                               SEQUENCE LISTING

<110> F. HOFFMANN-LA ROCHE AG
      

<120> ISOQUINOLINES AS INHIBITORS OF HPK1

<130> P34138-WO-2

<140> To be assigned
<141> 

<150> PCT/CN2017/078790
<151> 2017-03-30

<150> PCT/CN2018/076908
<151> 2018-02-18

<160> 4    

<170> PatentIn version 3.5
  

<210> 1
<211> 2502
<212> DNA
<213> Homo sapiens

<400> 1
atggacgtcg tggaccctga cattttcaat agagaccccc gggaccacta tgacctgcta       60

cagcggctgg gtggcggcac gtatggggaa gtctttaagg ctcgagacaa ggtgtcaggg      120

gacctggtgg cactgaagat ggtgaagatg gagcctgatg atgatgtctc cacccttcag      180

aaggaaatcc tcatattgaa aacttgccgg cacgccaaca tcgtggccta ccatgggagt      240

tatctctggt tgcagaaact ctggatctgc atggaattct gtggggctgg ttctctccag      300

gacatctacc aagtgacagg ctccctgtca gagctccaga ttagctatgt ctgccgggaa      360

gtgctccagg gactggccta tttgcactca cagaagaaga tacacaggga catcaaggga      420

gctaacatcc tcatcaatga tgctggggag gtcagattgg ctgactttgg catctcggcc      480

cagattgggg ctacactggc cagacgcctc tctttcattg ggacacccta ctggatggct      540

ccggaagtgg cagctgtggc cctgaaggga ggatacaatg agctgtgtga catctggtcc      600

ctgggcatca cggccatcga actggccgag ctacagccac cgctctttga tgtgcaccct      660

ctcagagttc tcttcctcat gaccaagagt ggctaccagc ctccccgact gaaggaaaaa      720

ggcaaatggt cggctgcctt ccacaacttc atcaaagtca ctctgactaa gagtcccaag      780

aaacgaccca gcgccaccaa gatgctcagt catcaactgg tatcccagcc tgggctgaat      840

cgaggcctga tcctggatct tcttgacaaa ctgaagaatc ccgggaaagg accctccatt      900

ggggacattg aggatgagga gcccgagcta ccccctgcta tccctcggcg gatcagatcc      960

acccaccgct ccagctctct ggggatccca gatgcagact gctgtcggcg gcacatggag     1020

ttcaggaagc tccgaggaat ggagaccaga cccccagcca acaccgctcg cctacagcct     1080

cctcgagacc tcaggagcag cagccccagg aagcaactgt cagagtcgtc tgacgatgac     1140

tatgacgacg tggacatccc cacccctgca gaggacacac ctcctccact tccccccaag     1200

cccaagttcc gttctccatc agacgagggt cctgggagca tgggggatga tgggcagctg     1260

agcccggggg tgctggtccg gtgtgccagt gggcccccac caaacagccc ccgtcctggg     1320

cctcccccat ccaccagcag cccccacctc accgcccatt cagaaccctc actctggaac     1380

ccaccctccc gggagcttga caagccccca cttctgcccc ccaagaagga aaagatgaag     1440

agaaagggat gtgcccttct cgtaaagttg ttcaatggct gccccctccg gatccacagc     1500

acggccgcct ggacacatcc ctccaccaag gaccagcacc tgctcctggg ggcagaggaa     1560

ggcatcttca tcctgaaccg gaatgaccag gaggccacgc tggaaatgct ctttcctagc     1620

cggactacgt gggtgtactc catcaacaac gttctcatgt ctctctcagg aaagaccccc     1680

cacctgtatt ctcatagcat ccttggcctg ctggaacgga aagagaccag agcaggaaac     1740

cccatcgctc acattagccc ccaccgccta ctggcaagga agaacatggt ttccaccaag     1800

atccaggaca ccaaaggctg ccgggcgtgc tgtgtggcgg agggtgcgag ctctgggggc     1860

ccgttcctgt gcggtgcatt ggagacgtcc gttgtcctgc ttcagtggta ccagcccatg     1920

aacaaattcc tgcttgtccg gcaggtgctg ttcccactgc cgacgcctct gtccgtgttc     1980

gcgctgctga ccgggccagg ctctgagctg cccgctgtgt gcatcggcgt gagccccggg     2040

cggccgggga agtcggtgct cttccacacg gtgcgctttg gcgcgctctc ttgctggctg     2100

ggcgagatga gcaccgagca caggggaccc gtgcaggtga cccaggtaga ggaagatatg     2160

gtgatggtgt tgatggatgg ctctgtgaag ctggtgaccc cggaggggtc cccagtccgg     2220

ggacttcgca cacctgagat ccccatgacc gaagcggtgg aggccgtggc tatggttgga     2280

ggtcagcttc aggccttctg gaagcatgga gtgcaggtgt gggctctagg ctcggatcag     2340

ctgctacagg agctgagaga ccctaccctc actttccgtc tgcttggctc ccccaggctg     2400

gagtgcagtg gcacgatctc gcctcactgc aacctcctcc tcccaggttc aagcaattct     2460

cctgcctcag cctcccgagt agctgggatt acaggcctgt ag                        2502


<210> 2
<211> 833
<212> PRT
<213> Homo sapiens

<400> 2
Met Asp Val Val Asp Pro Asp Ile Phe Asn Arg Asp Pro Arg Asp His 
1               5                   10                  15      


Tyr Asp Leu Leu Gln Arg Leu Gly Gly Gly Thr Tyr Gly Glu Val Phe 
            20                  25                  30          


Lys Ala Arg Asp Lys Val Ser Gly Asp Leu Val Ala Leu Lys Met Val 
        35                  40                  45              


Lys Met Glu Pro Asp Asp Asp Val Ser Thr Leu Gln Lys Glu Ile Leu 
    50                  55                  60                  


Ile Leu Lys Thr Cys Arg His Ala Asn Ile Val Ala Tyr His Gly Ser 
65                  70                  75                  80  


Tyr Leu Trp Leu Gln Lys Leu Trp Ile Cys Met Glu Phe Cys Gly Ala 
                85                  90                  95      


Gly Ser Leu Gln Asp Ile Tyr Gln Val Thr Gly Ser Leu Ser Glu Leu 
            100                 105                 110         


Gln Ile Ser Tyr Val Cys Arg Glu Val Leu Gln Gly Leu Ala Tyr Leu 
        115                 120                 125             


His Ser Gln Lys Lys Ile His Arg Asp Ile Lys Gly Ala Asn Ile Leu 
    130                 135                 140                 


Ile Asn Asp Ala Gly Glu Val Arg Leu Ala Asp Phe Gly Ile Ser Ala 
145                 150                 155                 160 


Gln Ile Gly Ala Thr Leu Ala Arg Arg Leu Ser Phe Ile Gly Thr Pro 
                165                 170                 175     


Tyr Trp Met Ala Pro Glu Val Ala Ala Val Ala Leu Lys Gly Gly Tyr 
            180                 185                 190         


Asn Glu Leu Cys Asp Ile Trp Ser Leu Gly Ile Thr Ala Ile Glu Leu 
        195                 200                 205             


Ala Glu Leu Gln Pro Pro Leu Phe Asp Val His Pro Leu Arg Val Leu 
    210                 215                 220                 


Phe Leu Met Thr Lys Ser Gly Tyr Gln Pro Pro Arg Leu Lys Glu Lys 
225                 230                 235                 240 


Gly Lys Trp Ser Ala Ala Phe His Asn Phe Ile Lys Val Thr Leu Thr 
                245                 250                 255     


Lys Ser Pro Lys Lys Arg Pro Ser Ala Thr Lys Met Leu Ser His Gln 
            260                 265                 270         


Leu Val Ser Gln Pro Gly Leu Asn Arg Gly Leu Ile Leu Asp Leu Leu 
        275                 280                 285             


Asp Lys Leu Lys Asn Pro Gly Lys Gly Pro Ser Ile Gly Asp Ile Glu 
    290                 295                 300                 


Asp Glu Glu Pro Glu Leu Pro Pro Ala Ile Pro Arg Arg Ile Arg Ser 
305                 310                 315                 320 


Thr His Arg Ser Ser Ser Leu Gly Ile Pro Asp Ala Asp Cys Cys Arg 
                325                 330                 335     


Arg His Met Glu Phe Arg Lys Leu Arg Gly Met Glu Thr Arg Pro Pro 
            340                 345                 350         


Ala Asn Thr Ala Arg Leu Gln Pro Pro Arg Asp Leu Arg Ser Ser Ser 
        355                 360                 365             


Pro Arg Lys Gln Leu Ser Glu Ser Ser Asp Asp Asp Tyr Asp Asp Val 
    370                 375                 380                 


Asp Ile Pro Thr Pro Ala Glu Asp Thr Pro Pro Pro Leu Pro Pro Lys 
385                 390                 395                 400 


Pro Lys Phe Arg Ser Pro Ser Asp Glu Gly Pro Gly Ser Met Gly Asp 
                405                 410                 415     


Asp Gly Gln Leu Ser Pro Gly Val Leu Val Arg Cys Ala Ser Gly Pro 
            420                 425                 430         


Pro Pro Asn Ser Pro Arg Pro Gly Pro Pro Pro Ser Thr Ser Ser Pro 
        435                 440                 445             


His Leu Thr Ala His Ser Glu Pro Ser Leu Trp Asn Pro Pro Ser Arg 
    450                 455                 460                 


Glu Leu Asp Lys Pro Pro Leu Leu Pro Pro Lys Lys Glu Lys Met Lys 
465                 470                 475                 480 


Arg Lys Gly Cys Ala Leu Leu Val Lys Leu Phe Asn Gly Cys Pro Leu 
                485                 490                 495     


Arg Ile His Ser Thr Ala Ala Trp Thr His Pro Ser Thr Lys Asp Gln 
            500                 505                 510         


His Leu Leu Leu Gly Ala Glu Glu Gly Ile Phe Ile Leu Asn Arg Asn 
        515                 520                 525             


Asp Gln Glu Ala Thr Leu Glu Met Leu Phe Pro Ser Arg Thr Thr Trp 
    530                 535                 540                 


Val Tyr Ser Ile Asn Asn Val Leu Met Ser Leu Ser Gly Lys Thr Pro 
545                 550                 555                 560 


His Leu Tyr Ser His Ser Ile Leu Gly Leu Leu Glu Arg Lys Glu Thr 
                565                 570                 575     


Arg Ala Gly Asn Pro Ile Ala His Ile Ser Pro His Arg Leu Leu Ala 
            580                 585                 590         


Arg Lys Asn Met Val Ser Thr Lys Ile Gln Asp Thr Lys Gly Cys Arg 
        595                 600                 605             


Ala Cys Cys Val Ala Glu Gly Ala Ser Ser Gly Gly Pro Phe Leu Cys 
    610                 615                 620                 


Gly Ala Leu Glu Thr Ser Val Val Leu Leu Gln Trp Tyr Gln Pro Met 
625                 630                 635                 640 


Asn Lys Phe Leu Leu Val Arg Gln Val Leu Phe Pro Leu Pro Thr Pro 
                645                 650                 655     


Leu Ser Val Phe Ala Leu Leu Thr Gly Pro Gly Ser Glu Leu Pro Ala 
            660                 665                 670         


Val Cys Ile Gly Val Ser Pro Gly Arg Pro Gly Lys Ser Val Leu Phe 
        675                 680                 685             


His Thr Val Arg Phe Gly Ala Leu Ser Cys Trp Leu Gly Glu Met Ser 
    690                 695                 700                 


Thr Glu His Arg Gly Pro Val Gln Val Thr Gln Val Glu Glu Asp Met 
705                 710                 715                 720 


Val Met Val Leu Met Asp Gly Ser Val Lys Leu Val Thr Pro Glu Gly 
                725                 730                 735     


Ser Pro Val Arg Gly Leu Arg Thr Pro Glu Ile Pro Met Thr Glu Ala 
            740                 745                 750         


Val Glu Ala Val Ala Met Val Gly Gly Gln Leu Gln Ala Phe Trp Lys 
        755                 760                 765             


His Gly Val Gln Val Trp Ala Leu Gly Ser Asp Gln Leu Leu Gln Glu 
    770                 775                 780                 


Leu Arg Asp Pro Thr Leu Thr Phe Arg Leu Leu Gly Ser Pro Arg Leu 
785                 790                 795                 800 


Glu Cys Ser Gly Thr Ile Ser Pro His Cys Asn Leu Leu Leu Pro Gly 
                805                 810                 815     


Ser Ser Asn Ser Pro Ala Ser Ala Ser Arg Val Ala Gly Ile Thr Gly 
            820                 825                 830         


Leu 
    


<210> 3
<211> 2466
<212> DNA
<213> Homo sapiens

<400> 3
atggacgtcg tggaccctga cattttcaat agagaccccc gggaccacta tgacctgcta       60

cagcggctgg gtggcggcac gtatggggaa gtctttaagg ctcgagacaa ggtgtcaggg      120

gacctggtgg cactgaagat ggtgaagatg gagcctgatg atgatgtctc cacccttcag      180

aaggaaatcc tcatattgaa aacttgccgg cacgccaaca tcgtggccta ccatgggagt      240

tatctctggt tgcagaaact ctggatctgc atggaattct gtggggctgg ttctctccag      300

gacatctacc aagtgacagg ctccctgtca gagctccaga ttagctatgt ctgccgggaa      360

gtgctccagg gactggccta tttgcactca cagaagaaga tacacaggga catcaaggga      420

gctaacatcc tcatcaatga tgctggggag gtcagattgg ctgactttgg catctcggcc      480

cagattgggg ctacactggc cagacgcctc tctttcattg ggacacccta ctggatggct      540

ccggaagtgg cagctgtggc cctgaaggga ggatacaatg agctgtgtga catctggtcc      600

ctgggcatca cggccatcga actggccgag ctacagccac cgctctttga tgtgcaccct      660

ctcagagttc tcttcctcat gaccaagagt ggctaccagc ctccccgact gaaggaaaaa      720

ggcaaatggt cggctgcctt ccacaacttc atcaaagtca ctctgactaa gagtcccaag      780

aaacgaccca gcgccaccaa gatgctcagt catcaactgg tatcccagcc tgggctgaat      840

cgaggcctga tcctggatct tcttgacaaa ctgaagaatc ccgggaaagg accctccatt      900

ggggacattg aggatgagga gcccgagcta ccccctgcta tccctcggcg gatcagatcc      960

acccaccgct ccagctctct ggggatccca gatgcagact gctgtcggcg gcacatggag     1020

ttcaggaagc tccgaggaat ggagaccaga cccccagcca acaccgctcg cctacagcct     1080

cctcgagacc tcaggagcag cagccccagg aagcaactgt cagagtcgtc tgacgatgac     1140

tatgacgacg tggacatccc cacccctgca gaggacacac ctcctccact tccccccaag     1200

cccaagttcc gttctccatc agacgagggt cctgggagca tgggggatga tgggcagctg     1260

agcccggggg tgctggtccg gtgtgccagt gggcccccac caaacagccc ccgtcctggg     1320

cctcccccat ccaccagcag cccccacctc accgcccatt cagaaccctc actctggaac     1380

ccaccctccc gggagcttga caagccccca cttctgcccc ccaagaagga aaagatgaag     1440

agaaagggat gtgcccttct cgtaaagttg ttcaatggct gccccctccg gatccacagc     1500

acggccgcct ggacacatcc ctccaccaag gaccagcacc tgctcctggg ggcagaggaa     1560

ggcatcttca tcctgaaccg gaatgaccag gaggccacgc tggaaatgct ctttcctagc     1620

cggactacgt gggtgtactc catcaacaac gttctcatgt ctctctcagg aaagaccccc     1680

cacctgtatt ctcatagcat ccttggcctg ctggaacgga aagagaccag agcaggaaac     1740

cccatcgctc acattagccc ccaccgccta ctggcaagga agaacatggt ttccaccaag     1800

atccaggaca ccaaaggctg ccgggcgtgc tgtgtggcgg agggtgcgag ctctgggggc     1860

ccgttcctgt gcggtgcatt ggagacgtcc gttgtcctgc ttcagtggta ccagcccatg     1920

aacaaattcc tgcttgtccg gcaggtgctg ttcccactgc cgacgcctct gtccgtgttc     1980

gcgctgctga ccgggccagg ctctgagctg cccgctgtgt gcatcggcgt gagccccggg     2040

cggccgggga agtcggtgct cttccacacg gtgcgctttg gcgcgctctc ttgctggctg     2100

ggcgagatga gcaccgagca caggggaccc gtgcaggtga cccaggtaga ggaagatatg     2160

gtgatggtgt tgatggatgg ctctgtgaag ctggtgaccc cggaggggtc cccagtccgg     2220

ggacttcgca cacctgagat ccccatgacc gaagcggtgg aggccgtggc tatggttgga     2280

ggtcagcttc aggccttctg gaagcatgga gtgcaggtgt gggctctagg ctcggatcag     2340

ctgctacagg agctgagaga ccctaccctc actttccgtc tgcttggctc ccccaggcct     2400

gtagtggtgg agacacgccc agtggatgat cctactgctc ccagcaacct ctacatccag     2460

gaatga                                                                2466


<210> 4
<211> 821
<212> PRT
<213> Homo sapiens

<400> 4
Met Asp Val Val Asp Pro Asp Ile Phe Asn Arg Asp Pro Arg Asp His 
1               5                   10                  15      


Tyr Asp Leu Leu Gln Arg Leu Gly Gly Gly Thr Tyr Gly Glu Val Phe 
            20                  25                  30          


Lys Ala Arg Asp Lys Val Ser Gly Asp Leu Val Ala Leu Lys Met Val 
        35                  40                  45              


Lys Met Glu Pro Asp Asp Asp Val Ser Thr Leu Gln Lys Glu Ile Leu 
    50                  55                  60                  


Ile Leu Lys Thr Cys Arg His Ala Asn Ile Val Ala Tyr His Gly Ser 
65                  70                  75                  80  


Tyr Leu Trp Leu Gln Lys Leu Trp Ile Cys Met Glu Phe Cys Gly Ala 
                85                  90                  95      


Gly Ser Leu Gln Asp Ile Tyr Gln Val Thr Gly Ser Leu Ser Glu Leu 
            100                 105                 110         


Gln Ile Ser Tyr Val Cys Arg Glu Val Leu Gln Gly Leu Ala Tyr Leu 
        115                 120                 125             


His Ser Gln Lys Lys Ile His Arg Asp Ile Lys Gly Ala Asn Ile Leu 
    130                 135                 140                 


Ile Asn Asp Ala Gly Glu Val Arg Leu Ala Asp Phe Gly Ile Ser Ala 
145                 150                 155                 160 


Gln Ile Gly Ala Thr Leu Ala Arg Arg Leu Ser Phe Ile Gly Thr Pro 
                165                 170                 175     


Tyr Trp Met Ala Pro Glu Val Ala Ala Val Ala Leu Lys Gly Gly Tyr 
            180                 185                 190         


Asn Glu Leu Cys Asp Ile Trp Ser Leu Gly Ile Thr Ala Ile Glu Leu 
        195                 200                 205             


Ala Glu Leu Gln Pro Pro Leu Phe Asp Val His Pro Leu Arg Val Leu 
    210                 215                 220                 


Phe Leu Met Thr Lys Ser Gly Tyr Gln Pro Pro Arg Leu Lys Glu Lys 
225                 230                 235                 240 


Gly Lys Trp Ser Ala Ala Phe His Asn Phe Ile Lys Val Thr Leu Thr 
                245                 250                 255     


Lys Ser Pro Lys Lys Arg Pro Ser Ala Thr Lys Met Leu Ser His Gln 
            260                 265                 270         


Leu Val Ser Gln Pro Gly Leu Asn Arg Gly Leu Ile Leu Asp Leu Leu 
        275                 280                 285             


Asp Lys Leu Lys Asn Pro Gly Lys Gly Pro Ser Ile Gly Asp Ile Glu 
    290                 295                 300                 


Asp Glu Glu Pro Glu Leu Pro Pro Ala Ile Pro Arg Arg Ile Arg Ser 
305                 310                 315                 320 


Thr His Arg Ser Ser Ser Leu Gly Ile Pro Asp Ala Asp Cys Cys Arg 
                325                 330                 335     


Arg His Met Glu Phe Arg Lys Leu Arg Gly Met Glu Thr Arg Pro Pro 
            340                 345                 350         


Ala Asn Thr Ala Arg Leu Gln Pro Pro Arg Asp Leu Arg Ser Ser Ser 
        355                 360                 365             


Pro Arg Lys Gln Leu Ser Glu Ser Ser Asp Asp Asp Tyr Asp Asp Val 
    370                 375                 380                 


Asp Ile Pro Thr Pro Ala Glu Asp Thr Pro Pro Pro Leu Pro Pro Lys 
385                 390                 395                 400 


Pro Lys Phe Arg Ser Pro Ser Asp Glu Gly Pro Gly Ser Met Gly Asp 
                405                 410                 415     


Asp Gly Gln Leu Ser Pro Gly Val Leu Val Arg Cys Ala Ser Gly Pro 
            420                 425                 430         


Pro Pro Asn Ser Pro Arg Pro Gly Pro Pro Pro Ser Thr Ser Ser Pro 
        435                 440                 445             


His Leu Thr Ala His Ser Glu Pro Ser Leu Trp Asn Pro Pro Ser Arg 
    450                 455                 460                 


Glu Leu Asp Lys Pro Pro Leu Leu Pro Pro Lys Lys Glu Lys Met Lys 
465                 470                 475                 480 


Arg Lys Gly Cys Ala Leu Leu Val Lys Leu Phe Asn Gly Cys Pro Leu 
                485                 490                 495     


Arg Ile His Ser Thr Ala Ala Trp Thr His Pro Ser Thr Lys Asp Gln 
            500                 505                 510         


His Leu Leu Leu Gly Ala Glu Glu Gly Ile Phe Ile Leu Asn Arg Asn 
        515                 520                 525             


Asp Gln Glu Ala Thr Leu Glu Met Leu Phe Pro Ser Arg Thr Thr Trp 
    530                 535                 540                 


Val Tyr Ser Ile Asn Asn Val Leu Met Ser Leu Ser Gly Lys Thr Pro 
545                 550                 555                 560 


His Leu Tyr Ser His Ser Ile Leu Gly Leu Leu Glu Arg Lys Glu Thr 
                565                 570                 575     


Arg Ala Gly Asn Pro Ile Ala His Ile Ser Pro His Arg Leu Leu Ala 
            580                 585                 590         


Arg Lys Asn Met Val Ser Thr Lys Ile Gln Asp Thr Lys Gly Cys Arg 
        595                 600                 605             


Ala Cys Cys Val Ala Glu Gly Ala Ser Ser Gly Gly Pro Phe Leu Cys 
    610                 615                 620                 


Gly Ala Leu Glu Thr Ser Val Val Leu Leu Gln Trp Tyr Gln Pro Met 
625                 630                 635                 640 


Asn Lys Phe Leu Leu Val Arg Gln Val Leu Phe Pro Leu Pro Thr Pro 
                645                 650                 655     


Leu Ser Val Phe Ala Leu Leu Thr Gly Pro Gly Ser Glu Leu Pro Ala 
            660                 665                 670         


Val Cys Ile Gly Val Ser Pro Gly Arg Pro Gly Lys Ser Val Leu Phe 
        675                 680                 685             


His Thr Val Arg Phe Gly Ala Leu Ser Cys Trp Leu Gly Glu Met Ser 
    690                 695                 700                 


Thr Glu His Arg Gly Pro Val Gln Val Thr Gln Val Glu Glu Asp Met 
705                 710                 715                 720 


Val Met Val Leu Met Asp Gly Ser Val Lys Leu Val Thr Pro Glu Gly 
                725                 730                 735     


Ser Pro Val Arg Gly Leu Arg Thr Pro Glu Ile Pro Met Thr Glu Ala 
            740                 745                 750         


Val Glu Ala Val Ala Met Val Gly Gly Gln Leu Gln Ala Phe Trp Lys 
        755                 760                 765             


His Gly Val Gln Val Trp Ala Leu Gly Ser Asp Gln Leu Leu Gln Glu 
    770                 775                 780                 


Leu Arg Asp Pro Thr Leu Thr Phe Arg Leu Leu Gly Ser Pro Arg Pro 
785                 790                 795                 800 


Val Val Val Glu Thr Arg Pro Val Asp Asp Pro Thr Ala Pro Ser Asn 
                805                 810                 815     


Leu Tyr Ile Gln Glu 
            820     
