DEGRADATION OF BRUTON TYROSINE KINASE (BTK) BY CONJUGATION OF BTK INHIBITORS WITH E3 LIGAND AND METHODS OF APPLICATION

Claims

1. Compound of formula (I): or a pharmaceutically acceptable salt or stereoisomer thereof, Where: fragment is a fragment of E3 ubiquitin ligase selected from each Cy1a, Cy1b and Cy1c independently represents a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered saturated ring or unsaturated ring containing 0-3 heteroatoms selected from nitrogen, oxygen and sulfur as ring member(s); Cy2 is a 5- or 6-membered saturated ring or unsaturated ring (preferably an aromatic ring) containing 0-3 heteroatoms selected from nitrogen, oxygen and sulfur as ring member(s); Cy3 is a 5- or 6-membered saturated ring or an unsaturated ring containing no additional heteroatom; each of L a , L b , L c and L dindependently represents a single bond, -O-, -S-, -C(O)-, -(CR a R b ) n - or -NR c -; each of L 1 and L 2 independently represents a single bond, -O-, -S-, -C(O)-, -(CR a R b ) n - or -NR c -; each of Z 1 and Z 2 independently represents CH, CR 14 or N; every X e independently represents CR 14 or N; in each case, each of R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , R 10 , R 11 , R 13 and R 14 independently represents hydrogen, halogen, -C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONRc R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e or NR c SO2R d , each of the specified -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, hydroxy, -halogen C 1-8 alkyl, -C 1-8 alkyloxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; each of R 6 , R 7 and R 12 independently represents hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of the specified - C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, hydroxy, -halogen C 1-8 alkyl, -C 1-8 alkyloxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 5 is a 5- or 6-membered aromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen and sulfur as ring member(s); 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, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR cSO2NR d R e or NR c SO2R d , each of the specified -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with -C 1-8 alkyl, halogen, hydroxy, -halogen C 1-8 alkyl, -C 1-8 alkyloxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; each of p1, p2, p3, p4, p5 and p6 is independently equal to 0, 1, 2, 3 or 4; each of s1, s2 and s3 is independently equal to 0, 1; n is 0, 1, 2, 3, 4, 5, or 6; each of R a and R b independently represents hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NRc R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e or NR c SO2R d , each of the specified -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, hydroxy, -halogen C 1-8 alkyl, -C 1-8 alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or R a and R b together with the atom(s) to which they are attached, form a 3-12 membered ring, said ring containing 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as a member of the ring(s), said ring optionally substituted with at least one substituent independently selected from halogen, -C1-8 alkyl, - C 1-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO2; each of R c , R d and R e independently represents hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or (R c and R d ) or (R d and R e ) together with the atom(s) to which they are attached form a 3-12 membered ring, said ring containing 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), said ring 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 -NO2.

2. The compound according to item 1, where the fragment selected from Where Cy3 is a 6-membered saturated ring or an unsaturated ring containing no additional heteroatoms; L 1 , X e , R 12 , R 13 and p6 correspond to the definitions presented in paragraph 1.

3. The compound according to item 1 or 2, where the fragment selected from L 1 , X e , R 12 , R 13 and p6 correspond to the definitions presented in paragraph 1.

4. The compound according to item 1, where the fragment selected from or L 1 , L 2 , Z 1 , Z 2 , X e , R 12 , R 13 and p6 correspond to the definitions presented in paragraph 1.

5. The compound according to item 1 or 4, where the fragment selected from or L 1 , L 2 , X e , R 12 , R 13 and p6 correspond to the definitions presented in paragraph 1.

6. The connection according to any one of paragraphs 1-5, where each of L 1 and L 2 independently represents a single bond, -O-, -S-, -C(O)-, -(CR a R b ) n - or -NR c -; n is 1, 2, 3, 4, 5, or 6; each of R a and R b independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or R a and R btogether with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring being 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 -NO2; each of R c independently represents 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.

7. A connection according to any one of paragraphs 1-6, where each of the p6 is independently equal to 0, 1, 2, 3, or 4; every X eindependently represents CR 14 or N; each of R 13 and R 14 independently represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 alkenyl, -C 2-8 alkynyl, heterocyclyl, phenyl, heteroaryl, oxo (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e or NR c SO2R d , each of the following methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 alkenyl, -C 2-8 alkynyl, heterocyclyl, phenyl or heteroaryl optionally substituted with F, Cl, Br, I, hydroxy, -halogen C 1-8 alkyl, -C 1-8 alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; each of R c , R d and R e independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or (R c and R d ) or (R d and R e) together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring being 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 -NO2; each R 12 independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, each of the said methyl, ethyl, propyl, butyl, pentyl, hexyl, -C 2-8 alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl optionally substituted with F, Cl, Br, I, hydroxy, -halogen C 1-8 alkyl, -C 1-8 alkyloxy, cycloalkyl, heterocyclyl, aryl or heteroaryl.

8. The connection according to any one of paragraphs 1-7, where each of L a , L b , L c and L d independently selected from a single bond -O-, -CO-, -(CR a R b ) n - or -NR c -; n is 1, 2, 3, 4 or 5; each of R a and R b independently represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO2, -ORc , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e or -NR c SO2R d ; each of the indicated methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl optionally substituted with F, Cl, Br, I, hydroxy, -halogen C 1-8alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or R a and R b together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring being 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 -NO2.

9. The connection according to any one of paragraphs 1-8, where each of L a , Lb , L c and L d independently selected from a single bond -O-, -CO-, -(CR a R b ) n - or -NR c -; n is 1, 2, 3, 4 or 5; each of R a and R b independently represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NRd R e or NR c SO2R d .

10. The connection according to any one of paragraphs 1-9, where each of L a , L b , L c and L d independently selected from a single bond -O-, -CO-, -N(CH3)-, -NH-, -(CH2) n -, -[CH(CH3)] n -, -[C(CH3)2] n -; n is 1, 2, 3, 4, or 5; preferably each of L a , L b , L c and L d independently selected from a single bond, -O-, -CO-, -N(CH3)-, -NH-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-.

11. A compound according to any one of claims 1 to 10, wherein each Cy1a is independently optionally substituted with R 9 , each of n1, n2, n3, n4, and n5 is independently equal to 0, 1, 2, 3, or 4; each of X 3 and X 4 independently selected from -CR a or N; each of X 5 , X 6 and X 7 independently selected from -NR c-, -O-, -S- and -CR a R b -; R a , R b and R c correspond to the definitions presented in paragraph 1; *1a refers to the position attached to the fragment a **1a refers to the position attached to the fragment 12. A compound according to any one of paragraphs 1-11, wherein each Cy1a independently represents or optionally substituted with R 9 ; each of X 3 and X 4 independently selected from -CR a or N; each of X 5 , X 6 and X 7 independently selected from -NR c -, -O-, -S- and -CR a R b -; each of R a and R b independently represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e or NR c SO2R d ; each of the indicated methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl optionally substituted with F, Cl, Br, I, hydroxy, -halogen C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; R c independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl.

13. A compound according to any one of claims 1-11, wherein each Cy1a is independently 14. A compound according to any one of claims 1-13, wherein each Cy1b is independently optionally substituted with R 10 , each of n1, n2, n3, n4, and n5 is independently equal to 0, 1, 2, 3, or 4; each of X 3 and X 4 independently selected from -CR a or N; each of X 5 , X 6 and X 7 independently selected from -NR c -, -O-, -S- and -CR a R b -; R a , R b and R c correspond to the definitions presented in paragraph 1; *1b refers to the position attached to the fragment a **1b refers to the position attached to the fragment 15. A compound according to any one of claims 1-14, wherein each Cylb independently represents or optionally substituted with R 10 ; each of X 3 and X 4 independently selected from -CR a or N; each of X 5 , X 6 and X 7 independently selected from -NR c -, -O-, -S- and -CR a R b -; each of R a and R b independently represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e or NR c SO2R d; each of the indicated methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl optionally substituted with F, Cl, Br, I, hydroxy, -halogen C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; R c independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl.

16. A compound according to any one of claims 1-15, wherein each Cy1b is independently 17. A compound according to any one of claims 1 to 16, wherein each Cy1c independently represents optionally substituted with R 11 , each of n1, n2, n3, n4, and n5 is independently equal to 0, 1, 2, 3, or 4; each of X 3 and X 4 independently selected from -CR a or N; each of X 5 , X 6 and X 7 independently selected from -NR c -, -O-, -S- and -CR a R b -; R a , R b and R c correspond to the definitions presented in paragraph 1; *1c refers to the position attached to the fragment a ** 1c refers to the position attached to the fragment 18. A compound according to any one of claims 1-17, wherein each Cylc independently represents optionally substituted with R 11 ; each of X 3 and X4 independently selected from -CR a or N; each of X 5 , X 6 and X 7 independently selected from -NR c -, -O-, -S- and -CR a R b -; each of R a and R b independently represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR cSO2NR d R e or -NR c SO2R d ; each of the indicated methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl optionally substituted with F, Cl, Br, I, hydroxy, -halogen C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; R c independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl.

19. A compound according to any one of claims 1 to 18, wherein each Cy1c independently represents 20. The compound according to any one of paragraphs 1-19, where the fragment represents refers to the position attached to the fragment a *Lb refers to the position attached to the fragment 21. The connection according to any one of paragraphs 1-20, where R 1 represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e, -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e or NR c SO2R d , each of the following methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl optionally substituted with F, Cl, Br, I, hydroxy, -halogen C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; each of R c , R d and R eindependently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or (R c and R d ) or (R d and R e ) together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring being 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 -NO2.

22. The connection according to any one of paragraphs 1-21, where R 1represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO2; preferably R 1 represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl.

23. The connection according to any one of paragraphs 1-22, where R 2 represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d, -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e or NR c SO2R d , each of the following methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl optionally substituted with F, Cl, Br, I, hydroxy, -halogen C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; each of R c , Rd and R e independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or (R c and R d ) or (R d and R e ) together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring being 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 -NO2.

24. The connection according to any one of paragraphs 1-23, where R 2represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO2; preferably R 2 represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, -CN or -NO2.

25. The connection according to any one of paragraphs 1-24, where each of R 3 and R 4 independently represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -ORc , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e or NR c SO2R d , each of the following methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl optionally substituted with F, Cl, Br, I, hydroxy, -halogen C 1-8alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; each of R c , R d and R e independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or (R c and R d ) or (R d and R e) together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring containing 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), said ring 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 -NO2.

26. The compound according to any one of paragraphs 1-25, where each of R 3 and R 4 independently represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl or -CN; preferably each of R 3 and R 4independently represents hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl or cyclopentyl.

27. The compound according to any one of paragraphs 1-26, where the fragment represents where *3 refers to the position attached to the fragment and **3 refers to the position attached to the fragment 28. The compound according to any one of paragraphs 1-27, where each of R 6 and R 7 independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, each of the said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl optionally substituted with F, Cl, Br, I, hydroxy, -halogen C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; preferably, each of R 6 and R 7 independently represents H, methyl, ethyl, propyl butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

29. The connection according to any one of paragraphs 1-28, where R 5 represents each of Y 1 , Y 2 , Y 3 and Y 4 independently selected from CH, O, S, or N; each R 15 independently selected from hydrogen, halogen, -C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e or NR c SO2R d , each of the specified -C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, hydroxy, -halogen C 1-8 alkyl, -C 1-8 alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; each of R c , R d , and R e independently satisfies the definitions given in paragraph 1; and p7 is equal to 0, 1, 2, 3 or 4.

30. The connection according to item 29, where Y 1 represents CH, S, N, or O; Y 2 represents CH, S, O, or N; Y 3 represents CH, O, S, or N; and Y 4 represents CH, O, S or N.

31. The connection according to item 28, where selected from 32. The compound according to item 29, where R 15 selected from -H, -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -C6H 13 , methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH(OH)CH2CH3, -CH2CH(OH)CH3, -CH2OCH3, -CFH2, -CF2H, -CF3, -CH2CF3, -CH2CH2CF3, each of the specified -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -C6H 13 , methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 2-8 alkenyl, -C 2-8alkynyl is optionally substituted with at least one F, Cl, Br, I, hydroxy, -halogen C 1-8 alkyl, -C 1-8 alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

33. The compound according to item 29, where R 15 selected from or 34. The compound according to any one of paragraphs 1-33, where the fragment represents 35. A compound according to any one of claims 1 to 34, wherein Cy2 is a 5- or 6-membered aromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen and sulfur as ring member(s).

36. The connection according to any one of paragraphs 1-35, where represents each of Y 1 , Y 2 , Y 3 and Y 4 independently corresponds to the definitions given in paragraph 29; where *Су2 refers to the position attached to the fragment and **3 refers to the position attached to the fragment 37. The connection according to any one of paragraphs 1-36, where represents 38. The connection according to any one of paragraphs 1-37, where R 8 represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e , or -NR c SO2Rd , each of the following methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl optionally substituted with F, Cl, Br, I, hydroxy, -halogen C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; each of R c , R d and R e independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or (R c and R d) or (R d and R e ) together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring being 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 -NO2.

39. The connection according to any one of paragraphs 1-38, where R 8 represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO2; preferably R2 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, -CN or -NO2.

40. A connection according to any one of paragraphs 1-39, where represents 41. A compound according to any one of paragraphs 1-39, where the fragment selected from 42. A compound according to any one of paragraphs 1-41, wherein the compound is selected from 43. A pharmaceutical composition comprising a compound according to any one of claims 1-42 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

44. A method for inhibiting BTK activity, which comprises administering to an individual a compound according to any one of claims 1-42 or a pharmaceutically acceptable salt thereof, including a compound of formula (I) or specific compounds exemplified herein.

45. A method of treating a disease or disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1-42 or a pharmaceutically acceptable salt thereof as an inhibitor of BTK kinase, wherein the disease or disorder is associated with inhibition of BTK, preferably the disease or disorder is cancer.