 30: Synthesis of Compound UB-030

[0444] Step 1: UB-030b

[0445] (S)-2-(Piperazin-2-yl)ethan-1-ol

[0446] UB-030a (460 mg, 2 mmol) and 8 mL of DCM solution were added to the reaction flask, stirred until uniform, and TFA (2 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain a white solid compound (UB-030b, 300 mg, 100% yield). This was used directly in the next reaction. LCMS [M+1] + =131.2

[0447] Step 2: UB-030

[0448] (S)-2-(4-(6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)piperazin-2-yl)ethan-1-ol

[0449] A solution of UB-030b (138 mg, 1.058 mmol), UB-007f (80 mg, 0.0.212 mmol), DIPEA (220 mg, 1.7 mmol), and NMP (4 mL) was added to a microwave tube. The mixture was stirred at 180°C for 3 hours under microwave conditions. The reaction mixture was poured into H2O. The resulting precipitate was collected by filtration, and the filtrate was extracted three times with EA. The combined organic phases were filtered and purified by silica gel column chromatography [eluent: DCM / (10% MeOH / DCM) = 0-100%] to obtain the compound (UB-030, 59 mg, 59.0% yield) as a white solid. LCMS [M+1] + =472.3. 1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.84(s,1H),7.64–7.60(m,2H),7.58(d,J=8.2Hz,2H),7.44 (t,J=8.1Hz,4H),7.33(t,J=7.3Hz,1H),4.57(td,J=13.3,6.5Hz,3H),4.48(d,J=10.8Hz,1H),4. 42(d,J=12.8Hz,1H),3.53(td,J=6.4,2.2Hz,2H),2.90(d,J=11.8Hz,1H),2.76(d,J=11.5Hz,1H) ,2.62(dd,J=16.8,10.5Hz,2H),2.45(d,J=10.3Hz,1H),1.54–1.48(m,2H),1.46(d,J=6.8Hz,6H).

[0450] Example 31: Synthesis of Compound UB-031

[0451] Step 1: UB-031h

[0452] To a mixture of compound UB-031h (313 mg, 1.36 mmol) in CH2Cl2 (3 mL) was added HCl / dioxane (4N, 3.5 mL). The reaction mixture was stirred at 25°C for 17 hours. The reaction mixture was concentrated and adjusted to pH 8-9 with saturated aqueous Na2CO3. After extraction with CH2Cl2 (20 mL*3), the combined organic layers were washed with brine and dried over anhydrous Na2SO4. The mixture was then concentrated under reduced pressure to give the product UB-031h (177 mg, yield: 100%) as a white solid. LCMS [M+1] + =131.2 Step 2: UB-031

[0453] Compound UB-007f (70 mg, 0.19 mmol), compound UB-031h (177 mg, 0.47 mmol), DIPEA (192 mg, 1.48 mmol), and N-methylpyrrolidone (3 mL) were added to a microwave tube, and the mixture was heated at 180°C for 6 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (4 g, 40 mL / min; DCM: 10% MeOH in DCM = 0-33%) to obtain the crude product (48 mg, yield: 55%) as a brown-yellow liquid. The crude product was further purified by preparative liquid chromatography (Prep.HPLC, mobile phase: HCl / water / acetonitrile) to obtain the product UB-031 (31.5 mg, yield: 36%) as a yellow solid. LCMS [M+1] + =472.3. 1 H NMR (400MHz, DMSO-d6) δ8.19(s,1H),7.91(s,1H),7.64–7.56(m,5H),7.47–7.41(m,5H),7.33(dd,J=10.4,4.3Hz,2H),4.65–4.45(m,6H),3. 56(dd,J=11.3,5.8Hz,2H),3.18(d,J=12.1Hz,1H),3.09(d,J=11.0Hz,3H),2.87(s,3H),1.67(td,J=14.5,7.0Hz,3H),1.47(d,J=6.8Hz,8H).

[0454] Example 32: Synthesis of Compound UB-032

[0455] Step 1: UB-032

[0456] N-([1,1'-Biphenyl]-4-ylmethyl)-9-cyclobutyl-2-(piperazin-1-yl)-9H-purin-6-amine

[0457] UB-007f (60 mg, 0.16 mmol), UB-032b (148 mg, 0.80 mmol), DIPEA (164 mg, 1.27 mmol), and NMP (3 mL) were added to a 10 mL microwave tube. The resulting mixture was microwaved at 180°C for 3 hours. After the reaction, 30 mL of water was added. The precipitated solid was filtered, and the filter cake was separated by column chromatography (eluent: DCM / (10% MeOH in DCM) = 100 / 0 to 30 / 70) to obtain UB-032 (30 mg, 42% yield) as a white solid. LCMS [M+H] + =456.3. 1H NMR (400MHz, DMSO-d6) δ8.03(s,1H),7.84(s,1H),7.65–7.60(m,2H),7.57(d,J=8.2Hz,2H),7.48–7.40(m,4H),7.34(d,J=7.3Hz,1H),4.56(dt, J=13.4,6.7Hz,3H),3.76(dd,J=12.7,3.0Hz,2H),3.41(dd,J=12.8,6.2Hz,3H),3.15(s,2H),1.46(dd,J=6.7,4.7Hz,6H),1.01(d,J=6.3Hz,6H).

[0458] Example 33: Synthesis of Compound UB-033

[0459] Step 1: UB-033h

[0460] To a three-necked flask were added compound UB-007f (270 mg, 0.72 mmol), UB-033g (416 mg, 2.34 mmol), Cs2CO3 (624 mg, 2.15 mmol), Pd2(dba)3 (90 mg, 0.10 mmol), and XPhos (234 mg, 0.49 mmol) in sequence. The mixture was purged with argon three times, then anhydrous 1,4-dioxane (16 mL) was added and the mixture was stirred at 100°C for 19 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM: 10% MeOH in DCM = 0-78%) to obtain the product UB-033h (109 mg, yield: 27%). LCMS [M+1] + =558.3

[0461] Step 2: UB-033

[0462] To a mixture of compound UB-033h (109 mg, 0.20 mmol) in CH2Cl2 (3 mL) was added HCl / dioxane (4 N, 1.5 mL). The reaction mixture was stirred at 25°C for 17 hours. The reaction mixture was concentrated and adjusted to pH 8-9 with saturated aqueous Na2CO3. After extraction with CH2Cl2 (20 mL*3), the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM: 10% MeOH in DCM = 0-100%) to obtain the product UB-033 (59.3 mg, yield: 60%) as a light yellow solid. LCMS [M+1] + =458.3. 1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.82 (s,1H),7.65–7.60(m,2H),7.58(d,J=8.2Hz,2H),7.48–7.41(m,4H),7. 33(t,J=7.3Hz,1H),4.62(s,2H),4.55(m,3H),4.37(d,J=12.5Hz,1H),3. 80(t,J=9.4Hz,1H),3.42–3.35(m,2H),3.16(d,J=12.0Hz,1H),2.86(t,J=12.8Hz,2H),2.58(dd,J=12.1,3.8Hz,1H),1.46(dd,J=6.7,0.9Hz,6H).

[0463] Example 34: Synthesis of Compound UB-034

[0464] Step 1: UB-034c

[0465] tert-Butyl (R)-3-(((6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)oxy)methyl)piperazine-1-carboxylate

[0466] To a reaction flask under Ar was added UB-007f (300 mg, 0.8 mmol), UB-034b (520 mg, 2.4 mmol), and anhydrous dioxane solution (18 mL). Pd2(dba)3 (80 mg, 0.08 mmol), Cs2CO3 (800 mg, 2.4 mmol), and XPhos (200 mg, 0.4 mmol) were also added. The mixture was stirred at 100°C for 3 hours. The reaction was concentrated and purified by flash chromatography using DCM / (DCM:MeOH=10:1)=0-40% as the eluent to give UB-034c as a yellow oil (200 mg, 44.8% yield). LCMS [M+1] + =558.3

[0467] Step 2: UB-034

[0468] (R)-N-([1,1'-biphenyl]-4-ylmethyl)-9-isopropyl-2-(piperazin-2-ylmethoxy)-9H-purin-6-amine

[0469] UB-034c (200 mg, 0.359 mmol), 8 mL of DCM solution, and a dioxane solution of HCl (2 mL) were added to the reaction flask. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with NaHCO₃ (4 mL) and extracted with DCM (20 mL*3). The organic phase was separated, washed with brine (20 mL*3), and dried over Na₂SO₄, then concentrated and purified by flash chromatography using DCM / (DCM:MeOH=10:1)=0-100% as the eluent to obtain the compound (UB-034, 80.5 mg, 49% yield) as a light yellow solid. LCMS [M+1] + =458.3. 1 H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.05(s,1H),7.61(dd,J=11.1,7.8Hz,4H ),7.43(dd,J=11.9,5.2Hz,4H),7.35(d,J=7.3Hz,1H),4.80–4.50(m,3H),4.0 6(d,J=5.6Hz,2H),2.86(d,J=9.2Hz,2H),2.77(d,J=10.6Hz,1H),2.70(d,J=1 1.1Hz,1H),2.61–2.55(m,1H),2.32(d,J=10.7Hz,1H),1.49(d,J=6.7Hz,6H).

[0470] Example 35: Synthesis of Compound UB-035

[0471] Step 1: UB-035c

[0472] tert-Butyl 4-(9-isopropyl-6-((2-propoxy-[1,1'-biphenyl]-4-yl)methyl)amino)-9H-purin-2-yl)piperazine-1-carboxylate

[0473] UB-007f (80 mg, 0.147 mmol), UB-035b (54 mg, 0.439 mmol), cesium carbonate (142 mg, 0.436 mmol), and DMF (5 mL) were added to a 100 mL round-bottom flask. The resulting mixture was reacted at room temperature for 1 hour. After the reaction, 20 mL of water was added and the mixture was extracted three times with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate and dried to obtain a yellow solid compound UB-035c (70 mg, 81% yield). LCMS [M+H] + =586.2

[0474] Step 2: UB-035

[0475] 9-Isopropyl-2-(piperazin-1-yl)-N-(2-propoxy-[1,1'-biphenyl]-4-yl)methyl)-9H-purin-6-amine

[0476] UB-035c (70 mg, 0.11 mmol), dichloromethane (3 mL), and dioxane hydrochloride (2 mL, 8 mmol) were added to a 50 mL round-bottom flask. The resulting mixture was reacted at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution until the pH was neutral, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure. The residue was prepared to give compound UB-035 (14 mg, 25% yield) as a white solid. LCMS [M+1] + =428.3. 1 H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.80(s,1H),7.66–7.55(m,4H),7.51–7.40(m,4 H),7.33(t,J=7.3Hz,1H),4.65(s,1H),4.56(dt,J=13.4,6.7Hz,1H),3.66(t,J=5.4H z,1H),3.59(dd,J=11.5,5.7Hz,2H),3.53–3.44(m,2H),3.27–3.18(m,2H),2.06(td, J=13.1,6.8Hz,1H),1.90(s,2H),1.73(dd,J=12.4,6.4Hz,1H),1.47(d,J=6.8Hz,6H).

[0477] Example 36: Synthesis of Compound UB-036

[0478] Step 1: UB-036c

[0479] tert-Butyl (R)-(1-(6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)pyrrolidin-3-yl)carbamate

[0480] Compound UB-036b (198 mg, 1.06 mmol) and compound UB-007f (80 mg, 0.21 mmol) were dissolved in 2 mL of NMP and reacted in a microwave oven at 180°C for 3 hours. The reaction mixture was cooled to room temperature, and water was added until a solid precipitated. The solid was then filtered. The residue was dissolved and purified on a silica gel column (DCM / MeOH = 10%) to afford compound UB-036c (25 mg, 57% yield) as a yellow oil. LCMS [M+1]+ = 528.3.

[0481] Step 2: UB-036

[0482] (R)-N-([1,1'-biphenyl]-4-ylmethyl)-2-(3-aminopyrrolidin-1-yl)-9-isopropyl-9H-purin-6-amine

[0483] Compound UB-036c (25 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL) and 1,4-dioxane hydrochloride (2 mmol, 0.5 mL) was added. The reaction was stirred at 40°C for 4 hours. After completion of the reaction, a saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8-9, and the mixture was extracted with DCM (40 mL*3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The extract was concentrated and lyophilized to obtain the desired compound UB-036 (3.5 mg, 10% yield) as a white solid. LCMS [M+1] + =428.2. 1 H NMR(400MHz, DMSO-d6)δ7.88(s,1H),7.79(d,J=5.9Hz,1H),7.64–7.56(m,4H),7.45(dd,J=14.6,7.5Hz,4H),7.33(t,J=7.3Hz,1H),4.78–4.50(m,3H) ,3.53(dddd,J=17.9,15.8,14.0,10.9Hz,4H),3.13(dd,J=10.8,5.0Hz,1H) ,1.99(dt,J=12.3,6.7Hz,1H),1.63(td,J=13.1,6.6Hz,1H),1.47(d,J=6.8 Hz,6H).

[0484] Example 37: Synthesis of Compound UB-037

[0485] Step 1: UB-037c

[0486] (S)-tert-Butyl 3-((6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)amino)pyrrolidine-1-carboxylate

[0487] UB-007f (100 mg, 0.265 mmol), UB-037b (160 mg, 0.8 mmol), Pd2(dba)3 (146.6 mg, 0.16 mmol), Cs2CO3 (172.7 mg, 0.53 mmol), X-phos (380.8 mg, 0.8 mmol), and 1,4-dioxane (10 mL) were added to a reaction flask. The reaction mixture was purged with argon three times and then heated to 100°C and stirred overnight. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL*3). The organic phase was separated, washed with brine (50 mL), and dried over anhydrous sodium sulfate. It was then concentrated and purified by chromatography (dichloromethane:dichloromethane / methanol 10 / 1 = 75:25) to obtain the product as a yellow solid compound (UB-037c, 120 mg, 35.58% yield). LCMS [M+1] + =528.2

[0488] Step 2: UB-037

[0489] N 6 -([1,1'-biphenyl]-4-ylmethyl)-9-isopropyl-N2-(pyrrolidin-3-yl)-9H-purine-2,6-diamine

[0490] To a 100 mL bottom flask was added UB-037c (121.2 mg, 0.23 mmol), a solution of hydrochloric acid in 1,4-dioxane (4 mL) and dichloromethane (8.0 mL) at room temperature. The solution was then stirred at room temperature for 2 hours. The reaction mixture was filtered, the filter cake was washed with dichloromethane (5 mL), neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane (3*50 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then methanol and water were added and freeze-dried to give a yellow solid product (UB-037, 54.7 mg, yield: 56.3%). LCMS [M+1] + =428.2. 1H NMR (400MHz, DMSO-d6) δ7.79(s,1H),7.60(dd,J=15.0,7.9Hz,4H),7.44(t,J=7.6Hz,4H),7. 33(t,J=7.3Hz,1H),6.28(d,J=6.6Hz,1H),4.67(s,1H),4.53(dt,J=13.6,6.7Hz,1H),4.20(d ,J=6.2Hz,1H),2.90(dd,J=11.4,6.6Hz,1H),2.87–2.81(m,1H),2.73–2.64(m,1H),2.57(dd ,J=11.0,4.2Hz,1H),1.91(dd,J=12.8,6.3Hz,1H),1.63–1.50(m,1H),1.47(d,J=6.7Hz,6H).

[0491] Example 38: Synthesis of Compound UB-038

[0492] Step 1: UB-038c

[0493] (R)-tert-Butyl-3-(6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)amino)pyrrolidine-1-carboxylate

[0494] To a 100 mL round-bottom flask were added compound UB-038a (400 mg, 1.06 mmol), UB-038b (1.18 g, 6.36 mmol), Pd2(dba)3 (97 mg, 0.106 mmol), XPhos (252 mg, 0.53 mmol), Cs2CO3 (1.03 g, 3.18 mmol), and 1,4-dioxane (10 mL). The resulting mixture was replaced with argon three times and heated to 100°C for 24 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was separated by column chromatography (eluent: DCM:PE:EA = 100 / 0 to 80 / 20) to afford compound UB-038c (200 mg, 36% yield) as a pale yellow solid. LCMS [M+H] + =528.3.

[0495] Step 2: UB-038

[0496] (R)-N6-([1,1'-biphenyl]-4-ylmethyl)-9-isopropyl-N2-(pyrrolidin-3-yl)-9H-purine-2,6-diamine

[0497] UB-038c (80 mg, 0.15 mmol), dichloromethane (3 mL), and trifluoroacetic acid (128 mg, 1.13 mmol) were added to a 50 mL round-bottom flask. The resulting mixture was reacted at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution until the pH was neutral, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure. The residue was separated by column chromatography (eluent: DCM / (10% MeOH in DCM) = 100 / 0 to 90 / 10) to obtain UB-038 (42 mg, 87% yield) as a white solid. LCMS [M+1] + =428.3. 1 H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.07(s,1H),7.91(s,1H),7.69–7.55(m,2H), 7.48–7.39(m,2H),7.34(t,J=7.3Hz,1H),6.73(s,1H),4.67(s,1H),4.56(dt,J=13 .5,6.8Hz,1H),4.39(d,J=4.8Hz,1H),3.40–3.27(m,2H),3.28–3.16(m,1H),3.12( s,1H),2.12(dd,J=13.4,7.0Hz,1H),1.97(d,J=5.7Hz,1H),1.48(d,J=6.8Hz,6H).

[0498] Example 39: Synthesis of Compound UB-039

[0499] Step 1: UB-039c

[0500] tert-Butyl ((1R,3S)-3-((6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclopentyl)carbamate

[0501] To a reaction flask were added UB-007f (100 mg, 0.265 mmol), UB-039b (160 mg, 0.8 mmol), Pd2(dba)3 (146.6 mg, 0.16 mmol), Cs2CO3 (172.7 mg, 0.53 mmol), X-phos (380.8 mg, 0.8 mmol), and 1,4-dioxane (10 mL). The reaction mixture was purged with argon three times, then heated to 100°C and stirred overnight. After completion of the reaction, the mixture was dried and purified on a silica gel column with DCM / MeOH = 0-25% (10% MeOH) to afford UB-039c (40 mg, 28% yield) as a yellow solid. LCMS [M+1] +=542.3.

[0502] Step 2: UB-039

[0503] N6-([1,1'-biphenyl]-4-ylmethyl)-N2-((1S,3R)-3-aminocyclopentyl)-9-isopropyl-9H-purine-2,6-diamine

[0504] UB-039c (50 mg, 0.09 mmol) was dissolved in 3 mL of THF, and HCl / dioxane (1 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by silica gel chromatography to obtain UB-039 (3.3 mg, 8% yield) as a white solid. LCMS [M+1] + =442.3. 1 H NMR (400 MHz, DMSO-d6) 1 H NMR(400MHz,)δ7.88(s,1H),7.82(s,1H),7.61(dd,J=13.6,7.8Hz,4H),7.44(dd,J=11.9,5.3Hz, 4H),7.34(t,J=7.3Hz,1H),6.44(d,J=7.1Hz,1H),4.66(s,2H),4.53(dt,J=13.4,6.8Hz,1H),4.18(d,J=7.0Hz,1H),2.43–2.30(m,1H),2. 00(dd,J=14.8,7.0Hz,1H),1.89(s,2H),1.65(d,J=4.8Hz,2H),1.47(d,J=6.7Hz,6H),1.36–1.28(m,2H),1.25(s,2H),1.22–1.22(m,1H).

[0505] Example 40: Synthesis of Compound UB-040

[0506] Step 1: UB-040c

[0507] tert-Butyl ((1S,3S)-3-((6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclopentyl)carbamate

[0508] To a reaction flask were added UB-007f (50 mg, 0.13 mmol), UB-040b (96.1 mg, 0.48 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), Xphos (38.2 mg, 0.08 mmol), Cs2CO3 (156.4 mg, 0.48 mmol), and 1,4-dioxane (10 mL). The reaction mixture was purged with argon three times and then heated to 100°C and stirred overnight. The reaction mixture was then stirred at 100°C for 24 hours. The reaction mixture was diluted with water (30 mL), then extracted with ethyl acetate (30 mL*3), the organic phase was separated, washed with brine (50 mL) and dried over anhydrous sodium sulfate, then concentrated and purified by chromatography (dichloromethane: dichloromethane / methanol 10 / 1=75:25) to give the product as a yellow solid compound (UB-040c, 38 mg, yield: 21.9%). LCMS [M+1] + =542.3.

[0509] Step 2: UB-040

[0510] N 6 -([1,1'-biphenyl]-4-ylmethyl)-N2-((1S,3S)-3-aminocyclopentyl)-9-isopropyl-9H-purine-2,6-diamine

[0511] To a 100 mL bottom flask was added UB-040c (37.9 mg, 0.07 mmol), a solution of hydrochloric acid in 1,4-dioxane (2 mL), and dichloromethane (4.0 mL) at room temperature. The solution was then stirred at room temperature for 2 hours. The reaction mixture was filtered, the filter cake was washed with dichloromethane (5 mL), neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane (3*50 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Methanol and water were then added, and the mixture was freeze-dried to give a yellow solid product (UB-040, 13.9 mg, yield: 44.8%). LCMS [M+1] + =428.2. 1H NMR (400MHz, DMSO-d6) δ7.78 (s, 1H), 7.64–7.61 (m, 2H), 7.58 (d, J = 8.2Hz, 2H), 7.47–7.40 ( m,5H),7.33(t,J=7.3Hz,1H),6.19(d,J=7.0Hz,1H),4.67(s,2H),4.53(dt,J=13.3,6.6Hz, 1H),4.31(dd,J=14.1,7.1Hz,1H),2.07–2.00(m,1H),1.90–1.82(m,1H),1.68(dd,J=13.1, 6.6Hz,1H),1.64–1.56(m,1H),1.47(d,J=6.7Hz,6H),1.43–1.34(m,2H),1.25–1.14(m,2H).

[0512] Example 41: Synthesis of Compound UB-041

[0513] Step 1: UB-041c

[0514] tert-Butyl 2-((1s,3s)-3-((6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)amino)

[0515] Compound UB-041b (158 mg, 0.85 mmol), compound UB-007f (80 mg, 0.21 mmol), cesium carbonate (207 mg, 0.64 mmol), Pd2(dba)3 (25 mg, 0.02 mmol), and Xphos (51 mg, 0.11 mmol) were dissolved in 5 mL of ultra-dry dioxane and reacted at 100°C overnight. After completion, the reaction mixture was cooled to room temperature, concentrated, and purified on a silica gel column (EA / PE = 50%) to obtain compound UB-041c (30 mg, 5% yield) as a yellow solid. LCMS [M+1]+ = 528.3.

[0516] Step 2: UB-041

[0517] (1s,3s)-3-((6-(([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclobutane-1-ammonium chloride.

[0518] Compound UB-041c (30 mg, 0.06 mmol) was dissolved in dichloromethane (2 mL) and 1,4-dioxane hydrochloride (2 mmol, 0.5 mL) was added. The reaction was stirred at 40°C for 4 hours. After completion of the reaction, a saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8-9, and the mixture was extracted with DCM (40 mL*3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The extract was concentrated and lyophilized to obtain the desired compound UB-041 (14.9 mg, 55% yield) as a white solid. LCMS [M+1] + =428.3. 1 H NMR (400MHz, DMSO-d6) δ9.60(d,J=117.0Hz,1H),8.73(s,1H),8.31(s,3H),7.64(d,J=7.7Hz,4H),7.55–7.44(m,4H),7.36(t,J=7.3Hz ,1H),5.30(d,J=16.8Hz,1H),4.86–4.62(m,3H),4.13(s,1H),2.67(s,2H),2.13(d,J=7.7Hz,2H),1.53(d,J=6.3Hz,6H),1.23(s,1H).

[0519] Example 42: Synthesis of Compound UB-042

[0520] Step 1: UB-042c

[0521] 2-Hydroxy-[1,1'-biphenyl]-4-carbonitrile

[0522] To a 100 mL round-bottom flask were added compound UB-042a (1.55 g, 7.57 mmol), UB-042b (1.85 g, 15.14 mmol), Pd(dppf)Cl2 (550 mg, 0.757 mmol), K2CO3 (3.13 g, 22.71 mmol), 1,4-dioxane (45 mL), and water (10 mL). The resulting mixture was replaced with argon three times and heated to 100°C for overnight reaction. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was separated by column chromatography (eluent: DCM:PE:EA = 100 / 0 to 30 / 70) to afford compound UB-042c (1.1 g, 78% yield) as a pale yellow solid. LCMS [M+H] + =196.1.

[0523] Step 2: UB-042d

[0524] 4-(Aminomethyl)-[1,1'-biphenyl]-2-ol

[0525] A 100 mL round-bottom flask was charged with UB-042c (1.1 g, 5.64 mmol), Raney nickel (110 mg), and amine methanol (10 mL). The resulting mixture was replaced with hydrogen three times and reacted at room temperature for 1 hour. After completion of the reaction, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (eluent: DCM / (10% MeOH in DCM) = 100 / 0 to 50 / 50) to obtain UB-042d (840 mg, 63% yield) as a white solid. LCMS [M+H] + =200.1.

[0526] Step 3: UB-042f

[0527] 4-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)-[1,1'-biphenyl]-2-ol

[0528] UB-042d (840 mg, 4.22 mmol), UB-042e (1.02 g, 4.43 mmol), triethylamine (1.28 g, 12.66 mmol), and isopropanol (15 mL) were added to a 100 mL round-bottom flask. The resulting mixture was reacted at 110°C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. The precipitated solid was filtered and the filter cake was washed with ethanol and water in a ratio of 10:1 to obtain a white solid compound UB-042f (1.3 g, 78% yield). LCMS [M+H] + =394.1.

[0529] Step 4: UB-042h

[0530] tert-Butyl 4-(6-((2-hydroxy-[1,1'-biphenyl]-4-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)piperazine-1-carboxylate

[0531] UB-042f (1.0 g, 2.54 mmol), UB-042g (2.36 g, 12.72 mmol), DIPEA (2.62 g, 20.35 mmol), and NMP (8 mL) were added to a 20 mL microwave tube. The resulting mixture was microwaved at 180°C for 3 hours. After the reaction, 30 mL of water was added. The precipitated solid was filtered, and the filter cake was separated by column chromatography (eluent: DCM / (10% MeOH in DCM) = 100 / 0 to 30 / 70) to obtain UB-042h as a white solid (900 mg, 65% yield). LCMS [M+H] + =544.3

[0532] Step 5: UB-042

[0533] 4-(9-Isopropyl-2-(piperazin-1-yl)-9H-purin-6-yl)amino)methyl)-[1,1'-biphenyl]-2-ol

[0534] UB-042h (60 mg, 0.11 mmol), dichloromethane (3 mL), and dioxane hydrochloride (2 mL, 8 mmol) were added to a 50 mL round-bottom flask. The resulting mixture was reacted at room temperature for 4 hours. The reaction was quenched with saturated sodium bicarbonate solution until the pH was neutral, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure. The residue was prepared to give the white solid compound UB-042 (14 mg, 29% yield). LCMS [M+1] + =444.1. 1 H NMR (400MHz, DMSO-d6) δ9.42(s,1H),8.85(s,2H),8.16(d,J=14.5Hz,1H),7.93(s,1H),7.56–7.44(m,2H),7.36(t,J=7.6Hz,2H),7.26(t,J=7.3 Hz,1H),7.16(d,J=7.8Hz,1H),6.94(s,1H),6.87(d,J=7.9Hz,1H),4.73 –4.32(m,3H),3.87(d,J=4.8Hz,4H),3.08(s,4H),1.48(d,J=6.8Hz,6H).

[0535] Example 43: Synthesis of Compound UB-043

[0536] Step 1: UB-043c

[0537] tert-Butyl 4-(6-(((2-(2-hydroxyethoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)piperazine-1-carboxylate

[0538] Compound UB-043a (100 mg, 0.18 mmol), compound UB-043b (112.6 mg, 0.90 mmol), K2CO3 (124.2 mg, 0.90 mmol), and 5 mL of N-methylpyrrolidone were added to a microwave tube. The reaction mixture was heated to 150°C in a microwave tube for 4 hours. The reaction mixture was poured into water and filtered to obtain a filter cake. The filtrate was extracted twice with ethyl acetate. The organic phase and filter cake were combined, the solvent was removed, and the concentrate was purified by flash chromatography (methanol:dichloromethane (1:10) / dichloromethane = 0-70%) to obtain compound UB-043c (73.0 mg, 66.7% yield) as a white solid. LCMS [M+1] + =588.3.

[0539] Step 2: UB-043

[0540] 2-((4-(((9-Isopropyl-2-(piperazin-1-yl)-9H-purin-6-yl)amino)methyl)-[1,1'-biphenyl]-2-yl)oxy)ethanol

[0541] Compound UB-043c (73.0 mg, 0.12 mmol) was dissolved in 4 mL of dichloromethane, and a dioxane hydrochloride solution (1 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized with sodium bicarbonate solution and extracted with dichloromethane. The organic phase was collected, dried, and the solvent removed. The concentrate was purified by flash chromatography (methanol:dichloromethane (1:10) / dichloromethane = 0-100%) to afford compound UB-043 (29.7 mg, 49.0% yield) as a white solid. LCMS [M+1] + =488.3. 1 H NMR(400MHz,DMSO-d6)δ7.97(s,1H),7.85(s,1H),7.56–7.48(m,2H),7.36 (t,J=7.5Hz,2H),7.31–7.24(m,1H),7.24–7.15(m,2H),7.02(d,J=7.7Hz,1 H),4.76(s,1H),4.57(dt,J=13.5,6.7Hz,3H),3.98(t,J=5.2Hz,2H),3.62( dd,J=12.8,8.1Hz,6H), 2.71(dd,J=8.3,3.4Hz,4H), 1.46(d,J=6.8Hz,6H).

[0542] Example 44: Synthesis of Compound UB-044

[0543] Step 1: UB-044c

[0544] (S)-tert-Butyl (1-(6-([1,1'-biphenyl]-4-ylmethyl)amino)-9-isopropyl-9H-purin-2-yl)pyrrolidin-3-yl)carbamate

[0545] UB-044a (80 mg, 0.212 mmol), UB-044b (197 mg, 1.06 mmol), DIPEA (218 mg, 1.69 mmol), and NMP (3 mL) were added to a 10 mL microwave tube. The resulting mixture was microwaved at 180°C for 3 hours. After the reaction, 30 mL of water was added. The precipitated solid was filtered, and the filter cake was separated by column chromatography (eluent: DCM / (10% MeOH in DCM) = 100 / 0 to 30 / 70) to obtain UB-044c (60 mg, 54% yield) as a white solid. LCMS [M+H] + =528.3

[0546] Step 2: UB-044

[0547] (S)-N-([1,1'-biphenyl]-4-ylmethyl)-2-(3-aminopyrrolidin-1-yl)-9-isopropyl-9H-purin-6-amine

[0548] UB-044c (60 mg, 0.11 mmol), dichloromethane (3 mL), and dioxane hydrochloride (2 mL, 8 mmol) were added to a 50 mL round-bottom flask. The resulting mixture was reacted at room temperature for 4 hours. The reaction was quenched with saturated sodium bicarbonate solution until the pH was neutral, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure. The residue was separated by column chromatography (eluent: DCM / (10% MeOH in DCM) = 100 / 0 to 90 / 10) to obtain UB-044 (14 mg, 29% yield) as a white solid. LCMS [M+1] + =486.2. 1 H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.04(s,1H),7.87(s,1H),7.46(d,J=7.2Hz,2H), 7.37(t,J=7.6Hz,2H),7.28(t,J=7.3Hz,1H),7.20(d,J=7.7Hz,1H),7.15(s,1H),7.01 (d,J=7.0Hz,1H),4.57(dd,J=13.5,6.8Hz,3H),3.89(t,J=6.4Hz,2H),3.70(s,5H),2. 83(s,4H),1.64(dd,J=13.9,6.7Hz,2H),1.47(d,J=6.8Hz,6H),0.89(t,J=7.4Hz,3H).

[0549] Example 45: Synthesis of Compound UB-045

[0550] Step 1: UB-045c

[0551] tert-Butyl 4-(6-(((2-(4-((tert-butyldimethylsilyl)oxy)butoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)piperazine-1-carboxylate

[0552] To a 100 mL reaction flask, compound UB-045a (80 mg, 0.147 mmol), cesium carbonate (96 mg, 0.294 mmol), and 5 mL of N,N-dimethylformamide were added. The reaction mixture was stirred until it turned slightly yellow, followed by the addition of compound UB-045b (80 mg, 0.294 mmol). The reaction mixture was heated to 80°C for 18 hours. After cooling to room temperature and removing the solvent, the concentrate was purified by flash chromatography (ethyl acetate / petroleum ether = 0-50%) to afford compound 1225c (110.0 mg, 97% yield) as a white solid. LCMS [M+1] + =616.4.

[0553] Step 2: UB-045

[0554] 4-((4-(((9-Isopropyl-2-(piperazin-1-yl)-9H-purin-6-yl)amino)methyl)-[1,1'-biphenyl]-2-yl)oxy)butan-1-ol

[0555] Compound UB-045c (110.0 mg, 0.179 mmol) was dissolved in 4 mL of dichloromethane, and a dioxane hydrochloride solution (1 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized with sodium bicarbonate solution and extracted with dichloromethane. The organic phase was collected, dried, and the solvent removed. The concentrate was purified by flash chromatography (methanol:dichloromethane (1:10) / dichloromethane = 0-100%) to afford compound UB-045 (41.7 mg, 48.1% yield) as a white solid. LCMS [M+1] + =516.3. 1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.91(s,1H),7.48–7.42(m,2H),7.36(dd,J=15 .2,7.4Hz,2H),7.28(t,J=7.3Hz,1H),7.19(dd,J=14.0,7.2Hz,2H),7.01(d,J=7.0Hz ,1H),4.58(dd,J=13.5,6.7Hz,3H),3.94(t,J=6.5Hz,2H),3.82(d,J=3.8Hz,4H),3.3 9(d,J=6.4Hz,2H),3.00(s,4H),1.66(dd,J=14.6,6.7Hz,2H),1.48(t,J=6.8Hz,8H).

[0556] Example 46: Synthesis of Compound UB-046

[0557] Step 1: UB-046c

[0558] 2'-Hydroxy-[1,1'-biphenyl]-4-carbonitrile

[0559] To a solution of UB-046a (3.0 g, 16.5 mmol) and UB-046b (3.4 g, 24.7 mmol) in 1,4-dioxane (60 mL) and H2O (20 mL) were added (dppf)PdCl2 (600 mg, 0.82 mmol) and K2CO3 (6.8 g, 49.4 mmol) under N2. The mixture was stirred at reflux for 4 hours, and the mixture gradually became turbid. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography [eluent: PE / EA = 0-40%] to obtain the compound (UB-046c, 3.26 g, 100% yield) as a yellow solid. LCMS [M+1] + =177.1

[0560] Step 2: UB-046d

[0561] 4'-(Aminomethyl)-[1,1'-biphenyl]-2-ol

[0562] UB-046c (2.8 g, 14.36 mmol), Raney Ni (280 mg), and a methanol solution of NH3 (15 mL) were added under H2. The mixture was stirred at room temperature overnight. The mixture was filtered through celite, the filtrate was concentrated, and purified by silica gel column chromatography [eluent: DCM / 10% MeOH / DCM = 0-50%] to give the compound (UB-046d, 1.4 g, 49% yield) as a white solid. LCMS [M+1] +=200.1

[0563] Step 3: UB-046f

[0564] 4'-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)-[1,1'-biphenyl]-2-ol

[0565] UB-046d (1090 mg, 5.48 mmol), UB-046e (1290 mg, 5.58 mmol), Et3N (1660 mg, 16.44 mmol) and isopropanol (20 mL) were added to the reaction flask. The mixture was stirred at 80°C for 4 hours. The mixture was concentrated and purified by silica gel column chromatography [eluent: DCM / 10% MeOH / DCM = 0-50%] to give compound 1218f (1.8 g, 83.4% yield) as a yellow solid. LCMS [M+1] + =394.2

[0566] Step 4: UB-046h

[0567] tert-Butyl 4-(6-(((2'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)piperazine-1-carboxylate

[0568] UB-046f (1500 mg, 3.807 mmol), UB-046g (3.54 g, 19.03 mmol), DIPEA (3.93 g, 30.4 mmol), and NMP (6 mL) were added to a microwave tube. The mixture was stirred at 180°C for 3 hours under microwave conditions. The reaction mixture was poured into H2O. The resulting precipitate was collected by filtration, and the filtrate was extracted three times with EA. The organic phases were combined, concentrated, and purified by silica gel column chromatography [eluent: DCM / 10% MeOH / DCM = 0-20%] to give the compound (UB-046h, 1.11 g, 53.2% yield) as a white solid. LCMS [M+1] + =544.3

[0569] Step 5: UB-046

[0570] 4'-(((9-Isopropyl-2-(piperazin-1-yl)-9H-purin-6-yl)amino)methyl)-[1,1'-biphenyl]-2-ol

[0571] To a solution of UB-046h (50 mg, 0.09 mmol) in 3 mL of DCM was added a solution of HCl in dioxane (1 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with NaHCO 3 and extracted with DCM (10 mL*3). The organic phase was separated, washed with brine (10 mL*3) and dried over Na 2 SO 4 , then concentrated and purified by flash chromatography [eluent: DCM / 10% MeOH / DCM=0-100%] to give the compound (UB-046, 13.5 mg, 33.9% yield) as a white solid. LCMS [M+1] + =444.3. 1 H NMR (400MHz, DMSO-d6) δ9.44(s,1H),7.96(s,1H),7.84(s,1H),7.44(d,J=8.2Hz,2H),7.37(d,J=8.1Hz,2H),7.20(dd,J=7.6,1.6Hz,1H),7.15–7 .09(m,1H),6.91(d,J=8.0Hz,1H),6.84(t,J=7.4Hz,1H),4.69–4.47(m, 3H), 3.61 (d, J = 5.0Hz, 4H), 2.71 (d, J = 4.5Hz, 4H), 1.46 (d, J = 6.7Hz, 6H).

[0572] Example 47: Synthesis of Compound UB-047

[0573] Step 1: UB-047c

[0574] tert-Butyl 4-(6-(((2'-(2-hydroxyethoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)piperazine-1-carboxylate

[0575] A solution of UB-047a (80 mg, 0.147 mmol), UB-047b (92 mg, 0.737 mmol), and K2CO3 (102 mg, 0.737 mmol) in NMP (3 mL) was added to a microwave tube. The mixture was stirred at 150°C for 4 hours under microwave conditions. The reaction mixture was poured into H2O. The resulting precipitate was collected by filtration, and the filtrate was extracted three times with EA. The organic phases were combined, concentrated, and purified by silica gel column chromatography [eluent: DCM: 10% MeOH / DCM = 0-70%] to obtain the compound (UB-047c, 60 mg, 69.5% yield) as a white solid. LCMS [M+1] + =588.3

[0576] Step 2: UB-047

[0577] 2-((4'-(((9-Isopropyl-2-(piperazin-1-yl)-9H-purin-6-yl)amino)methyl)-[1,1'-biphenyl]-2-yl)oxy)ethan-1-ol

[0578] UB-047c (60 mg, 0.102 mmol) and 3 mL of DCM solution were added to a reaction flask, followed by a solution of HCl in dioxane (2 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with NaHCO₃ and extracted with DCM (10 mL*3). The organic phase was separated, washed with brine (10 mL*3), and dried over Na₂SO₄, then concentrated and purified by flash chromatography using DCM: 10% MeOH / DCM = 0-100% to afford the compound (UB-047, 39 mg, 78.5% yield) as a light yellow solid. LCMS [M+1] + =488.1. 1 H NMR (400MHz, DMSO-d6) δ8.04(d,J=19.2Hz,1H),7.86(s,1H),7.48(d,J=8.2Hz,2H),7.37(d,J=8.2Hz,2H),7.29(dd,J=13.3,4.8Hz,2H),7.09(d,J= 8.0Hz,1H),6.99(t,J=7.0Hz,1H),4.58(td,J=13.8,7.1Hz,3H),4.01(t,J =5.1Hz,2H),3.68–3.62(m,6H),2.81–2.72(m,4H),1.47(d,J=6.8Hz,6H).

[0579] Example 48: Synthesis of Compound UB-048

[0580] Step 1: UB-048h

[0581] A mixture of compound UB-048f (80 mg, 0.15 mmol) and Cs2CO3 (384 mg, 1.18 mmol) in DMF (3 mL) was stirred at room temperature for 5 minutes, then compound UB-048g (264 mg, 1.18 mmol) was added to the mixture and stirred at 60°C for 2.5 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography [dichloromethane (dichloromethane:methanol = 10:1) = 0-21%] to obtain the product UB-048h (64 mg, yield: 63%) as a white solid. LCMS [M+1] + =687.2.

[0582] Step 2: UB-048

[0583] To a mixture of compound UB-048h (64 mg, 0.09 mmol) in CH2Cl2 (3 mL) was added HCl / dioxane (4N, 1.5 mL). The reaction mixture was stirred at 25°C for 17 hours. The reaction mixture was concentrated and adjusted to pH 8-9 with saturated aqueous Na2CO3. After extraction with CH2Cl2 (20 mL*3), the combined organic layers were washed with brine and dried over anhydrous Na2SO4. The mixture was then concentrated under reduced pressure to give the product UB-048 (29.3 mg, yield: 65%) as a white solid. LCMS [M+1] + =487.3. 1 H NMR (400MHz, DMSO-d6) δ7.97 (s, 1H), 7.86–7.81 (s, 1H), 7.44 (d, J = 8.2Hz, 2H), 7.3 8(d,J=8.2Hz,2H),7.27(dt,J=7.7,4.5Hz,2H),7.08(d,J=7.9Hz,1H),7.00(t,J=7 .1Hz,1H),4.57(td,J=13.6,6.8Hz,3H),3.93(t,J=5.6Hz,2H),3.70(d,J=24.2Hz, 1H),3.65–3.55(m,4H),2.81(t,J=5.6Hz,2H),2.70(s,4H),1.46(d,J=6.8Hz,6H).

[0584] Example 49: Synthesis of Compound UB-049

[0585] Step 1: UB-049h

[0586] A mixture of compound UB-049f (100 mg, 0.18 mmol) and Cs2CO3 (180 mg, 0.55 mmol) in DMF (3 mL) was stirred at room temperature for 5 minutes, and then compound UB-049g (86 mg, 0.70 mmol) was added to the mixture and stirred at room temperature for 1 hour. H2O (20 mL) was added to the reaction mixture, and the aqueous layer was extracted with dichloromethane (30 mL×4). The organic layers were combined and dried over anhydrous Na2SO4, and the mixture was concentrated under reduced pressure to obtain the crude product UB-049h (89 mg, yield: 83%) as a light yellow liquid, which was used directly in the next reaction without purification. LCMS [M+1] + =586.4

[0587] Step 2: UB-049

[0588] To a mixture of compound UB-049h (89 mg, 0.15 mmol) in CH2Cl2 (3 mL) was added HCl / dioxane (4N, 1.5 mL). The reaction mixture was stirred at 25°C for 17 hours. The reaction mixture was concentrated and adjusted to pH 8-9 with saturated aqueous Na2CO3. After extraction with CH2Cl2 (20 mL*3), the combined organic layers were washed with brine and dried over anhydrous Na2SO4. The mixture was then concentrated under reduced pressure to give the product UB-049 (54 mg, yield: 70%) as a white solid. LCMS [M+1] + =486.3. 1 H NMR (400MHz, DMSO-d6) δ7.97 (s, 1H), 7.84 (s, 2H), 7.42 (d, J = 8.2Hz, 3H), 7.3 7(d,J=8.2Hz,3H),7.32–7.23(m,3H),7.06(d,J=8.1Hz,1H),6.98(t,J=7.3Hz ,2H),4.68–4.50(m,4H),3.92(t,J=6.3Hz,3H),3.65–3.54(m,6H),2.70(s,6H ), 1.65 (dd, J = 13.8, 6.6 Hz, 3H), 1.46 ( d, J = 6.8 Hz, 9H), 0.91 ( t, J = 7.4 Hz, 5H).

[0589] Example 50: Synthesis of Compound UB-050

[0590] Step 1: UB-050b

[0591] (4-Bromobutoxy)(tert-butyl)dimethylsilane

[0592] To a reaction flask, UB-050a (500 mg, 3.268 mmol) and DCM (10 mL) were added under an ice bath. Imidazole (666 mg, 9.8 mmol) was added and stirred for 10 minutes. TBSCl (738 mg, 4.9 mmol) was slowly added and stirred for 3 hours. The DCM was concentrated, diluted with 30 mL of EA, and washed with 10% NaHCO solution and brine (30 x 2 mL). The organic solvent was dried over NaSO and evaporated in vacuo to afford UB-050b as a colorless oil (620 mg, 71% yield), which was used directly in the next step.

[0593] Step 2: UB-050e

[0594] tert-Butyl 4-(6-(((2'-(4-((tert-butyldimethylsilyl)oxy)butoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)piperazine-1-carboxylate

[0595] UB-050c (80 mg, 0.147 mmol), Cs2CO3 (96 mg, 0.294 mmol), and DMF solution (5 mL) were added to the reaction flask. The mixture was replaced with nitrogen under vacuum three times. The reaction mixture turned yellow after stirring at room temperature. UB-050d (80 mg, 0.294 mmol) was then added and the reaction mixture was heated at 80°C for 18 hours. The reaction mixture was then cooled to room temperature and filtered. The solvent was concentrated, and the resulting residue was purified by silica gel column chromatography [eluent: PE / EA = 0-50%] to give a light yellow solid compound (UB-050e, 110 mg, 97% yield). LCMS [M+1] + =616.4

[0596] Step 3: UB-050

[0597] 4-((4'-(((9-Isopropyl-2-(piperazin-1-yl)-9H-purin-6-yl)amino)methyl)-[1,1'-biphenyl]-2-yl)oxy)butan-1-ol

[0598] UB-050e (100 mg, 0.162 mmol) and 8 mL of DCM solution were added to the reaction flask, and a dioxane solution of HCl (3 mL) was added. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with NaHCO3 (5 mL) and extracted with DCM (10 mL*3). The organic phase was separated, washed with brine (10 mL*3), and dried over Na2SO4, then concentrated and purified by flash chromatography using DCM: 10% MeOH / DCM = 0-100% to obtain a white solid compound (UB-050, 14 mg, 16.7% yield). LCMS [M+1] + =516.3. 1H NMR (400MHz, DMSO-d6) δ7.97 (s, 1H), 7.84 (s, 1H), 7.42 (d, J = 8.3Hz, 2H), 7. 37(d,J=8.3Hz,2H),7.31–7.22(m,2H),7.07(d,J=7.8Hz,1H),7.02–6.95(m ,1H),4.73–4.50(m,3H),3.97(t,J=6.6Hz,2H),3.65–3.57(m,4H),3.40(t, J=6.4Hz,2H),2.77–2.66(m,4H),1.68(s,2H),1.48(dd,J=14.1,7.5Hz,8H).

[0599] Example 51: Synthesis of Compound UB-051

[0600] Step 1: UB-051c

[0601] tert-Butyl 4-(6-(((2'-(3-cyanopropoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)piperazine-1-carboxylate

[0602] Under N2, UB-051a (100 mg, 0.185 mmol), Cs2CO3 (120 mg, 0.925 mmol) and DMF solution (5 mL) were added to the reaction flask. Stirring at room temperature, the reaction solution turned yellow. UB-051b (55 mg, 0.925 mmol) was then added and the reaction solution was heated at 80°C for 3 hours. The reaction solution was then cooled to room temperature and filtered. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography [eluent: PE / EA = 0-80%] to obtain a colorless oil compound (UB-051c, 100 mg, 88.6% yield). LCMS [M+1] + =611.3

[0603] Step 2: UB-051

[0604] 4-((4'-(((9-Isopropyl-2-(piperazin-1-yl)-9H-purin-6-yl)amino)methyl)-[1,1'-biphenyl]-2-yl)oxy)butanenitrile

[0605] UB-051c (100 mg, 0.16 mmol), 6 mL of DCM solution, and trifluoroacetic acid (2 mL) were added to the reaction flask. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with NaHCO3 (4 mL) and extracted with DCM (20 mL*3). The organic phase was separated, washed with brine (20 mL*3), and dried over Na2SO4, then concentrated and purified by flash chromatography using DCM / (DCM:MeOH=10:1)=0-100% as the eluent to obtain the compound (UB-051, 11.4 mg, 14% yield) as a white solid. LCMS [M+1] + =511.2. 1 H NMR (400MHz, DMSO-d6) δ7.99(s,1H),7.85(s,1H),7.44–7.37(m,4H),7.34–7.24(m,2H),7.10(d,J=8.2Hz,1H),7.02(t,J=7.5Hz,1H),4 .78–4.43(m,3H),4.03(t,J=6.0Hz,2H),3.62(s,4H),2.73(s,4H),2.53(d,J=5.2Hz,2H),1.95(p,J=6.6Hz,2H),1.47(d,J=6.8Hz,6H).

[0606] Example 52: Synthesis of Compound UB-052

[0607] Step 1: UB-052c

[0608] N-([1,1'-Biphenyl]-4-ylmethyl)-2-chloro-9-cyclobutyl-9H-purin-6-amine

[0609] To a 100 mL round-bottom flask were added compound UB-052a (100 mg, 0.298 mmol), UB-052b (60 mg, 0.446 mmol), (dppf)PdCl2 (22 mg, 0.029 mmol), Cs2CO3 (386 mg, 1.19 mmol), and DMF (5 mL). The resulting mixture was replaced with argon three times and heated to 100°C for 5 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was separated by column chromatography (eluent: DCM:PE:EA = 100 / 0 to 80 / 20) to afford compound UB-052c (80 mg, 46% yield) as a pale yellow solid. LCMS [M+1] + =390.1.

[0610] Step 2: UB-052

[0611] N-([1,1'-Biphenyl]-4-ylmethyl)-9-cyclobutyl-2-(piperazin-1-yl)-9H-purin-6-amine

[0612] UB-052c (60 mg, 0.15 mmol), UB-052d (66 mg, 0.77 mmol), DIPEA (158 mg, 1.23 mmol), and NMP (3 mL) were added to a 10 mL microwave tube. The resulting mixture was microwaved at 180°C for 3 hours. After the reaction, 30 mL of water was added. The precipitated solid was filtered, and the filter cake was separated by column chromatography (eluent: DCM / (10% MeOH in DCM) = 100 / 0 to 30 / 70) to obtain UB-052 (30 mg, 45% yield) as a white solid. LCMS [M+H] + =440.2. 1 H NMR(400MHz, DMSO-d6)δ8.01(s,1H),7.94(s,1H),7.66–7.60(m,2H),7.58(d,J=8.2Hz,2H),7.49–7.39(m,4H),7.33(t,J=7.3Hz,1H),4.92–4.75 (m,1H),4.63(s,2H),3.72–3.49(m,5H),2.71(dd,J=14.2,9.6Hz,4H),2 .59(ddd,J=19.3,9.7,2.5Hz,2H),2.42–2.27(m,2H),1.92–1.73(m,2H).

[0613] Example 53: Synthesis of Compound UB-053

[0614] Step 1: UB-053c

[0615] 2,6-Dichloro-9-phenyl-9H-purine tert-butyl

[0616] To a solution of UB-053a (519.40 mg, 2.65 mmol) in dichloromethane (20 mL) were added UB-053b (645.01 mg, 5.29 mmol), Cu(OAc)2 (960.82 mg, 5.29 mmol), and TEA (804.46 mg, 7.95 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by chromatography (dichloromethane) to give a white solid (UB-053c, 63.1 mg, yield: 7.5%). LCMS [M+1] + =265.0;267.0.

[0617] Step 2: UB-053e

[0618] N-([1,1'-Biphenyl]-4-ylmethyl)-2-chloro-9-phenyl-9-hydrogen-purin-6-amine

[0619] To a solution of UB-053c (43.55 mg, 0.24 mmol) in tert-butanol (4 mL) was added UB-053d (63.07 mg, 0.24 mmol) and TEA (96.33 mg, 0.95 mmol), and the mixture was stirred at 110°C overnight. After the reaction, the mixture was filtered and the filter cake was washed with ethanol:water (10:1) (20 mL) and drained to afford a white solid (UB-053e, 67.6 mg, yield: 69%). LCMS [M+1] + =412.1.

[0620] Step 3: UB-053

[0621] N-([1,1'-Biphenyl]-4-ylmethyl)-9-phenyl-2-(piperazin-1-yl)-9H-purin-6-amine

[0622] UB-053e (41.2 mg, 0.10 mmol), UB-053f (41.3 mg, 0.48 mmol), DIPEA (98.2 mg, 0.76 mmol) and NMP (3 mL) were added to a microwave tube and microwaved at 180°C for 3 h. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (3×70 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane: dichloromethane / methanol: 10 / 1 = 10:90) to give a white solid (UB-053, 34.0 mg, yield: 51.15%). LCMS [M+1] + =462.2. 1 H NMR (400MHz, DMSO-d6) δ9.07 (s, 2H), 8.50 (s, 1H), 8.43 (s, 1H), 7.88 (d, J = 7.8Hz, 2H), 7.65–7.60 (m, 4H), 7.5 7(t,J=7.9Hz,2H),7.50–7.39(m,5H),7.35(t,J=7.3Hz,1H),4.69(s,2H),3.89(d,J=4.7Hz,4H),3.08(s,4H).

[0623] Example 54: Synthesis of Compound UB-054

[0624] Step 1: UB-054c

[0625] 2,6-Dichloro-9-(3-fluorophenyl)-9H-purine

[0626] Compound UB-054b (740 mg, 5.29 mmol) and compound UB-054a (500 mg, 2.64 mmol) were dissolved in 10 mL of dichloromethane, followed by the addition of copper acetate (961 mg, 5.29 mmol) and triethylamine (804 mg, 7.96 mmol). The mixture was allowed to react at room temperature for 3 hours. After completion, the reaction solution was concentrated and purified on a silica gel column (dichloromethane) to yield compound UB-054c (200 mg, 26% yield) as a yellow solid. LCMS [M+1] = 283.0 & 284.9.

[0627] Step 2: UB-054e

[0628] N-([1,1'-biphenyl]-4-ylmethyl)-2-chloro-9-(3-fluorophenyl)-9H-purin-6-amine

[0629] Compound UB-054c (200 mg, 0.71 mmol), UB-054d (120 mg, 0.68 mmol), and triethylamine (206 mg, 2.04 mmol) were dissolved in isopropanol (3 mL). The reaction was stirred at 80°C for 2 hours. After completion, the reaction solution was cooled to room temperature. The reaction solution was filtered to yield the desired compound UB-054e (75 mg, 53% yield) as a white solid. LCMS [M+1] = 430.1.

[0630] Step 3: UB-054

[0631] N-([1,1'-biphenyl]-4-ylmethyl)-9-(3-fluorophenyl)-2-(piperazin-1-yl)-9H-purin-6-amine

[0632] Compound UB-054f (40 mg, 0.47 mmol), UB-054e (40 mg, 0.09 mmol) and DIPEA (96 mg, 0.74 mmol) were dissolved in NMP (3 mL). The reaction was stirred at 180°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature. Water was added until a solid precipitated from the reaction solution and filtered. The filter residue was dissolved and purified on a silica gel column (DCM / MeOH = 30%) and lyophilized to obtain the desired compound UB-0450 (16 mg, 20% yield) as a white solid. LCMS [M+1] + =480.2. 1H NMR (400MHz, DMSO-d6) δ8.34(s,1H),8.25(s,1H),7.92(dt,J=10.8,2.2Hz,1H),7.88–7.83(m,1H),7.65–7.56(m,5H),7.48–7.41(m ,4H),7.34(t,J=7.3Hz,1H),7.22(td,J=8.5,2.2Hz,1H),4.67(s,2H),3.70–3.57(m,4H),2.81–2.66(m,4H),1.29(d,J=49.5Hz,3H).

[0633] Example 55: Synthesis of Compound UB-055

[0634] Step 1: UB-055c

[0635] 2,6-Dichloro-9-(1-methyl-1H-pyrazol-4-yl)-9H-purine

[0636] Compound UB-055b (666 mg, 5.29 mmol) and compound UB-055a (500 mg, 2.64 mmol) were dissolved in 10 mL of dichloromethane, followed by the addition of copper acetate (961 mg, 5.29 mmol) and triethylamine (804 mg, 7.96 mmol). The mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated and purified on a silica gel column (dichloromethane) to yield compound UB-055c (120 mg, 16.9% yield) as a yellow solid. LCMS [M+1] = 269.1.

[0637] Step 2: UB-055e

[0638] N-([1,1'-biphenyl]-4-ylmethyl)-2-chloro-9-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine

[0639] Compound UB-055c (120 mg, 0.45 mmol), UB-055d (80 mg, 0.43 mmol), and triethylamine (130 mg, 1.29 mmol) were dissolved in isopropanol (2 mL). The reaction was stirred at 80°C for 2 hours. After completion, the reaction solution was cooled to room temperature. The reaction solution was filtered to yield the desired compound UB-055e (95 mg, 53% yield) as a white solid. LCMS [M+1] = 416.2.

[0640] Step 3: UB-055

[0641] N-([1,1'-biphenyl]-4-ylmethyl)-9-(1-methyl-1H-pyrazol-4-yl)-2-(piperazin-1-yl)-9H-purin-6-amine

[0642] Compound UB-055f (99 mg, 1.15 mmol), UB-055e (95 mg, 0.23 mmol), and DIPEA (238 mg, 1.84 mmol) were dissolved in NMP (3 mL). The reaction was stirred in a microwave oven at 180°C for 3 hours. After completion, the reaction solution was cooled to room temperature. Water was added until a solid precipitated from the reaction solution and filtered. The dissolved residue was purified on a silica gel column (DCM / MeOH = 60%) and lyophilized to obtain the desired compound UB-055 (64 mg, 59% yield) as a white solid. LCMS [M+1] + =466.2. 1 H NMR (400MHz, DMSO-d6) δ8.29(s,1H),8.29(s,1H),8.28–8.12(m,2H),8.15(d,J=4.4Hz,1 H),7.98(s,1H),7.98(s,1H),7.68–7.55(m,4H),7.66–7.58(m,4H),7.48–7.42(m,4H),7. 52–7.39(m,4H),7.34(t,J=7.3Hz,1H),7.34(t,J=7.3Hz,1H),4.66(s,2H),4.66(s,2H),3 .92(s,3H),3.92(s,3H),3.69–3.61(m,4H),3.75–3.58(m,4H),2.74(s,4H),2.74(s,4H).

[0643] Examples 59-63: Synthesis of Compounds UB-056 to UB-063

[0644] The synthesis method of UB-059 and UB-060 is similar to that of UB-032.

[0645] The synthesis method of UB-061 is similar to that of UB-041.

[0646] The synthesis methods of UB-062 and UB-063 are similar to those of UB-043.

[0647] Table A1

[0648] Table A2

[0649] Table A3

[0650] Table A4

[0651] B. Test Examples

[0652] Test Example 1: Cell proliferation experiment

[0653] Reagents: RPMI-1640 medium, McCoy's 5A medium, IMDM medium, MEM medium, L-15 medium, fetal bovine serum, blue-chain double antibody, trypsin, 2-mercaptoethanol, NEAA, pyruvate, etc.

[0654] The test cells were routinely cultured and passaged for at least 2 generations before plating.

[0655] 1000 HT-29, N87, SKOV3, Colo-205 and MDA-MB-231 cells were seeded in 384-well plates with black walls and transparent bottoms in 25 uL. Compounds at different concentrations were added and cultured overnight at 37°C and 5% CO2.

[0656] 1500 H82 and H69 cells were seeded in 25uL of 384-well plates with black walls and transparent bottoms, and 25uL of compounds at different concentrations were added to culture the cells at 37°C and 5% CO2 for 72 hours. The 384-well plates were equilibrated at room temperature, and 25μL of Cell Reagent, shake on a horizontal shaker for 2 minutes to lyse the cells, incubate at room temperature for 10 minutes to stabilize the luminescent signal, and then use Envision to detect the chemiluminescent signal.

[0657] All cells were subjected to IC of the corresponding test samples. 50 Determination.

[0658] The fluorescence intensity of each well was detected using the Alarm blue method, and the IC 50 .

[0659] IC 50 Calculated by the following formula: Y=Max+(Min-Max) / [1+(X / IC 50 )×Slope]

[0660] Where Min, Max, and Slope represent the minimum value, maximum value, and slope, respectively.

[0661] The results are shown in Table 1. The compounds of the present invention were subjected to cell inhibition experiments on multiple tumor cell lines. The results showed that most of the compounds exhibited strong cell killing effects in multiple tumor cells and have the potential to be developed as anti-tumor drugs.

[0662] Table 1

[0663] Test Example 2: Immunohistochemistry (IHC)

[0664] Add appropriate amount of compound to the cultured cells and incubate in a 37°C tissue culture incubator for 2 hours.

[0665] The cultured cells were washed twice with PBS and then fixed with 100 μL of 10% neutral buffered formalin for 20 minutes.

[0666] After washing three times with PBS, immunohistochemical staining was performed using CCNK antibody and a universal two-step detection kit (mouse / rabbit enhanced polymer detection system, PV-9000, Zsbio Inc, Beijing).

[0667] Specifically, 100 μL of the endogenous peroxidase blocker in the kit was added and incubated at room temperature for 10 minutes; and then rinsed with PBS buffer for 3 minutes × 3 times.

[0668] Add 100 μL of CCNK antibody diluted 1:5000 and incubate at 37°C for 60 minutes; then rinse with PBS buffer for 3 minutes × 3 times.

[0669] Add 100 μL of reaction enhancement solution and incubate at 37°C for 20 minutes; rinse with PBS buffer for 3 minutes × 3 times.

[0670] Add 100 μL of enhanced enzyme-labeled goat anti-mouse / rabbit IgG polymer and incubate at 37°C for 20 minutes; rinse with PBS buffer for 3 minutes × 3 times.

[0671] Place in 75% ethanol, soak for 3 minutes × 2 times; place in 95% ethanol, soak for 3 minutes × 2 times; after removing excess liquid, place in anhydrous ethanol, soak for 3 minutes × 3 times; after removing excess liquid, air dry, seal the slide and observe under a microscope and take pictures.

[0672] The results are shown in FIG1 and Table 2. It can be seen that the compounds of the present invention can quickly and effectively degrade Cyclin K protein, and most of the compounds have significantly better Cyclin K degradation activities than CR8.

[0673] Test Example 3: Western blotting

[0674] A transparent 12-well plate was coated with 500 μL of 0.01 mg / mL poly-D-lysine hydrobromide and incubated at 37°C for 1 hour. The coating solution was removed and the plate was washed twice with 1 mL of PBS. 400,000 HEK293 cells were seeded into the 12-well plate. The cells were treated with the compound for 24 hours. The medium was removed, the plate was washed with PBS, and the cells were lysed with RIPA buffer. After adding loading buffer to the cell lysate, an appropriate volume was slowly added to the corresponding wells of the plate and run on a 4%-12% SDS-PAGE gel. After the run, the gel was transferred to a PVDF membrane and blocked with 5% skim milk powder for 1 hour at room temperature. The membrane was then incubated with an anti-cyclin K primary antibody diluted in 5% skim milk powder and shaken overnight at 4°C. After the primary antibody incubation, the membrane was washed three times with TBST on a shaker. An anti-rabbit HRP secondary antibody corresponding to the primary antibody was added in 5% skim milk powder and shaken for 1 hour at room temperature. After secondary antibody incubation, wash the membrane three times with TBST on a shaker. Place the PVDF membrane flat in a dark box, evenly soak the bands with ECL developer, and photograph using a ChemDoc XRS+ gel imager. Quantitatively analyze protein band intensities using ImageJ software.

[0675] The results are shown in FIG2 and Table 2, which show that the compounds of the present invention can quickly and effectively degrade Cyclin K protein, and most of the compounds have significantly better Cyclin K degradation activities than CR8.

[0676] Table 2

[0677] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, R 1 Each independently is H or C 1-4 alkyl; Subscript n1 is 1, 2, or 3; Cyclic Ar 1 Select from the following group: C 6-10 Aromatic ring, 5- to 10-membered heteroaromatic ring, 5- to 10-membered bridged ring; Cyclic Cr 1 Selected from the following group: H, C 3-10 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl; R a and R b Each independently selected from the group consisting of: H, R e or R; or R a and R b With cyclic Ar 1 and cyclic Cr 1 Jointly formed in, X 7 Each independently selected from the group consisting of: -O-, -S-, -N(R c )-、-C(R c )2-、-C(R c )2-C(R c )2-; Subscripts n5 and n6 are each independently 0, 1, 2 or 3; R e Each independently selected from the group consisting of: hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Alkylene-R f ; Among them, R f Selected from the group consisting of: -CN, -OH, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2; Subscripts n3 and n4 are each independently 0, 1, 2, 3 or 4; R 2 Selected from the group consisting of H, CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl; X 1 、X 2 and X 6 Each independently is N or C(R c ); X 3 、X 4 and X 5 are each independently N or C; M 1 Select from the following groups: None, X 8 、(M 4 ) s ;in, X 8 N(R c ) or C(R c )2; M 4 Each independently selected from the group consisting of O, S, C(O)O, C(O), N(R c ) and C 1-4 alkylene; s is 1, 2, or 3; M 2 is none or a ring as shown in formula A; In formula A, X 9 It is with M 1 The location of the connection, X 10 It is with M 3 Connection location; X 9 N or C(R m ), X 10 Select from the following Group: O, S, N or C(R m );X 11 and X 12 Each independently selected from the group consisting of: -C(R m )2-、-N(R m )-; subscripts m1 and m2 are each independently 0, 1, 2 or 3, and m1+m2≥2; Among them, R m Each independently is R c or R m1 ;in, R m1 Each independently selected from the group consisting of: hydroxy, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Hydroxyalkyl, optionally substituted C 1-6 haloalkyl; or, two R m1 Together form a single bond, optionally substituted C 1-4 alkylene or optionally substituted 1- to 4-membered heteroalkylene; M 3 Select from the following group: None, R 3 、-NH-R 3 ;in, R 3 Selected from the group consisting of: H, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6- Hydroxyalkyl, optionally substituted C 1-6- alkyl halide; R c Each independently is H or C 1-4 alkyl; Unless otherwise defined, the optional substitution refers to unsubstituted or one or more (such as 1, 2, 3 or 4) hydrogen in the group is replaced by a substituent R, and R is selected from the following groups: D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -OR', -NO2, -NR'R", -SR', -OC(O)R', -C(O)R', -CO2R', -CONR', -OC(O)NR'R", -NR"C(O)R', -NR"-C(O)NR'R", -NR"C(O)2R', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR"S(O)2R', C(O)2R', optionally substituted with one or more R' 3-10 Cycloalkyl, 4 to 10 membered heterocycloalkyl optionally substituted by one or more R'", C 6-10 aryl, 5- to 10-membered heteroaryl optionally substituted by one or more R'", -C 1-4 Alkylene-C 3-10 Cycloalkyl, optionally substituted with one or more R'"-C 1-4 Alkylene-4 to 10 membered heterocycloalkyl, optionally substituted with one or more R'"-C 1-4 Alkylene-C 6-10 Aryl, optionally substituted with one or more R'" -C 1-4 Alkylene-5 to 10 membered heteroaryl; Each R' is independently H, D, or a group selected from the group consisting of: C 1-6 Alkyl, C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, -C 1-4 Alkylene-4 to 10 membered heterocycloalkyl, -C 1-4 Alkylene-C 6-10 Aryl-C 1-4 Alkylene-5 to 10 membered heteroaryl; Each R" is selected from the group consisting of H, D, C 1-4 Alkyl, C 1-4 Haloalkyl, and C 3-4 Cycloalkyl; Each R"' is independently selected from the group consisting of D, halogen, hydroxy, nitro, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Cyclic Ar 1 Select from the following groups: Among them, * represents the ring Cr 1 Connection location; X a 、X b 、X c and X d are independently CH and N; X g Selected from the group consisting of NH, O, S; X h 、X i and X j Each is independently -CH2- or -CH2-CH2-; and / or, cyclic Cr 1 Select from the following groups: Among them, X d and X e are each independently N or CH; X f NH, S, O; X g is N or CH.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Select from the following groups:

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Cyclic Cr 1 Ring Ar 2 ; and cyclic Ar 2 C 6-10 Aryl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Cyclic Ar 2 It is a phenyl group.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound is shown in formula I-1 Alternatively, the compound is as shown in formula I-2 Alternatively, the compound is as shown in formula I-3 Alternatively, the compound is as shown in formula I-4 7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein The compound is a compound of formula I-1, in, for m3 is 0, 1 or 2.

8. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein Cyclic Cr 1 Ring Ar 2 ; and cyclic Ar 2 It is a phenyl group.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound is selected from Table A1, A2, A3 and Table A4.

10. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (i) the compound according to claim 1 or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

11. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.

12. A conjugate or a pharmaceutically acceptable salt thereof, characterized in that: The conjugate is a conjugate formed by the compound according to claim 1 and a polypeptide element or a targeting ligand.

13. The conjugate according to claim 12 or a pharmaceutically acceptable salt thereof, wherein: The conjugate is shown in formula II D -M L -M P (II) in, M D is a moiety derived from the compound represented by formula (I) as described in the first aspect; M L None or used to connect M D and M P The connecting part; M P A moiety derived from a polypeptide element or a targeting ligand.

14. A pharmaceutical composition comprising: (i) the conjugate according to claim 12 or a pharmaceutically acceptable salt thereof; as well as (ii) a pharmaceutically acceptable carrier.

15. Use of the conjugate according to claim 12 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.

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