IP Library › Granted Patent US 7,872,014

Granted Patent B2

US 7,872,014 · App. 10/565,657 · Granted Jan 18, 2011

Anaplastic lymphoma kinase modulators and methods of use

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Quick Facts

Patent No.: US 7,872,014
App. No.: 10/565,657
Granted: Jan 18, 2011
Kind: B2

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Abstract

The present invention comprises compounds and pharmaceutical compositions comprising the compounds that are inhibitors of ALK. The invention also comprises methods of using the compounds and compositions to treat diseases mediated by ALK, including diseases such as cancer, immunological disorders, cardiovascular diseases, and other degenerative disorders.

Claims (460)

1. A compound according to formula I,

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

A is a five- to ten-membered ring containing up to three heteroatoms;

R 1 is selected from —H, halo, trihalomethyl, —CN, —NO 2 , —OR 4 , —N(R 4 )R 4 , —S(O) 0-2 R 4 , —SO 2 N(R 4 )R 4 , —CO 2 R 4 , —C(═O)N(R 4 )R 4 , —C(═O)R 4 , —C(═NR 5 )N(R 4 )R 4 , —C(═NR 5 )R 4 , —N(R 4 )SO 2 R 4 , —N(R 4 )C(O)R 4 , alkoxy, C 1-6 alkyl, aryl, aryl C 1-6 alkyl, heterocyclyl, and heterocyclyl C 1-6 alkyl;

two adjacent of R 1 , together with the annular atoms to which they are attached, can form a five- to six-membered ring containing up to two heteroatoms and optionally substituted with up to four of R 10 ;

R 2 and R 3 , together with the annular atoms to which they are attached, form a five- to six-membered ring containing up to two heteroatoms and optionally substituted with up to five of R 6 ;

each R 4 is selected from —H; C 1-6 alkyl optionally substituted with 1, 2, or 3 halogen; C 1-6 alkyl optionally substituted with alkoxy; C 1-6 alkyl substituted with amino where the amino is optionally substituted with one or groups selected from methyl, ethyl, —CH 2 CH 2 OCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , and N-methyl-pyrrolidin3-yl; aryl; aryl C 1-6 alkyl; heterocyclyl; and heterocyclyl C 1-6 alkyl where the heterocyclyl is optionally substituted with alkyl, acyl, NH 2 , alkylamino, dialkylamino, heterocyclyl, cyclohexyl, —CH 2 OCH 3 , —CH 2 C(O)NHCH(CH 3 ) 2 , or —CH 2 OCH 3 ;

two of R 4 , when taken together with a common nitrogen to which they are attached, form an five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P;

each R 5 is selected from —H, —CN, —NO 2 , —OR 4 , —S(O) 0-2 R 4 , —CO 2 R 4 , C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

Y is ═N— or ═C(H);

X 1 and X 2 are each independently either ═N— or ═C(R 9 )—;

X 3 is —N(R 7 )—;

R 7 is hydrogen;

each of R 6 and R 10 is independently selected from —H, halo, trihalomethyl, —CN, —NO 2 , —OR 4 , —N(R 4 )R 4 , —S(O) 0-2 R 4 , —SO 2 N(R 4 )R 4 , —CO 2 R 4 , —C(═O)N(R 4 )R 4 , —C(═NR 5 )N(R 4 )R 4 , —C(═NR 5 )R 4 , —N(R 4 )SO 2 R 4 , —N(R 4 )C(O)R 4 , —C(═O)R 4 , optionally substituted alkoxy, C 1-6 alkyl, aryl, aryl C 1-6 alkyl, heterocyclyl, and heterocyclyl C 1-6 alkyl;

two adjacent of R 6 , together with the annular atoms to which they are attached, can form a five- to seven-membered ring containing up to two heteroatoms; and

each R 9 is independently selected from —H; halo; trihalomethyl; —CN; —NO 2 ; —OR 4 ; —N(R 4 )R 4 ; —S(O) 0-2 R 4 ; —SO 2 N(R 4 )R 4 ; —CO 2 R 4 ; —C(═O)N(R 4 )R 4 ; —C(═NR 5 )N(R 4 )R 4 ; —C(═NR 5 )R 4 ; —N(R 4 )SO 2 R 4 ; —N(R 4 )C(O)R 4 ; —C(═O)R 4 ; alkoxy; C 1-6 alkyl optionally substituted with one group selected from alkoxy, benzylamino, and 2-oxo-pyrrolidinyl; aryl C 1-6 alkyl substituted on the aryl with 1 or 2 groups selected from alkyl and alkoxy; heterocyclyl optionally substituted with —C(O)Ot-Bu; and heterocyclyl C 1-6 alkyl; provided when R 9 is aryl, heteroaryl, —C(H)═C(H)R or —C(H)═NR, where R is an optionally substituted alkyl, cycloalkyl, heteroalicyclic, aryl, or heteroaryl, then Y is not ═C(H)—.

2. The compound according to claim 1 , wherein the five- to six-membered ring formed by R 2 and R 3 is an aryl or a heteroaryl optionally substituted with up to five of R 6 ; or a pharmaceutically acceptable salt or stereoisomer, thereof.

3. The compound according to claim 2 , wherein the five- to six-membered ring formed by R 2 and R 3 is phenyl or pyridyl optionally substituted with up to five of R 6 ; or a pharmaceutically acceptable salt or stereoisomer, thereof.

4. The compound according to claim 3 , of formula II,

or a pharmaceutically acceptable salt or stereoisomer, thereof.

5. The compound according to claim 4 , wherein X 1 is ═C(R 9 )—, X 2 is ═N—, X 3 is —N(R 7 )—, and R 7 is hydrogen; or a pharmaceutically acceptable salt or stereoisomer, thereof.

6. The compound according to claim 5 , wherein Y is ═N—; or a pharmaceutically acceptable salt or stereoisomer, thereof.

7. The compound according to claim 6 , wherein A is either a six- to ten-membered aryl or a five- to ten-membered heteroaryl containing up to three heteroatoms and where A is substituted with 1-5 R 1 ; or a pharmaceutically acceptable salt or stereoisomer, thereof.

8. The compound according to claim 7 , wherein A is either a six-membered aryl or a five- or six-membered heteroaryl containing up to three heteroatoms; and where A is substituted with 1-5 R 1 ; or a pharmaceutically acceptable salt or stereoisomer, thereof.

9. The compound according to claim 8 , wherein R 1 is selected from —H, halo, trihalomethyl, —CN, —OR 4 , —N(R 4 )R 4 , —SO 2 N(R 4 )R 4 , —CO 2 R 4 , —C(═O)N(R 4 )R 4 , —C(═NR)N(R 4 )R 4 , —C(═NR 5 )R 4 , —N(R 4 )SO 2 R 4 , —N(R 4 )C(O)R 4 , alkoxy, C 1-6 alkyl, heterocyclyl, and heterocyclyl C 1-6 alkyl; or a pharmaceutically acceptable salt or stereoisomer, thereof.

10. The compound according to claim 9 , of formula III,

wherein R 7 is hydrogen and at least one of R 1 is —OH; or a pharmaceutically acceptable salt or stereoisomer, thereof.

11. The compound according to claim 10 , wherein the compound is either of Formula IIa or IIIb:

or a pharmaceutically acceptable salt or stereoisomer, thereof.

12. The compound according to claim 11 , wherein R 9 is selected from —H; trihalomethyl; C 1-6 alkyl optionally substituted with one group selected from alkoxy, benzylamino, and 2-oxo-pyrrolidinyl; aryl C 1-6 alkyl substituted on the aryl with 1 or 2 groups selected from alkyl and alkoxy; heterocyclyl optionally substituted with —C(O)Ot-Bu; and heterocyclyl C 1-6 alkyl; or a pharmaceutically acceptable salt or stereoisomer, thereof.

13. The compound according to claim 12 , wherein R 6 is selected from —H, halo, trihalomethyl, —CN, —OR 4 , —N(R 4 )R 4 , —CO 2 R 4 , —C(═O)N(R 4 )R 4 , —N(R 4 )SO 2 R 4 , —N(R 4 )C(O)R 4 , —C(═O)R 4 , C 1-6 alkyl, heterocyclyl, heterocyclyl C 1-6 alkyl, and a six- or seven-membered heteroalicyclic formed by two adjacent of R 6 , together with the annular atoms to which they are attached, said six- or seven-membered heteroalicyclic containing up to two heteroatoms; or a pharmaceutically acceptable salt or stereoisomer, thereof.

14. The compound according to claim 13 , wherein R 6 is selected from —H, halo, —OR 4 , —N(R 4 )R 4 , C 1-6 alkyl, heterocyclyl, heterocyclyl C 1-6 alkyl, and a six-or seven-membered heteroalicyclic formed by two adjacent of R 6 , together with the annular atoms to which they are attached, said six- or seven-membered heteroalicyclic containing up to two heteroatoms; or a pharmaceutically acceptable salt or stereoisomer, thereof.

15. The compound according to claim 14 , wherein at least one of R 6 is —OR 4 and R 4 is C 1-6 alkyl optionally substituted with 1, 2, or 3 halogen; C 1-6 alkyl optionally substituted with alkoxy; C 1-6 alkyl substituted with amino where the amino is optionally substituted with one or groups selected from methyl, ethyl, —CH 2 CH 2 OCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , and N-methyl-pyrrolidin3-yl; and heterocyclyl where the heterocyclyl is optionally substituted with alkyl, acyl, NH 2 , alkylamino, dialkylamino, heterocyclyl, cyclohexyl, —CH 2 OCH 3 , —CH 2 C(O)NHCH(CH 3 ) 2 , or —CH 2 OCH 3 ; or a pharmaceutically acceptable salt or stereoisomer, thereof.

16. The compound according to claim 15 , wherein at least one of R 1 is halo or methyl; or a pharmaceutically acceptable salt or stereoisomer, thereof.

17. The compound according to claim 16 , wherein R 9 is selected from —H, trihalomethyl, and C 1-6 alkyl optionally substituted with one group selected from alkoxy, benzylamino, and 2-oxo-pyrrolidinyl; or a pharmaceutically acceptable salt or stereoisomer, thereof.

18. The compound according to claim 14 , wherein at least one of R 6 is —OR 4 and R 4 is heterocyclyl C 1-6 alkyl where the heterocyclyl is a heteroalicyclic; or a pharmaceutically acceptable salt or stereoisomer, thereof.

19. The compound according to claim 18 , wherein said heteroalicyclic is selected from the group consisting of dioxolanyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl, morpholinyl, quinuclidinyl, tetrahydrofuryl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, 2,5-diaza-bicyclo[2.2.1]heptanyl, and thiamorpholinyl sulfone; or a pharmaceutically acceptable salt or stereoisomer, thereof.

20. A compound according to Formula IIIa or IIIb,

each R I is independently selected from —H, halo trihalomethyl, —CN, —OR 4 , —N(R 4 )R 4 , —SO 2 N(R 4 )R 4 , —CO 2 R 4 , —C(═O)N(R 4 )R 4 , —C(═NR 5 )N(R 4 )R 4 , —C(═NR 5 )R 4 , —N(R 4 )SO 2 R 4 , —N(R 4 )C(O)R 4 , C 1-6 alkyl, heterocyclyl, and heterocyclyl C 1-6 alkyl;

R 9 is selected from —H, trihalomethyl; C 1-6 alkyl optionally substituted with one group selected from alkoxy, benzylamino, and 2-oxo-pyrrolidinyl; aryl C 1-6 alkyl substituted on the aryl with 1 or 2 groups selected from alkyl and alkoxy; heterocyclyl optionally substituted with —C(O)Ot-Bu; and heterocyclyl C 1-6 alkyl; and

wherein at least one of R 6 is —OR 4 and R 4 is alkyl substituted with at least one additional of alkoxyl, amino, dialkylamino, and monoalkylamino where the amino of the monoalkylamino is further substituted with N-methyl-pyrrolidin-3-yl and where each alkyl of monoalkylamino and dialkylamino are independently optionally substituted with —NH 2 , —NHCH 3 , or —N(CH—) 2 ; or a pharmaceutically acceptable salt or stereoisomer, thereof.

21. The compound according to claim 1 , selected from Table 3; or a pharmaceutically acceptable salt or stereoisomer, thereof

TABLE 3

Entry

Name

Structure

4-{7,8-bis(methyloxy)-1-[(4- methylphenyl)methyl]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

4-(7,8-bis(methyloxy)-1-{[4- (methyloxy)phenyl]methyl}- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl)phenol

4-{7,8-bis(methyloxy)-1-[(2- methylphenyl)methyl]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

4-{7,8-bis(methyloxy)-1-[(3- methylphenyl)methyl]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

4-[1-methyl-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-[1-{[3,4- bis(methyloxy)phenyl]methyl}- 7,8-bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-(7,8-bis(methyloxy)-1-{[3- (methyloxy)phenyl]methyl}- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl)phenol

4-[1-ethyl-7,8-bis(methyloxy)- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl]phenol

4-[1-methyl-6,7,8- tris(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-[7,8-bis(methyloxy)-1- (trifluoromethyl)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-[1-(1-methylethyl)-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-[7,8-bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-[1-methyl-6,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-[6,8-bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-[6,7,8-tris(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-[1-methyl-7,8,9- tris(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-[1-methyl-8-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

2-methyl-4-[1-methyl-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-[1-methyl-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]-2-(methyloxy)phenol

4-{1-methyl-8-(methyloxy)-7- [(2-morpholin-4-ylethyl)oxy]- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl}phenol

2-(ethyloxy)-4-[1-methyl-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

2-chloro-4-[1-methyl-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

2-fluoro-4-[1-methyl-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

2-bromo-4-[1-methyl-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

1-{[5-(4-hydroxyphenyl)-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-1- yl]methyl}pyrrolidin-2-one

4-{1-methyl-7-(methyloxy)-5- [(piperidin-4-ylmethyl)oxy]- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl}phenol

4-{1-methyl-8-(methyloxy)-7- [(piperidin-4-ylmethyl)oxy]- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl}phenol

4-[8-(ethyloxy)-1-methyl-7- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

4-[1-methyl-8,9- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-[7-(ethyloxy)-1-methyl-8- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

4-{1-methyl-8-(methyloxy)-9- [(piperidin-4-ylmethyl)oxy]- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl}phenol

2-ethyl-4-[1-methyl-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-(1-methyl-8-(methyloxy)-9- {[(1-methylpiperidin-4- yl)methyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

4-(1-methyl-7-(methyloxy)-8- {[(1-methylpiperidin-4- yl)methyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

4-[1,7-dimethyl-8-(methyloxy)- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl]phenol

1,1-dimethylethyl 4-[5-(4- hydroxyphenyl)-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-1- yl]piperidine-1-carboxylate

2-chloro-4-[1-methyl-8,9- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

2-fluoro-4-[1-methyl-8,9- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

2-methyl-4-[1-methyl-8,9- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

2-bromo-4-[1-methyl-8,9- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

2-[(difluoromethyl)oxy]-4-[1- methyl-7,8-bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-[1,9-dimethyl-8-(methyloxy)- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl]phenol

4-[6,9-difluoro-1-methyl-8- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

2-bromo-4-{1-methyl-8- (methyloxy)-9-[(2-morpholin- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

2-chloro-4-{1-methyl-8- (methyloxy)-9-[(2-morpholin- 4-ylethyl)oxy]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

4-(7,8-bis(methyloxy)-1- {[(phenylmethyl)amino]methyl}- 3H-pyrazolo[3,4- c]isoquinolin-5-yl)phenol

2,5-dimethyl-4-[1-methyl-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

2,5-dichloro-4-[1-methyl-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

2-bromo-4-(1-methyl-8- (methyloxy)-9-{[(1- methylpiperidin-4- yl)methyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

2-chloro-4-(1-methyl-7- (methyloxy)-8-{[(1- methylpiperidin-4- yl)methyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

4-[9-fluoro-1-methyl-8- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

4-(1-methyl-8-(methyloxy)-9- {[2-(methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

2-chloro-4-(1-methyl-8- (methyloxy)-9-{[(1- methylpiperidin-4- yl)methyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

4-[6-bromo-1,7-dimethyl-8- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

4-[6-fluoro-1-methyl-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-[9-chloro-1,7-dimethyl-8- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

2-chloro-4-[8-{[(1- ethylpiperidin-4- yl)methyl]oxy}-1-methyl-7- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

3-chloro-4-[1-methyl-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

4-(1-methyl-8,9-bis{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

4-(1-methyl-3H-pyrazolo[3,4- c]isoquinolin-5-yl)phenol

2-chloro-4-(1-methyl-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

100

2-bromo-4-(1-methyl-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

101

2-chloro-4-[1,7-dimethyl-8- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

102

2-bromo-4-[1,7-dimethyl-8- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

103

2-chloro-4-[1-methyl-8-({[1-(1- methylethyl)piperidin-4- yl]methyl}oxy)-7-(methyloxy)- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl]phenol

104

4-[9-bromo-1-methyl-8- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

105

4-[7-chloro-9-fluoro-1-methyl- 8-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

106

4-[8-{[(1-acetylpiperidin-4- yl)methyl]oxy}-1-methyl-7- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]-2- chlorophenol

107

4-[9-{[(1-acetylpiperidin-4- yl)methyl]oxy}-1-methyl-8- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]-2- bromophenol

108

2-chloro-4-(1-methyl-9- (methyloxy)-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

109

4-[7-fluoro-1-methyl-8- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

110

2-chloro-4-(1-methyl-8,9- bis{[2-(methyloxy)ethyl]oxy}- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl)phenol

111

2-bromo-4-(1-methyl-8,9- bis{[2-(methyloxy)ethyl]oxy}- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl)phenol

112

2-chloro-4-(1-methyl-8- (methyloxy)-9-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c)isoquinolin-5- yl)phenol

113

2-bromo-4-(1-methyl-8- (methyloxy)-9-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

114

3-fluoro-4-[1-methyl-7,8- bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

115

2-chloro-4-(1-methyl-7- (methyloxy)-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

116

2-bromo-4-(1-methyl-7- (methyloxy)-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

117

2-chloro-4-(1-methyl-7,8- bis{[2-(methyloxy)ethyl]oxy}- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl)phenol

118

2-bromo-4-(1-methyl-7,8- bis{[2-(methyloxy)ethyl]oxy}- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl)phenol

120

4-(6,9-difluoro-1-methyl-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

121

2-chloro-5-fluoro-4-[1-methyl- 7,8-bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

122

2-bromo-5-fluoro-4-[1-methyl- 7,8-bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

123

4-[9-fluoro-1-methyl-7,8- bis(methyloxy)-3H- benzo[e]indazol-5-yl]phenol

125

3-fluoro-4-(1-methyl-7- (methyloxy)-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

126

4-(6,9-difluoro-1-methyl-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)-3-fluorophenol

127

2-chloro-4-(6,9-difluoro-1- methyl-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

128

2-chloro-4-[8-(ethyloxy)-1- methyl-7-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

129

2-chloro-4-[6-chloro-1-methyl- 7,8-bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

130

3-fluoro-4-(1-methyl-9- (methyloxy)-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

131

2-chloro-4-(1,7-dimethyl-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

132

3-fluoro-4-(6-fluoro-1-methyl- 7-(methyloxy)-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

133

2-chloro-4-[1-methyl-8-[(1- methylethyl)oxy]-7- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

134

2-chloro-4-{1-methyl-7- (methyloxy)-8-[(2- methylpropyl)oxy]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

135

2-bromo-5-fluoro-4-(1-methyl- 7-(methyloxy)-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

136

4-[7,8-bis(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]-2-chlorophenol

137

4-[7,8-bis(methyloxy)-1- (trifluoromethyl)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]-2-chlorophenol

138

4-{7,8-bis(methyloxy)-1- [(methyloxy)methyl]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}-2-chlorophenol

139

2-chloro-4-(1-methyl-3H- [1,3]dioxolo[4,5- g]pyrazolo[3,4-c]isoquinolin-5- yl)phenol

140

2-chloro-4-(1-methyl-8,9- dihydro-3H-[1,4]dioxino[2,3- g]pyrazolo[3,4-c]isoquinolin-5- yl)phenol

141

2-chloro-4-(1-methyl-9,10- dihydro-3H, 8H- [1,4]dioxepino[2,3- g]pyrazolo[3,4-c]isoquinolin-5- yl)phenol

142

2-chloro-4-[7- [(difluoromethyl)oxy]-1- methyl-8-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

143

2-chloro-5-fluoro-4-(6-fluoro- 1-methyl-9-(methyloxy)-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

144

2-chloro-4-(6,9-difluoro-1- methyl-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)-5-fluorophenol

145

2-chloro-4-(11-methyl-2,3- dihydro-9H-[1,4]dioxino[2,3- f]pyrazolo[3,4-c]isoquinolin-7- yl)phenol

146

2-chloro-5-fluoro-4-(11- methyl-2,3-dihydro-9H- [1,4]dioxino[2,3- f]pyrazolo[3,4-c]isoquinolin-7- yl)phenol

147

2-chloro-4-[1-methyl-6,7,8- tris(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

148

2-bromo-4-(6,9-difluoro-1- methyl-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)-5-fluorophenol

149

7-(3-chlorophenyl)-11-methyl- 2,3-dihydro-9H- [1,4]dioxino[2,3- f]pyrazolo[3,4-c]isoquinoline

150

2-chloro-5-fluoro-4-(6-fluoro- 1-methyl-8,9-dihydro-3H- [1,4]dioxino[2,3- g]pyrazolo[3,4-c]isoquinolin-5- yl)phenol

151

2-chloro-4-{1-methyl-7- (methyloxy)-8- [(tetrahydrofuran-2- ylmethyl)oxy]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

152

2-chloro-4-{1-methyl-7- (methyloxy)-8-[(tetrahydro-2H- pyran-2-ylmethyl)oxy]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

153

2-chloro-4-{1-methyl-7- (methyloxy)-8-[(2,2,2- trifluoroethyl)oxy]-3H- pyrazolo[3,4-c]isoqunolin-5- yl}phenol

154

2-chloro-5-fluoro-4-[9-fluoro- 1-methyl-6,7,8-tris(methyloxy)- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl]phenol

155

5-(3-chloro-4-hydroxyphenyl)- 6,9-difluoro-1-methyl-3H- pyrazolo[3,4-c]isoquinolin-8-ol

156

6,9-difluoro-5-(2- fluorophenyl)-1-methyl-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinoline

157

2-chloro-4-{8- [(difluoromethyl)oxy]-6,9- difluoro-1-methyl-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

158

2-chloro-4-(6,11-difluoro-1- methyl-8,9-dihydro-3H- [1,4]dioxino[2,3- g]pyrazolo[3,4-c]isoquinolin-5- yl)-5-fluorophenol

159

4-(1-methyl-3H- benzo[e]indazol-5-yl)phenol

160

6-fluoro-7-(2-fluorophenyl)-11- methyl-2,3-dihydro-9H- [1,4]dioxino[2,3- f]pyrazolo[3,4-c]isoquinoline

161

2-chloro-4-{1-methyl-7- (methyloxy)-8-[(tetrahydro-2H- pyran-4-ylmethyl)oxy]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

162

2-chloro-4-[8-{[2- (ethyloxy)ethyl]oxy}-1-methyl- 7-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

164

3-fluoro-4-(6-fluoro-11-methyl- 2,3-dihydro-9H- [1,4]dioxino[2,3- f]pyrazolo[3,4-c]isoquinolin-7- yl)phenol

165

2-chloro-5-fluoro-4-(6-fluoro- 11-methyl-2,3-dihydro-9H- [1,4]dioxino[2,3- f]pyrazolo[3,4-c]isoquinolin-7- yl)phenol

166

2-chloro-4-[8-(cyclopentyloxy)- 1-methyl-7-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

167

2-chloro-4-(1-methyl-7-(1- methylethyl)-8-{[2- (methyloxy)ethyl[oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

168

2-chloro-4-[9-ethyl-1-methyl-8- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

169

2-chloro-4-(6,9-difluoro-1- methyl-8-{[(1-methylpiperidin- 4-yl)methyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

170

5-(3-chloro-4-hydroxyphenyl)- 8-fluoro-1-methyl-7- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-6-ol

171

2-chloro-4-(6-fluoro-1-methyl- 7-(methyloxy)-8-{[(1- methylpiperidin-4- yl)methyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

172

2-chloro-4-(6-fluoro-1-methyl- 8,9-bis{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

173

5-[3-chloro-4- (methyloxy)phenyl]-6-fluoro-1- methyl-7-(methyloxy)-8-{[(1- methylpiperidin-4- yl)methyl]oxy}-3H- pyrazolo[3,4-c]isoquinoline

174

5-[3-chloro-4- (methyloxy)phenyl]-8-fluoro-1- methyl-7-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-6-ol

176

2-chloro-4-{6-fluoro-1-methyl- 7-(methyloxy)-8-[(2-piperidin- 1-ylethyl)oxy]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

177

2-chloro-4-[8-{[2-(4- ethylpiperazin-1-yl)ethyl]oxy}- 6-fluoro-1-methyl-7- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

178

2-chloro-4-[8-{[2- (diethylamino)ethyl]oxy}-6- fluoro-1-methyl-7-(methyloxy)- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl]phenol

179

2-chloro-4-(6-fluoro-1-methyl- 7-(methyloxy)-8-{[2- (methyloxy)ethyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

182

2-chloro-4-(6-fluoro-1-methyl- 9-(methyloxy)-8-{[(1- methylpiperidin-4- yl)methyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

183

2-bromo-4-(6-fluoro-1-methyl- 9-(methyloxy)-8-{[(1- methylpiperidin-4- yl)methyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

184

2-chloro-5-fluoro-4-(6-fluoro- 1-methyl-9-(methyloxy)-8-{[(1- methylpiperidin-4- yl)methyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

185

4-(6-fluoro-1-methyl-9- (methyloxy)-8-{[(1- methylpiperidin-4- yl)methyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)-2-methylphenol

186

2-chloro-4-{6,9-difluoro-1- methyl-8-[(2-piperidin-1- ylethyl)oxy]-3H-pyrazolo[3,4- c]isoquinolin-5-yl}phenol

187

2-chloro-4-(8-{[2-(4- ethylpiperazin-1-yl)ethyl]oxy}- 6,9-difluoro-1-methyl-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

188

2-chloro-4-(8-{[2- (diethylamino)ethyl]oxy}-6,9- difluoro-1-methyl-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

191

6,9-difluoro-5-(1H-indol-5-yl)- 1-methyl-3H-pyrazolo[3,4- c]isoquinolin-8-ol

193

5-(4-aminophenyl)-6,9- difluoro-1-methyl-3H- pyrazolo[3,4-c]isoquinolin-8-ol

194

2-chloro-4-(6-fluoro-1-methyl- 7-(methyloxy)-8-{[2-(4- methylpiperazin-1- yl)ethyl]oxy}-3H-pyrazolo[3,4- c]isoqunolin-5-yl)phenol

195

5-(2-amino-1,3-thiazol-5-yl)- 6,9-difluoro-1-methyl-3H- pyrazolo[3,4-c]isoquinolin-8-ol

196

2-chloro-4-[8-{[2-(4- ethylpiperazin-1-yl)ethyl]oxy}- 6-fluoro-1-methyl-9- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

197

2-chloro-4-(6-fluoro-1-methyl- 9-(methyloxy)-8-{[2-(4- methylpiperazin-1- yl)ethyl]oxy}-3H-pyrazolo[3,4- c]isoquinolin-5-yl)phenol

198

5-(6-aminopyridin-3-yl)-6,9- difluoro-1-methyl-3H- pyrazolo[3,4-c]isoquinolin-8-ol

199

5-(5-amino-2-thienyl)-6,9- difluoro-1-methyl-3H- pyrazolo[3,4-c]isoquinolin-8-ol

200

2-chloro-4-[8-{[3(4- ethylpiperazin-1- yl)propyl]oxy}-6-fluoro-1- methyl-9-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

201

2-chloro-4-(6-fluoro-1-methyl- 9-(methyloxy)-8-{[3-(4- methylpiperazin-1- yl)propyl]oxy}-3H- pyrazolo[3,4-c]isoquinolin-5- yl)phenol

202

6,9-difluoro-5-(1H-indol-6-yl)- 1-methyl-3H-pyrazolo[3,4- c]isoquinolin-8-ol

203

N-[5-(6,9-difluoro-8-hydroxy- 1-methyl-3H-pyrazolo[3,4- c]isoquinolin-5-yl)-1,3-thiazol- 2-yl]acetamide

206

2-chloro-4-{6-fluoro-1-methyl- 9-(methyloxy)-8-[(2- morpholin-4-ylethyl)oxy]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

207

4-[8-({2- [butyl(ethyl)amino]ethyl}oxy)- 6-fluoro-1-methyl-9- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]-2- chlorophenol

208

4-[8-{[(2R)-2-amino-3- methylbutyl]oxy}-6-fluoro-1- methyl-9-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]-2-chlorophenol

209

2-chloro-4-(6-fluoro-1-methyl- 9-(methyloxy)-8-{[2-(1- methylpiperidin-4- yl)ethyl]oxy}-3H-pyrazolo[3,4- c]isoquinolin-5-yl)phenol

210

2-chloro-4-[8-{[(1- ethylpiperidin-4- yl)methyl]oxy}-6-fluoro-1- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

212

5-(5-amino-1,3,4-thiadiazol-2- yl)-6,9-difluoro-1-methyl-3H- pyrazolo[3,4-c]isoquinolin-8-ol

213

4-[8-{[(2R)-2-amino-3,3- dimethylbutyl]oxy}-6-fluoro-1- methyl-9-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]-2-chlorophenol

214

2-chloro-4-[6-fluoro-1-methyl- 9-(methyloxy)-8-({2-[4-(2- methylpropyl)piperazin-1- yl]ethyl}oxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

215

2-chloro-4-[8-{[2-(5-ethyl-2,5- diazabicyclo[2.2.1]hept-2- yl)ethyl]oxy}-6-fluoro-1- methyl-9-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

216

2-chloro-4-[6-fluoro-1-methyl- 8-({2-[4-(1- methylethyl)piperazin-1- yl]ethyl}oxy)-9-(methyloxy)- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl]phenol

217

4-[8-{[2-(3-amino-8- azabicyclo[3.2.1]oct-8- yl)ethyl]oxy}-6-fluoro-1- methyl-9-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]-2-chlorophenol

218

2-chloro-4-[8-{[2-(1- ethylpiperidin-4-yl)ethyl]oxy}- 6-fluoro-1-methyl-9- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

219

2-chloro-4-[8-{[2- (diethylamino)ethyl]oxy}-6- fluoro-1-methyl-9-(methyloxy)- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl]phenol

220

2-chloro-5-{6-fluoro-1-methyl- 9-(methyloxy)-8-[(2-pyrrolidin- 1-ylethyl)oxy]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

223

2-chloro-4-[6-fluoro-1-methyl- 8-[(8-methyl-8- azabicyclo[3.2.1]oct-3-yl)oxy]- 9-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

224

2-chloro-4-{6-fluoro-1-methyl- 9-(methyloxy)-8-[(3-pyrrolidin- 1-ylpropyl)oxy]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

225

2-chloro-4-{6-fluoro-1-methyl- 9-(methyloxy)-8-[(3-piperidin- 1-ylpropyl)oxy]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

226

2-chloro-4-{6-fluoro-1-methyl- 9-(methyloxy)-8-[(3- morpholin-4-ylpropyl)oxy]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

227

2-chloro-4-[8-({2-[[2- (dimethylamino)ethyl](methyl) amino]ethyl}oxy)-6-fluoro-1- methyl-9-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

228

2-chloro-4-[8-({2-[[2- (diethylamino)ethyl](methyl) amino]ethyl}oxy)-6-fluoro-1- methyl-9-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

229

2-chloro-4-[8-({2-[[2- (dimethylamino)ethyl](ethyl) amino]ethyl}oxy)-6-fluoro-1- methyl-9-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

230

4-[8-[(2-{bis[3- (dimethylamino)propyl]amino} ethyl)oxy]-6-fluoro-1-methyl-9- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]-2- chlorophenol

231

2-chloro-4-[6-fluoro-1-methyl- 8-({2-[methyl(1- methylpyrrolidin-3- yl)amino]ethyl}oxy)-9- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]phenol

232

2-chloro-4-{6-fluoro-1-methyl- 9-(methyloxy)-8-[(2-{(2S)-2- [(methyloxy)methyl]pyrrolidin- 1-yl}ethyl)oxy]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

233

2-chloro-4-(6-fluoro-1-methyl- 9-(methyloxy)-8-{[2-(4- pyrrolidin-1-ylpiperidin-1- yl)ethyl]oxy}-3H-pyrazolo[3,4- c]isoquinolin-5-yl)phenol

234

2-chloro-4-[8-{[2-(4- cyclohexylpiperazin-1- yl)ethyl]oxy}-6-fluoro-1- methyl-9-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

235

2-[4-(2-{5-(3-chloro-4- hydroxyphenyl)-6-fluouo-1- methyl-9-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-8- yl]oxy}ethyl)piperazin-1-yl]-N- (1-methylethyl)acetamide

236

4-[8-{[2-(1,4′-bipiperidin-1′- yl)ethyl]oxy}-6-fluoro-1- methyl-9-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]-2-chlorophenol

237

2-chloro-4-[6-fluoro-1-methyl- 8-{[2-(4-methyl-1,4-diazepan- 1-yl)ethyl]oxy}-9-(methyloxy)- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl]phenol

238

2-chloro-4-(6-fluoro-1-methy]- 9-(methyloxy)-8-{[2-(4- pyridin-2-ylpiperazin-1- yl)ethyl]oxy}-3H-pyrazolo[3,4- c]isoquinolin-5-yl)phenol

239

2-chloro-4-[8-{[2-(2,6- dimethylmorpholin-4- yl)ethyl]oxy}-6-fluoro-1- methyl-9-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

240

2-chloro-4-{6-fluoro-1-methyl- 9-(methyloxy)-8-[(2- thiomorpholin-4-ylethyl)oxy]- 3H-pyrazolo[3,4-c]isoquinolin- 5-yl}phenol

241

2-chloro-4-[8-{[2-(2,6- dimethylpiperidin-1- yl)ethyl]oxy}-6-fluoro-1- methyl-9-(methyloxy)-3H- pyrazolo[3,4-c]isoquinolin-5- yl]phenol

242

2-chloro-4-(6-fluoro-1-methyl- 9-(methyloxy)-8-{[2- (octahydroquinolin-1(2H)- yl)ethyl]oxy}-3H-pyrazolo[3,4- c]isoquinolin-5-yl)phenol

243

4-[8-({2-[bis(1- methylethyl)amino]ethyl}oxy)- 6-fluoro-1-methyl-9- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]-2- chlorophenol

244

4-[8-[(2-{bis[2- (methyloxy)ethyl]amino}ethyl) oxy]-6-fluoro-1-methyl-9- (methyloxy)-3H-pyrazolo[3,4- c]isoquinolin-5-yl]-2- chlorophenol

245

2-chloro-4-{6-fluoro-1-methyl- 9-(methyloxy)-8-[(2-piperidin- 1-ylethyl)oxy]-3H- pyrazolo[3,4-c]isoquinolin-5- yl}phenol

22. A Compound selected from

4-[7,8-bis- (methyloxy)- 1-(phenyl- methyl)-3H- pyra-zolo[3,4- c]iso-quinolin- 5-yl]benzene- 1,2-diol

4-[7,8-bis- (methyloxy)-1- (1-phenyl- ethyl)-3H-pyra- zolo[3,4-c]iso- quinolin- 5-yl]phenol

4-[6,7,8- tris(methyl- oxy)-1-(phenyl- methyl)-3H- pyrazolo[3,4- c]iso-quinolin-5- yl]phenol

4-[8-(methyl- oxy)-1- (phenylmethyl)- 3H-pyrazolo- [3,4-c]iso- quinolin-5- yl]phenol

221

6,9-difluoro-5- (2-imino-3- methyl-2,3- dihydro-1,3- thiazol-5-yl)-1- methyl-3H-pyra- zolo[3,4-c]iso- quinolin-8-ol

23. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.

24. A method of treating diseases or disorders associated with uncontrolled, abnormal, and/or unwanted cellular activities, wherein the disease is an ALK-positive lymphoma, B-cell lymphoma, neuroblastoma, or inflammatory myofibroblastic tumor, the method comprising administering, to a mammal in need thereof, a therapeutically effective amount of a compound according to formula I: