DEGRADATION OF BRUTON'S TYROSINE KINASE (BTK) BY CONJUGATION OF BTK INHIBITORS WITH E3 LIGASE LIGAND AND METHODS OF USE

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein:

Cy1 is a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring comprising 0-3 heteroatoms selected from nitrogen, oxygen and sulfur;

Cy2 is a ring fused to the structure

 in Formula (I), said ring is an aromatic ring or a non-aromatic ring (preferably aromatic ring);

Cy3 is a saturated ring or unsaturated ring (preferably aromatic ring);

L a , L b and L c are each independently a single bond, —O—, —S—, —C(O)—, —(CR c R d ) n — or —NR c —;

the moiety is an E3 Ubiquitin ligase moiety selected from

L 1 and L 2 are each independently a single bond, —O—, —S—, —C(O)—, —(CR c R d ) n — or —NR c —;

Z 1 is N or CR za a if Z 1 is a part of a double bond in the ring; or Z 1 is NR za or C(R za ) 2 if Z 1 is not a part of a double bond in the ring;

Z 2 is N or CR za if Z 2 is a part of a double bond in the ring; or Z 2 is NR za or C(R za ) 2 if Z 2 is not a part of a double bond in the ring;

Z 3 is N or CR za if Z 3 is a part of a double bond in the ring; or Z 3 is NR za or C(R za ) 2 if Z 3 is not a part of a double bond in the ring;

Z 4 is N or CR za if Z 4 is a part of a double bond in the ring; or Z 4 is NR za or C(R za ) 2 if Z 4 is not a part of a double bond in the ring; provided that not all Z 1 , Z 2 , Z 3 and Z 4 are ═N—;

Z 5 is C if Z 5 is a part of a double bond in the ring; or Z 5 is N or CR za if Z 5 is not a part of a double bond in the ring;

Z 6 and Z 7 are each independently CR za or N;

X a , X b , X c , X d and X e are each independently CR 13 or N;

each of occurrence, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 11 , R 13 and R za are each independently hydrogen, halogen, —C 1-8 alkyl, —C 1-8 alkoxy, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO 2 , —OR a , —SO 2 R a , —COR a , —CO 2 R a , —CONR a R b , —C(═NR a )NR b R c , —NR a R b , —NR a COR b , —NR a CONR b R c , —NR a CO 2 R b , —NR a SONR b R c , —NR a SO 2 NR b R c , or —NR a SO 2 R b , each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8 alkyl, —C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

or R 1 and R 3 , together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent independently selected from halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO 2 , —OR a , —SO 2 R a , —COR a , —CO 2 R a , —CONR a R b , —C(═NR a )NR b R c , —NR a R b , —NR a COR b , —NR a CONR b R c , —NR a CO 2 R b , —NR a SONR b R c , —NR a SO 2 NR b R c , or —NR a SO 2 R b , each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8 alkyl, —C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R 5 , R 6 and R 12 are each independently hydrogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8 alkyl, —C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R 10 is 5- or 6-membered aromatic ring comprising 0-3 heteroatoms selected from nitrogen, oxygen and sulfur; said aromatic ring is optionally substituted with halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, —C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO 2 , —OR a , —SO 2 R a , —COR a , —CO 2 R a , —CONR a R b , —C(═NR a )NR b R c , —NR a R b , —NR a COR b , —NR a CONR b R c , —NR a CO 2 R b , —NR a SONR b R c , —NR a SO 2 NR b R c , or —NR a SO 2 R b , each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with —C 1-8 alkyl, halogen, hydroxy, -haloC 1-8 alkyl, —C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

or R 5 and R 10 , together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent independently selected from halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO 2 , —OR a , —SO 2 R a , —COR a , —CO 2 R a , —CONR a R b , —C(═NR a )NR b R c , —NR a R b , —NR a COR b , —NR a CONR b R c , —NR a CO 2 R b , —NR a SONR b R c , —NR a SO 2 NR b R c , or —NR a SO 2 R b , each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8 alkyl, —C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

m1, m2, m3, m4, p1, p2, p3, p4 and p5 are each independently 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3, 4, 5 or 6;

r is 0 or 1;

s is 0 or 1;

R a and R b are each independently hydrogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or

R a and R b together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent independently selected from halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN or —NO 2 ;

R c and R d are each independently hydrogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or

R c and R d together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent independently selected from halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN or —NO 2 .

2 . The compound according to claim 1 , wherein the compound is selected from formula (II) and formula (III),

Cy1, Cy2, Cy3, L a , L b , L c , , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , X a , X b , X c , X d , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , m1, m2, m3, m4, p1, p2, p3, p4, r and s are defined as claim 1 .

3 . The compound according to claim 1 , wherein the compound is selected from formula (IV) and formula (V),

Cy1, Cy2, Cy3, L a , L b , L c , , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , X a , X b , X c , X d , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , m1, m2, m3, m4, p1, p2, p3, p4, r and s are defined as claim 1 .

4 . The compound according to claim 1 , wherein Cy1 is

wherein X f and X g are each independently CR 11 or N;

*1 refers to the position attached to the

 moiety, and **1 refers to the position attached to

 moiety.

5 . The compound according to claim 1 , wherein Cy1 is

6 . The compound according to claim 1 , wherein Cy1 is selected from

7 . The compound according to claim 1 , wherein p2 is 0, 1, or 2, and each R 7 is independently selected hydrogen, —F, —Br, —Cl, —I, —CH 3 , —C 2 H 5 , —C 3 H 7 , —C 4 H 9 , —C 5 H 11 , —C 6 H 13 , —C 7 H 15 , —C 8 H 17 , —OCH 3 , —OC 2 H 5 , —OC 3 H 7 , —OC 4 H 9 , —OC 5 H 11 , —OC 6 H 13 , —OC 7 H 15 , —OC 8 H 17 , —C 2-8 alkenyl, —C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, —CN, —NO 2 , —OR a , —SO 2 R a , —COR a , —CO 2 R a , —CONR a R b , —C(═NR a )NR b R c , —NR a R b , —NR a COR b , —NR a CONR b R c , —NR a CO 2 R b , —NR a SONR b R c , —NR a SO 2 NR b R c , or —NR a SO 2 R b , each of said —CH 3 , —C 2 H 5 , —C 3 H 7 , —C 4 H 9 , —C 5 H 11 , —C 6 H 13 , —C 7 H 15 , —C 8 H 17 , —OCH 3 , —OC 2 H 5 , —OC 3 H 7 , —OC 4 H 9 , —OC 5 H 11 , —OC 6 H 13 , —OC 7 H 15 , —OC 8 H 17 , —C 2-8 alkenyl, —C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, is optionally substituted with —F, —Br, —Cl, —I, hydroxy, -haloC 1-8 alkyl, —C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R a , R b and R c are defined as claim 1 .

8 . The compound according to claim 1 , wherein p2 is 0, 1, or 2, and each R 7 is independently selected from hydrogen, —F, —Br, —Cl, —I, —CH 3 , —C 2 H 5 , —C 3 H 7 , —C 4 H 9 , —C 5 H 11 , —C 6 H 13 , methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

9 . The compound according to claim 1 , wherein the moiety is selected from

R 11 is selected from hydrogen, —F, —Br, —Cl, —I, —CH 3 , —C 2 H 5 , —C 3 H 7 , —C 4 H 9 , —C 5 H 11 , —C 6 H 13 , methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

R c and R d are each independently hydrogen, —CH 3 , —C 2 H 5 , —C 3 H 7 , —C 4 H 9 , —CH, —C 6 H 13 , —C 2-8 alkenyl, —C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclyl, aryl, or heteroaryl; or

R c and R d together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent independently selected from halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN or —NO 2 ,

and p5 is 0 or 1.

10 . The compound according to claim 6 , wherein the moiety is selected from

11 . The compound according to claim 6 , wherein the moiety is selected from

12 . The compound according to claim 1 , wherein L a , L b and L c are each independently selected from a single bond, —O—, —S—, —C(O)—, —(CR c R d ) n — or —NR c —;

n is 1, 2, 3, 4, 5 or 6;

R c and R d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or

R c and R d together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent independently selected from —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo, —CN or —NO 2 .

13 . The compound according to claim 1 , wherein L a , L b and L c are each independently selected from a single bond, —O—, —CO—, —(CH 2 ) n —, —[CH(CH 3 )] n —, —[C(CH 3 ) 2 ] n — or —NH—; n is 1, 2, 3, 4 or 5.

14 . The compound according to claim 1 , R 13 is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

15 . The compound according to claim 1 , wherein m1, m2, m3 and m4 are each independently selected from 0 or 1.

16 . The compound according to claim 1 , wherein p3 and p4 are each independently 0 or 1, R 8 and R 9 are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

17 . The compound according to claim 1 , wherein the

moiety is selected from

wherein *a refers to the position attached to the

 moiety, and **b refers to the position attached to

 moiety.

18 . The compound according to claim 1 , wherein the

moiety is selected from

wherein *a refers to the position attached to the

 moiety, and **b refers to the position attached to

 moiety.

19 . The compound according to claim 1 , wherein the

moiety is selected from

wherein *a refers to the position attached to the

 moiety, and **b refers to the position attached to

 moiety.

20 . The compound according to claim 1 , wherein the

moiety is selected from

wherein *a refers to the position attached to the

 moiety, and **b refers to the position attached to

 moiety.

21 . The compound according to claim 1 , wherein the

moiety is selected from —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(C 2 ) 4 —,

*L refers to the position attached to the

 moiety, and **L refers to the position attached to

 moiety.

22 . The compound according to claim 1 , wherein Z 1 and Z 4 are each independently CR za or N; R za is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, —C 2-8 alkenyl, —C 2-8 alkynyl, heterocyclyl, aryl, heteroaryl, —CN.

23 . The compound according to claim 1 , wherein one of Z 2 and Z 3 is C, and connects to Cy1; and the other one of Z 2 and Z 3 is CR za or N; R za is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, —C 2-8 alkenyl, —C 2-8 alkynyl, heterocyclyl, aryl, heteroaryl, —CN.

24 . The compound according to claim 1 , wherein at most two of Z 1 , Z 2 , Z 3 and Z 4 are N.

25 . The compound according to claim 1 , wherein at most one of Z 1 , Z 2 , Z 3 and Z 4 is N.

26 . The compound according to claim 1 , wherein R 1 is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH 2 CH 2 OH, —CH(OH)CH 3 , —CH 2 CH 2 CH 2 OH, —CH(OH)CH 2 CH 3 , —CH 2 CH(OH)CH 3 , —CH 2 OCH 3 , —CFH 2 , —CF 2 H, —CF 3 , —CH 2 CF 3 or —CH 2 CH 2 CF 3 .

27 . The compound according to claim 1 , wherein R 1 and R 3 , together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring comprising 0, 1 or 2 additional N atom as ring member(s), said ring is optionally substituted with at least one substituent independently selected from —F, —Cl, —Br, —I, —OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or —CH 2 OH.

28 . The compound according to claim 1 , wherein R 2 is H, —F, —Cl, —Br, —I, methyl, ethyl or propyl, and p1 is 0, 1, or 2.

29 . The compound according to claim 1 , wherein R 3 and R 4 are each independently —H, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

30 . The compound according to claim 1 , wherein the

moiety is

wherein *3 refers to the position attached to the

moiety, and **3 refers to the position attached to

moiety.

31 . The compound according to claim 1 , wherein R 5 and R 6 are each independently —H, methyl, ethyl, propyl.

32 . The compound according to claim 1 , wherein R 10 is

Y 1 , Y 2 , Y 3 and Y 4 are selected from CH, O, S or N; R 14 is selected from hydrogen, halogen, —C 1-8 alkyl, —C 1-8 alkoxy, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO 2 , —OR a , —SO 2 R a , —COR a , —CO 2 R a , —CONR a R b , —C(═NR a )NR b R c , —NR a R b , —NR a COR b , —NR a CONR b R c , —NR a CO 2 R b , —NR a SONR b R c , —NR a SO 2 NR b R c , or —NR a SO 2 R b , each of said —C 1-8 alkyl, —C 1-8 alkoxy, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8 alkyl, —C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R a , R b , and R c are each independently hydrogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and p6 is 0, 1, 2, 3 or 4.

33 . The compound according to claim 25 , wherein Y 1 is CH, S, N or O; Y 2 is CH, S, O or N; Y 3 is CH, O, S or N; and Y 4 is CH, O, S or N.

34 . The compound according to claim 25 , wherein

is selected from

35 . The compound according to claim 25 , wherein, R 14 is selected from —H, —F, —Cl, —Br, —I, —CH 3 , —C 2 H 5 , —C 3 H 7 , —C 4 H 9 , —C 5 H 11 , —C 6 H 13 , methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —C 2-8 alkenyl, —C 2-8 alkynyl, —CH 2 OH, —CH 2 CH 2 OH, —CH(OH)CH 3 , —CH 2 CH 2 CH 2 OH, —CH(OH)CH 2 CH 3 , —CH 2 CH(OH)CH 3 , —CH 2 OCH 3 , —CFH 2 , —CF 2 H, —CF 3 , —CH 2 CF 3 , —CH 2 CH 2 CF 3 , each of said —CH 3 , —C 2 H 5 , —C 3 H 7 , —C 4 H 9 , —C 5 H 11 , —C 6 H 13 , methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —C 2-8 alkenyl, —C 2-8 alkynyl is optionally substituted with at least one halogen, hydroxy, -haloC 1-8 alkyl, —C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

36 . The compound according to claim 25 , wherein, R 14 is selected from

37 . The compound according to claim 1 , wherein the compound is selected from

38 . A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

39 . A method of inhibiting BTK activity, which comprises administering to an individual the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, including the compound of formula (I) or the specific compounds exemplified herein.

40 . A method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof as an BTK kinase inhibitor, wherein the disease or disorder is associated with inhibition of BTK, preferably, the disease or disorder is cancer.